Journal articles on the topic 'Rat lung worm'
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Archer, C. E., C. C. Appleton, S. Mukaratirwa, and K. J. Hope. "The rat lung-worm Angiostrongylus cantonensis: A first report in South Africa." South African Medical Journal 101, no. 3 (March 1, 2011): 174. http://dx.doi.org/10.7196/samj.4309.
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Yoshikawa, S., S. G. Kayes, S. L. Martin, and J. C. Parker. "Eosinophilia-induced vascular and airway remodeling and hyperresponsiveness in rat lungs." Journal of Applied Physiology 81, no. 3 (September 1, 1996): 1279–87. http://dx.doi.org/10.1152/jappl.1996.81.3.1279.
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We evaluated the effects of pulmonary infiltration of eosinophils without exogenous activators on airway and vascular hyperresponsiveness to muscarinic challenge in the lungs of rats infected with Toxocara [correction of Toxicara] canis, the canine round worm. Bronchoalveolar lavage of infected lungs produced 4.26 x 10(7) cells with 85% eosinophils, 15% mononuclear cells, and essentially no neutrophils. Eosinophils were present in the air spaces and interstitial spaces surrounding airways and vessels. The smooth muscle thickness increased about fourfold in large airways and vessels, and medium and small vessels were muscularized in infected lungs. In the T. canis-infected lungs, baseline airway resistance increased 288%, total vascular resistance (RT) increased 202%, and capillary filtration coefficient increased 208% compared with uninfected control lungs. Lung compliance was 56% of control. The concentration of acetylcholine that produced 50% of maximal response was 18.4 times greater for airway resistance and 18.7 times greater for RT in uninfected controls than in infected lungs. Isoproterenol (10(-4) M) decreased RT and peak airway pressure by 21% in infected lungs but had no significant effect on controls. We conclude that pulmonary interstitial infiltrates of eosinophils cause airway and vascular remodeling and increase baseline resistances and muscarinic reactivities of airways and vessels in rat lungs infected with T. canis.
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Fan, P. C., H. Lu, and L. H. Lin. "Experimental transfer of Paragonimus westermani from rodents to rodents following subcutaneous and intraperitoneal routes." Journal of Helminthology 68, no. 1 (March 1994): 41–44. http://dx.doi.org/10.1017/s0022149x00013444.
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AbstractIn order to investigate the experimental transfer of Paragonimus westermani from rodents to rodents following subcutaneous and intraperitoneal routes, 13 rats and 23 mice were inoculated with a total of 115 (1 mature and 114 immature) worms of P. westermani subcutaneously and intraperitoneally. The age of worms before transfer was 25–193 days. The transfer was performed immediately after worm collection from rodents which were killed at various intervals from 4 to 144 days after infection. The location, development and size of worms were recorded. An infection rate of 58% (or 21/36) was demonstrated in rodents after experimental transfer of P. westermani by intraperitoneal and subcutaneous routes. Twenty-seven worms were recovered, giving a worm recovery rate of 23.5%. The rate was significantly higher by the subcutaneous route (34.8%) than by the intraperitoneal route (20.7%) but no difference was found between mice (23.9%) and rats (23.0%). The sizes of worms in the abdominal cavity, pleural cavity and thoracic muscles of mice, and in the leg muscles of rats were much less than in the pleural cavity and lung cysts of rats. A mature worm (7×5 mm) and numerous eggs were found in the uterus and pleural cavity of one rat. It is evidence that these rodents are unfavourable definitive hosts of P. westermani, because the worm size, infectivity, maturation and egg production are usually very low. However, the worms are usually widely distributed in their rodent hosts and remain small in size for a long period. Therefore, these rodents are good paratenic hosts for P. westermani and can play an important role in infecting cats and dogs with P. westermani in the laboratory.
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Blagojević, Miloš, Ivana Božičković, Gordana Ušćebrka, Olivera Lozanče, Milena Đorđević, Zoran Zorić, and Ivana Nešić. "Anatomical and histological characteristics of the lungs in the ground squirrel (Spermophilus citellus)." Acta Veterinaria Hungarica 66, no. 2 (June 2018): 165–76. http://dx.doi.org/10.1556/004.2018.016.
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The aim of this work was to study the topography, morphology, vascularisation, histology and innervation of the lungs in the ground squirrel (Spermophilus citellus) and compare these data with those concerning the rat, mole rat, rabbit and mouse. The research was carried out on 15 animals. It was revealed that the right lung has four lobes (cranial, middle, caudal and accessory lobes), while the left lung is not divided into segments. The functional vessels are a. pulmonalis dextra et sinistra and vv. pulmonales (5–6), while the nutritive vessels of the lungs are a. bronchoesophagea dextra and v. bronchoesophagea dextra. Histological tissue sections of the lungs revealed that the wall of terminal bronchioles contains no cartilage and the mucosal epithelium is pseudostratified, cubic and ciliated. Clara cells (club cells, bronchiolar exocrine cells) are present but have no cilia. The lung alveolar diameter is 37 μm on average, and the thickness of the alveolar wall and the interalveolar septa is 1.38 μm. Destruction of the alveolar walls, accumulation of erythrocytes in the capillaries of alveolar septa and destruction of the cytolemma of the capillary endothelium were detected. In addition, connective tissue fibres and peripheral nerves were detected by silver impregnation.
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Jarvi, Susan, Will Pitt, Antonio Osuna, Margaret Farias, Laura Shiels, Kay Howe, Steven Jacquier, et al. "Efficacy of a vaccine for Angiostrongylus costaricensis against rat lungworm disease caused by A. cantonensis in wild Hawaiian Rats (Rattus rattus) (VAC7P.978)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 141.23. http://dx.doi.org/10.4049/jimmunol.192.supp.141.23.
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Abstract The nematode Angiostrongylus cantonensis is a rat lungworm, a zoonotic pathogen which causes a global, emerging infectious disease known as rat lungworm disease (RLWD). RLWD has been reported in 30 countries, and Hawaii is the epicenter for RLWD in the United States. We conducted a study in wild Hawaiian rats (Rattus rattus) to determine the efficacy of a vaccine developed against a related species (A. costaricensis). Twenty-eight wild adult rats were captured from Waiakea Forest Reserve on the Island of Hawaii. Rats were mated and 41 F1 offspring were vaccinated with two doses of PP2A vaccine, a serine/threonine phosphatase 2A recombinant peptide (4 µg vaccine and 4 µg adjuvant/25 g body weight) at >3 mos. of age. Rats were gavaged with 50 L3 stage larvae at four weeks post-vaccination. Rats were euthanized and necropsies conducted at 51-53 days PI. Spleen weight, spleen length, and lung weight were recorded and number of worms in heart and lungs counted. Adult worms were found in all F1 rats. An average of 20.88 worms/rat reached adulthood with an infective dose of 50 L3 stage larvae. We found no significant differences between vaccinated rats (n=21) and unvaccinated rats (n=20) in spleen weight (p=0.963), spleen length (p=0.830), lung weight (p=0.830) or number of worms collected from the heart and lungs (p=0.882), suggesting the vaccine does not provide adequate protective immunity to guard against infection by A. cantonensis in wild Hawaiian rats.
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Silveira, Ana C., Luís Rato, Pedro Fontes Oliveira, Marco G. Alves, and Branca M. Silva. "White Tea Intake Abrogates Markers of Streptozotocin-Induced Prediabetes Oxidative Stress in Rat Lungs’." Molecules 26, no. 13 (June 25, 2021): 3894. http://dx.doi.org/10.3390/molecules26133894.
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Prediabetes (PrDM) is a prodromal stage of diabetes mellitus (DM) with an increasing prevalence worldwide. During DM progression, individuals gradually develop complications in various organs. However, lungs are suggested to be affected later than other organs, such as the eyes, heart or brain. In this work, we studied the effects of PrDM on male Wistar rats’ lungs and whether the regular consumption of white tea (WTEA) for 2 months contributes to the improvement of the antioxidant profile of this tissue, namely through improved activity of the first line defense antioxidant enzymes, the total antioxidant capacity and the damages caused in proteins, lipids and histone H2A. Our data shows that PrDM induced a decrease in lung superoxide dismutase and glutathione peroxidase activities and histone H2A levels and an increase in protein nitration and lipid peroxidation. Remarkably, the regular WTEA intake improved lung antioxidant enzymes activity and total antioxidant capacity and re-established the values of protein nitration, lipid peroxidation and histone H2A. Overall, this is the first time that lung is reported as a major target for PrDM. Moreover, it is also the first report showing that WTEA possesses relevant chemical properties against PrDM-induced lung dysfunction.
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Christofidou-Solomidou, Melpo, Giuseppe G. Pietra, Charalambos C. Solomides, Evgenia Arguiris, David Harshaw, Garret A. Fitzgerald, Steven M. Albelda, and Vladimir R. Muzykantov. "Immunotargeting of glucose oxidase to endothelium in vivo causes oxidative vascular injury in the lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 278, no. 4 (April 1, 2000): L794—L805. http://dx.doi.org/10.1152/ajplung.2000.278.4.l794.
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Vascular immunotargeting is a novel approach for site-selective drug delivery to endothelium. To validate the strategy, we conjugated glucose oxidase (GOX) via streptavidin with antibodies to the endothelial cell surface antigen platelet endothelial cell adhesion molecule (PECAM). Previous work documented that 1) anti-PECAM-streptavidin carrier accumulates in the lungs after intravenous injection in animals and 2) anti-PECAM-GOX binds to, enters, and kills endothelium via intracellular H2O2 generation in cell culture. In the present work, we studied the targeting and effect of anti-PECAM-GOX in animals. Anti-PECAM-GOX, but not IgG-GOX, accumulated in the isolated rat lungs, produced H2O2, and caused endothelial injury manifested by a fourfold elevation of angiotensin-converting enzyme activity in the perfusate. In intact mice, anti-PECAM-GOX accumulated in the lungs (27 ± 9 vs. 2.4 ± 0.3% injected dose/g for IgG-GOX) and caused severe lung injury and 95% lethality within hours after intravenous injection. Endothelial disruption and blebbing, elevated lung wet-to-dry ratio, and interstitial and alveolar edema indicated that anti-PECAM-GOX damaged pulmonary endothelium. The vascular injury in the lungs was associated with positive immunostaining for iPF2α-III isoprostane, a marker for oxidative stress. In contrast, IgG-GOX caused a minor lung injury and little (5%) lethality. Anti-PECAM conjugated with inert proteins induced no death or lung injury. None of the conjugates caused major injury to other internal organs. These results indicate that an immunotargeting strategy can deliver an active enzyme to selected target cells in intact animals. Anti-PECAM-GOX provides a novel model of oxidative injury to the pulmonary endothelium in vivo.
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Tchepichev, S., J. Ueda, C. Canessa, B. C. Rossier, and H. O'Brodovich. "Lung epithelial Na channel subunits are differentially regulated during development and by steroids." American Journal of Physiology-Cell Physiology 269, no. 3 (September 1, 1995): C805—C812. http://dx.doi.org/10.1152/ajpcell.1995.269.3.c805.
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Because the alpha-subunit of the rat lung epithelial Na channel (rENaC) is not expressed until late fetal gestation, the developmental immaturity of alpha-rENaC may be involved in the premature fetal lung's inability to mount a Na-absorptive response to appropriate agonists. As previous work has shown that the beta- and gamma-rENaC subunits of the Na channel are required for maximal alpha-rENaC activity, we determined their developmental expression in the fetal lung. In addition, because thyroid and corticosteroid therapy can mature the in vivo fetal lamb lung's ability to transport Na, we wished to determine whether such treatment increased the expression of alpha-, beta-, and gamma-rENaC. Lungs were harvested from normal rat fetuses of 17 through 22 days gestation (term = 22 days), normal rat pups during the first week of life, and adult rats. Initial expression of alpha-rENaC was detected at 19 days gestation and progressively increased in utero. beta- and gamma-rENaC mRNA were not detected until 21 and 22 days gestation, and then only at very low levels. During the first week after birth, the levels of alpha-rENaC declined, whereas beta- and gamma-rENaC mRNA levels increased. This pre- and postnatal pattern of alpha-rENaC expression correlates with the endogenous glucocorticosteroid levels in the fetus and the rat pup's early postnatal corticosteroid resistance. Combined or separate treatment of pregnant rats (16 through 22 days gestational age) with thyroid-releasing hormone (TRH) and/or dexamethasone (Dex) for 48 h showed that Dex, but not TRH, could increase fetal lung alpha-rENaC mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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Rogers, R. A., J. M. Antonini, J. Lai, B. A. Ekstein, E. H. Oldmixon, B. S. Ducatman, and J. D. Brain. "3-D imaging of respirable size asbestos fibers in rat and human lung tissue." Proceedings, annual meeting, Electron Microscopy Society of America 53 (August 13, 1995): 1018–19. http://dx.doi.org/10.1017/s0424820100141469.
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Pulmonary exposure to natural and artificial fibers can result in serious health impacts to many segments of the occupational work force in the U.S. and worldwide. The toxicological response of a fiber on the respiratory tract depends upon the site at which the fiber makes initial contact, through which it migrates, where it deposits, and the route through which it is cleared. Persistence of fibers in lung tissue influences the severity of lung disease. The pulmonary deposition and clearance of inhaled fibers is a major determinant in understanding the health outcome of environmental and occupational exposures to these materials. Current microscopic methods of fiber analysis result in disruption of fiber orientation relative to lung structures and may influence our understanding of fiber toxicity within lungs.The purpose of this study was to examine the in situ pulmonary fate of respirable fibers in lungs using simultaneous nonspecific fluorescent tissue staining and reflected light confocal microscopy. Serial optical sections were recorded using a Sarastro 2000 confocal laser scanning microscope (Molecular Dynamics, Inc.) optimized for reflected light imaging.
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Wang, Hai-Tao, Yi-Qun Fang, Pu Yu, Xiao-Chen Bao, Kai-Cheng Li, Jian Yao, Ci Li, and Heng-Rong Yuan. "PDTC ameliorates decompression induced-lung injury caused by unsafe fast buoyancy ascent escape via inhibition of NF-κB pathway." Undersea and Hyperbaric Medicine 45, no. 3 (May 1, 2018): 351–62. http://dx.doi.org/10.22462/05.06.2018.10.
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Nuclear factor kappa B (NF-κB) is the critical transcriptional factor in the pathogenesis of acute lung injury (ALI). NF-κB regulates the expression changes of inflammatory factors such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6). In a previous study we showed that decompression sickness (DCS) caused by simulated unsafe fast buoyancy ascent escape (FBAE) could result in ALI, which was characterized by expression changes of inflammatory factors in rat lung tissue. The purpose of the present work was to study the roles of NF-κB and TNF-α in the process of DCS-induced rat lung injury caused by simulated unsafe FBAE. The research methods aimed to detect the rat lung tissue messenger ribonucleic acid (mRNA) and protein level variations of NF-κB, inhibitory κB (IκB), TNF-α, IL-1β, IL-6, IL-10 and IL-13 by using pretreatment of the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and TNF-α antibody (Ab). Our experimental results demonstrated that PDTC could improve the survival rate of the rats with DCS caused by unsafe FBAE more effectively than TNF-α Ab. However, the inhibition of TNF-α Ab on the nuclear translocated protein expression of NF-κB was more effective than PDTC. Both PDTC and TNF-α Ab can abrogate the increment of the rat lung tissue mRNA levels of TNF-α, IL-1β, IL-6 and protein levels of NF-κB, TNF-α, IL-1β effectively and increase the rat lung tissue content of IκB significantly. In conclusion, TNF-α-mediated NF-κB signaling may be one of the critical signaling pathways in the pathogenesis of DCS-induced rat lung injury caused by simulated unsafe FBAE. PDTC may ameliorate this type of injury partly through inhibiting the NF-κB pathway.
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Cercone, Melissa A., William Schroeder, Stacey Schomberg, and Todd C. Carpenter. "EphA2 receptor mediates increased vascular permeability in lung injury due to viral infection and hypoxia." American Journal of Physiology-Lung Cellular and Molecular Physiology 297, no. 5 (November 2009): L856—L863. http://dx.doi.org/10.1152/ajplung.00118.2009.
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Ephrin family receptor tyrosine kinases are mediators of angiogenesis that may also regulate endothelial barrier function in the lung. Previous work has demonstrated that stimulation of EphA ephrin receptors causes increased vascular leak in the intact lung and increased permeability in cultured endothelial cells. Whether EphA receptors are involved in the permeability changes associated with lung injury is unknown. We studied this question in young rats exposed to viral respiratory infection combined with exposure to moderate hypoxia, a previously described lung injury model. We found that the EphA2 receptor is expressed in normal lung and that EphA2 expression is markedly upregulated in the lungs of hypoxic infected (HV) rats compared with normal control animals. Immunohistochemistry showed increased EphA2 expression principally in areas of edematous alveolar septae. In HV rats, EphA2 antagonism with either the soluble decoy receptor EphA2/Fc or with monoclonal anti-EphA2 antibody reduced albumin extravasation and histological evidence of edema formation ( P < 0.01). Vascular leak in HV rats is mediated in large part by increased lung endothelin (ET) levels. In HV rats, ET receptor antagonism with bosentan resulted in reduced EphA2 mRNA and protein expression ( P < 0.01). Experiments with cultured rat lung microvascular endothelial cells demonstrated that ET increases endothelial EphA2 expression. These results suggest that EphA2 expression is increased in lung injury, contributes to vascular leak in the injured lung, and is regulated in endothelial cells by ET. EphA2 may be a previously unrecognized contributor to the pathophysiology of lung injury.
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Rubin, Katarina, Pär Ewing, Erica Bäckström, Anna Abrahamsson, Britta Bonn, Satoshi Kamata, and Ken Grime. "Pulmonary Metabolism of Substrates for Key Drug-Metabolizing Enzymes by Human Alveolar Type II Cells, Human and Rat Lung Microsomes, and the Isolated Perfused Rat Lung Model." Pharmaceutics 12, no. 2 (February 1, 2020): 117. http://dx.doi.org/10.3390/pharmaceutics12020117.
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Significant pulmonary metabolism of inhaled drugs could have drug safety implications or influence pharmacological effectiveness. To study this in vitro, lung microsomes or S9 are often employed. Here, we have determined if rat and human lung microsomes are fit for purpose or whether it is better to use specific cells where drug-metabolizing enzymes are concentrated, such as alveolar type II (ATII) cells. Activities for major hepatic and pulmonary human drug-metabolizing enzymes are assessed and the data contextualized towards an in vivo setting using an ex vivo isolated perfused rat lung model. Very low rates of metabolism are observed in incubations with human ATII cells when compared to isolated hepatocytes and fewer of the substrates are found to be metabolized when compared to human lung microsomal incubations. Reactions selective for flavin-containing monooxygenases (FMOs), CYP1B1, CYP2C9, CYP2J2, and CYP3A4 all show significant rates in human lung microsomal incubations, but all activities are higher when rat lung microsomes are used. The work also demonstrates that a lung microsomal intrinsic clearance value towards the lower limit of detection for this parameter (3 µL/min/mg protein) results in a very low level of pulmonary metabolic clearance during the absorption period, for a drug dosed into the lung in vivo.
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Liu, Tiantian, Piaopiao Zhang, Yahao Ling, Guang Hu, Jianjun Gu, Hong Yang, Jinfeng Wei, Aiping Wang, and Hongtao Jin. "Protective Effect of Colla corii asini against Lung Injuries Induced by Intratracheal Instillation of Artificial Fine Particles in Rats." International Journal of Molecular Sciences 20, no. 1 (December 23, 2018): 55. http://dx.doi.org/10.3390/ijms20010055.
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Environmental issues pose huge threats to public health, particularly the damage caused by fine particulate matter (PM2.5). However, the mechanisms of injury require further investigation and medical materials that can protect the lungs from PM2.5 are needed. We have found that Colla corii asini, a traditional Chinese medicine that has long been used to treat various ailments, is a good candidate to serve this purpose. To understand the mechanisms of PM2.5-induced lung toxicity and the protective effects of Colla corii asini, we established a rat model of lung injury via intratracheal instillation of artificial PM2.5 (aPM2.5). Our results demonstrated that Colla corii asini significantly protected against lung function decline and pathologic changes. Inflammation was ameliorated by suppression of Arg-1 to adjust the disturbed metabolic pathways induced by aPM2.5, such as arginine and nitrogen metabolism and aminoacyl-tRNA biosynthesis, for 11 weeks. Our work found that metabolomics was a useful tool that contributed to further understanding of PM2.5-induced respiratory system damage and provided useful information for further pharmacological research on Colla corii asini, which may be valuable for therapeutic intervention.
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Verbanck, S., N. Gonzalez Mangado, G. Peces-Barba, and M. Paiva. "Multiple-breath washout experiments in rat lungs." Journal of Applied Physiology 71, no. 3 (September 1, 1991): 847–54. http://dx.doi.org/10.1152/jappl.1991.71.3.847.
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Multiple-breath washouts were performed on 30 Wistar rats postmortem in a study in which breaths of 90% O2–5% He-5% SF6 were given. Preliminary comparison of alveolar plateau slopes obtained from anesthetized rats in vivo and postmortem showed that ventilation distribution remains the same within 1 h after the animals were killed. For maneuvers with different preinspiratory lung volumes and end-inspiratory breathholding, we computed the normalized N2 slope (Sn) and Fowler and Bohr dead spaces [VDF(n) and VDB(n), respectively] as a function of breath number (n). For all maneuvers analyzed, Sn of all gases increased in the first two or three breaths and reached a horizontal asymptote thereafter. The value of Sn decreased, both with increasing preinspiratory lung volume and breath hold of 4 s. The fact that the horizontal Sn asymptote is reached after only two or three breaths suggests the absence of convection-dependent inhomogeneities (CDI) in rat lungs. This contrasts with multiple-breath washout experiments in humans, where interregional (gravity-dependent CDI) and intraregional CDI generate a marked increase in Sn throughout the entire washout. Also, in contrast with results in humans, VDF and VDB were independent of n. The present work suggests that rats may be used to study diffusion- and convection-dependent inhomogeneities without the influence of CDI or gas exchange.
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Coursin, D. B., H. P. Cihla, T. D. Oberley, and L. W. Oberley. "Immunolocalization of antioxidant enzymes and isozymes of glutathione S-transferase in normal rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 263, no. 6 (December 1, 1992): L679—L691. http://dx.doi.org/10.1152/ajplung.1992.263.6.l679.
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Polyclonal antisera to manganese and copper-zinc superoxide dismutases, catalase, glutathione peroxidase (GPx), and isozymes of glutathione S-transferase (liver and placental isolates, GST-L and GST-P, respectively) were used to localize these enzymes in normal rat lung by immunostaining. Light-microscopic results, using an immunoperoxidase technique, were expanded on by electron-microscopic immunogold localization. The findings were consistent with previous biochemical work. However, both GPx and GST-P were predominantly localized to extracellular connective tissue of the lung. These findings demonstrate the basal antioxidant enzyme phenotypes for parenchymal lung tissue at light- and electron-microscopic levels. Significant components of enzymatic defense to oxidant stress are heterogeneously distributed throughout rat lung tissue including both epithelial cell surfaces and the extracellular matrix.
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Miura, Tanya A., Joel Funk, Kathryn V. Holmes, and Robert J. Mason. "Rat coronavirus infection of alveolar type I cells causes neutrophil recruitment followed by resolution of infection (45.28)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 45.28. http://dx.doi.org/10.4049/jimmunol.182.supp.45.28.
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Abstract Viral infections in the lung are an important cause of morbidity and mortality in humans worldwide. In order to design strategies for vaccination and therapy, we need to understand the molecular mechanisms that initiate and regulate effective antiviral immune responses in the lung. This requires animal models in which in vitro mechanistic studies can be correlated with infections in vivo. We study rat coronavirus (RCoV) infection in rats and cultures of primary differentiated rat alveolar epithelial cells as a model for the early events in respiratory coronavirus pathogenesis. Intratracheal inoculation of adult rats with RCoV resulted in infection of the lung, primarily in alveolar type I cells. Infection caused transient weight loss and focal lesions and recruitment of neutrophils in the lung, followed by clearance of virus and resolution of inflammation. Thus, adult rats mounted an effective innate immune response to RCoV infection in the lung. In agreement, in primary cultures of differentiated rat alvoelar type I cells, RCoV replicated and induced expression of neutrophil chemotactic CXC chemokines. This in vitro model will elucidate the molecular interactions between RCoV and alveolar epithelial cells that initiate and regulate the innate antiviral immune response in the lung. This work was supported by NIH grants AI-059576 and HL-029891, and NCRR/NIH grant P20 RR015587.
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Chabé, M., S. L. Vargas, I. Eyzaguirre, E. M. Aliouat, A. Follet-Dumoulin, C. Creusy, L. Fleurisse, et al. "Molecular typing of Pneumocystis jirovecii found in formalin-fixed paraffin-embedded lung tissue sections from sudden infant death victims." Microbiology 150, no. 5 (May 1, 2004): 1167–72. http://dx.doi.org/10.1099/mic.0.26895-0.
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Previous studies have provided histological evidence of an association between primary Pneumocystis infection and sudden infant death syndrome (SIDS). The aim of this work was to determine the species of clustered Pneumocystis organisms found in formalin-fixed paraffin-embedded (FFPE) lung tissue sections from Chilean sudden infant death (SID) victims. This approach needed first to optimize a DNA extraction method from such histological sections. For that purpose, the QIAamp DNA Isolation from Paraffin-Embedded Tissue method (Qiagen) was first tested on FFPE lung tissue sections of immunosuppressed Wistar rats inoculated with rat-derived Pneumocystis. Successful DNA extraction was assessed by the amplification of a 346 bp fragment of the mitochondrial large subunit rRNA gene of the Pneumocystis species using a previously described PCR assay. PCR products were analysed by direct sequencing and sequences corresponding to Pneumocystis carinii were found in all the samples. This method was then applied to FFPE lung tissue sections from Chilean SID victims. Pneumocystis jirovecii was successfully identified in the three tested samples. In conclusion, an efficient protocol for isolating PCR-ready DNA from FFPE lung tissue sections was developed. It established that the Pneumocystis species found in the lungs of Chilean SID victims was P. jirovecii.
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Badea, C. T., X. Guo, D. Clark, S. M. Johnston, C. D. Marshall, and C. A. Piantadosi. "Dual-energy micro-CT of the rodent lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 10 (May 15, 2012): L1088—L1097. http://dx.doi.org/10.1152/ajplung.00359.2011.
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The purpose of this work is to investigate the use of dual-energy micro-computed tomography (CT) for the estimation of vascular, tissue, and air fractions in rodent lungs using a postreconstruction three material decomposition method. Using simulations, we have estimated the accuracy limits of the decomposition for realistic micro-CT noise levels. Next, we performed experiments involving ex vivo lung imaging in which intact rat lungs were carefully removed from the thorax, injected with an iodine-based contrast agent, and then inflated with different volumes of air ( n = 2). Finally, we performed in vivo imaging studies in C57BL/6 mice ( n = 5) using fast prospective respiratory gating in end inspiration and end expiration for three different levels of positive end expiratory pressure (PEEP). Before imaging, mice were injected with a liposomal blood pool contrast agent. The three-dimensional air, tissue, and blood fraction maps were computed and analyzed. The results indicate that separation and volume estimation of the three material components of the lungs are possible. The mean accuracy values for air, blood, and tissue were 93, 93, and 90%, respectively. The absolute accuracy in determining all fraction materials was 91.6%. The coefficient of variation was small (2.5%) indicating good repeatability. The minimum difference that we could detect in material fractions was 15%. As expected, an increase in PEEP levels for the living mouse resulted in statistically significant increases in air fractions at end expiration but no significant changes at end inspiration. Our method has applicability in preclinical pulmonary studies where changes in lung structure and gas volume as a result of lung injury, environmental exposures, or drug bioactivity would have important physiological implications.
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Desdiani, Iris Rengganis, Samsuridjal Djauzi, Agus Setiyono, Mohammad Sadikin, Sri Widia A. Jusman, Nurjati Chairani Siregar, Suradi, and Putri C. Eyanoer. "Green Tea Extract Reduces Rat Lung Fibrotic." Majalah Patologi Indonesia 29, no. 1 (January 20, 2020): 15–24. http://dx.doi.org/10.55816/mpi.v29i1.403.
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BackgroundPulmonary fibrosis is often found in infectious diseases and chemical exposure in the work environment. Antifibrotic effects can befibropreventive and fibrolysis. Bleomycin can cause inflammation and pulmonary fibrosis. Catechin is proven can repair liverdamages due to alcohol induction. The aim of this study is to examine the effect of antifibrotic green tea catechin on reducing thearea of rat lung fibrotic.MethodsThis research was carried out in vivo experimentally in the Laboratory Animal Management Unit at Faculty of Veterinary MedicineIPB in 4 groups of rat experiments, consisting of 3 rats in the negative control group, 3 rats in the positive control group, 3 rats in thegroup of rats given bleomycin on the 8th day and 28thwith green tea extract every day from day 0 to 49 days (fibropreventive), 3groups of rats given bleomycin days 0 and 21 with green tea extract every day from day 15 to 49 (fibrolysis). Histopathologicalexamination was performe for all groups of rats.ResultsThis study showed that administration of green tea extract in fibropreventive groups and fibrolysis groups could reduce the fibrosisarea in rat lungs based on Aschroft's modified scale.ConclusionBased on the results of this study it was found that the anti-fibrotic activity of green tea extract was proven to be able to suppressthe development of pulmonary fibrosis both by fibropreventive and fibrolysis
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Soukup, Benjamin, Audra Benjamin, Maria Orogo-Wenn, and Dafydd Walters. "Physiological effect of protein kinase C on ENaC-mediated lung liquid regulation in the adult rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 1 (January 1, 2012): L133—L139. http://dx.doi.org/10.1152/ajplung.00031.2011.
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Tight control of lung liquid (LL) regulation is vital for pulmonary function. The aim of this work was to determine whether PKC activation is involved in the physiological regulation of LL volume in a whole lung preparation. Rat lungs were perfused with a modified Ringer solution, and the lumen was filled with the same solution without glucose. LL volume was measured during a control period and after modulating drugs were administered, and net LL transepithelial movement ( Jv) was calculated. When the PKC activator PMA (10−5 M) and the Ca2+ ionophore ionomycin (10−6 M) were instilled into the lung together, Jv was significantly reduced ( P = 0.03). This reduction was blocked by the PKC inhibitor chelerythrine chloride (10−6 M; P = 0.56) and by a second PKC inhibitor GF109203X (10−5 M; P = 0.98). When PMA and ionomycin were added with the β-adrenergic agonist terbutaline, the terbutaline-induced increase in Jv was abolished. Addition of PMA and ionomycin with the epithelial Na+ channel (ENaC) blocker amiloride had no additional inhibitory effect. Together, these results suggest that PKC is likely to be involved in LL absorption, and the ability of PMA/ionomycin to block the terbutaline-induced increase in Jv suggests that the downstream target of PKC is ENaC.
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Gorr, Matthew W., Dane J. Youtz, Clayton M. Eichenseer, Korbin E. Smith, Timothy D. Nelin, Estelle Cormet-Boyaka, and Loren E. Wold. "In vitro particulate matter exposure causes direct and lung-mediated indirect effects on cardiomyocyte function." American Journal of Physiology-Heart and Circulatory Physiology 309, no. 1 (July 1, 2015): H53—H62. http://dx.doi.org/10.1152/ajpheart.00162.2015.
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Particulate matter (PM) exposure induces a pathological response from both the lungs and the cardiovascular system. PM is capable of both manifestation into the lung epithelium and entrance into the bloodstream. Therefore, PM has the capacity for both direct and lung-mediated indirect effects on the heart. In the present studies, we exposed isolated rat cardiomyocytes to ultrafine particulate matter (diesel exhaust particles, DEP) and examined their contractile function and calcium handling ability. In another set of experiments, lung epithelial cells (16HBE14o- or Calu-3) were cultured on permeable supports that allowed access to both the basal (serosal) and apical (mucosal) media; the basal media was used to culture cardiomyocytes to model the indirect, lung-mediated effects of PM on the heart. Both the direct and indirect treatments caused a reduction in contractility as evidenced by reduced percent sarcomere shortening and reduced calcium handling ability measured in field-stimulated cardiomyocytes. Treatment of cardiomyocytes with various anti-oxidants before culture with DEP was able to partially prevent the contractile dysfunction. The basal media from lung epithelial cells treated with PM contained several inflammatory cytokines, and we found that monocyte chemotactic protein-1 was a key trigger for cardiomyocyte dysfunction. These results indicate the presence of both direct and indirect effects of PM on cardiomyocyte function in vitro. Future work will focus on elucidating the mechanisms involved in these separate pathways using in vivo models of air pollution exposure.
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Reynolds, Lucy, Kelly BéruBé, Timothy Jones, and Roy Richards. "Gene Expression Profiling Following Instillation of Diesel Exhaust Particles in Rat Lung: A First Study." Microscopy and Microanalysis 6, S2 (August 2000): 910–11. http://dx.doi.org/10.1017/s1431927600037041.
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Epidemiological studies conducted first in the USA and later in the UK, suggest that a relationship exists between increased cardio-respiratory hospital admissions, morbidity and mortality rates and increases in PM10 concentrations. In urban environments, ultrafine diesel exhaust particles (DEP), accounts for 20-80 % by mass of the airborne PM10 arising from vehicular activities. In previous work, we used well characterised DEP as a surrogate for PM10 and examined its bioreactivity in vivo by assessing lung permeability, inflammation and epithelial cell markers in lavage fluid. Delivery of a single instillate of l mg DEP into the rat lung was not found to cause progressive damage but did produce a transient change in lung permeability. In the experiment described here, we instilled two different doses (control [NaCl], 0.25 and 1.25 mg) of DEP into the rat lung and assessed the responses using the methods described above with the addition of a new technique known as gene expression profiling.
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Bodas, Manish, Taehong Min, and Neeraj Vij. "Critical role of CFTR-dependent lipid rafts in cigarette smoke-induced lung epithelial injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 300, no. 6 (June 2011): L811—L820. http://dx.doi.org/10.1152/ajplung.00408.2010.
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Apoptosis of lung epithelial and endothelial cells by exposure to cigarette smoke (CS) severely damages the lung tissue, leading to the pathogenesis of emphysema, but the underlying mechanisms are poorly understood. We have recently established a direct correlation between decreased lipid raft CFTR expression and emphysema progression through increased ceramide accumulation. In the present work, we investigated the role of membrane CFTR in regulating apoptosis and autophagy responses to CS exposure. We report a constitutive and CS-induced increase in the number of TUNEL-positive apoptotic cells in Cftr−/− murine lungs compared with Cftr+/+ murine lungs that also correlated with a concurrent increase in the expression of ceramide, NF-κB, CD95/Fas, lipid raft proteins, and zonula occludens (ZO)-1/2 ( P < 0.001). We also verified that stable wild-type CFTR expression in CFBE41o− cells controls constitutively elevated caspase-3/7 activity (−1.6-fold, P < 0.001). Our data suggest that membrane CFTR regulates ceramide-enriched lipid raft signaling platforms required for the induction of Fas-mediated apoptotic signaling. In addition, lack of membrane CFTR also modulates autophagy, as demonstrated by the significant increase in constitutive ( P < 0.001) and CSE-induced ( P < 0.005) perinuclear accumulation of green fluorescent protein-microtubule-associated protein 1 light chain-3 (LC3) in the absence of membrane CFTR (CFBE41o− cells). The significant constitutive and CS-induced increase ( P < 0.05) in p62 and LC3β expression in CFTR-deficient cells and mice corroborates these findings and suggest a defective autophagy response in the absence of membrane CFTR. Our data demonstrate the critical role of membrane-localized CFTR in regulating apoptotic and autophagic responses in CS-induced lung injury that may be involved in the pathogenesis of severe emphysema.
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Mandell, Erica, Kyle N. Powers, Julie W. Harral, Gregory J. Seedorf, Kendall S. Hunter, Steven H. Abman, and R. Blair Dodson. "Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 12 (December 15, 2015): L1438—L1446. http://dx.doi.org/10.1152/ajplung.00302.2015.
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High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins ( P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work ( P < 0.05 vs. control and ETX+vit D) and elastic potential energy ( P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA ( P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.
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Hunt, Tracey A., Cora Kooi, Pamela A. Sokol, and Miguel A. Valvano. "Identification of Burkholderia cenocepacia Genes Required for Bacterial Survival In Vivo." Infection and Immunity 72, no. 7 (July 2004): 4010–22. http://dx.doi.org/10.1128/iai.72.7.4010-4022.2004.
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ABSTRACT Burkholderia cenocepacia (formerly Burkholderia cepacia complex genomovar III) causes chronic lung infections in patients with cystic fibrosis. In this work, we used a modified signature-tagged mutagenesis (STM) strategy for the isolation of B. cenocepacia mutants that cannot survive in vivo. Thirty-seven specialized plasposons, each carrying a unique oligonucleotide tag signature, were constructed and used to examine the survival of 2,627 B. cenocepacia transposon mutants, arranged in pools of 37 unique mutants, after a 10-day lung infection in rats by using the agar bead model. The recovered mutants were screened by real-time PCR, resulting in the identification of 260 mutants which presumably did not survive within the lungs. These mutants were repooled into smaller pools, and the infections were repeated. After a second screen, we isolated 102 mutants unable to survive in the rat model. The location of the transposon in each of these mutants was mapped within the B. cenocepacia chromosomes. We identified mutations in genes involved in cellular metabolism, global regulation, DNA replication and repair, and those encoding bacterial surface structures, including transmembrane proteins and cell surface polysaccharides. Also, we found 18 genes of unknown function, which are conserved in other bacteria. A subset of 12 representative mutants that were individually examined using the rat model in competition with the wild-type strain displayed reduced survival, confirming the predictive value of our STM screen. This study provides a blueprint to investigate at the molecular level the basis for survival and persistence of B. cenocepacia within the airways.
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Negrão-Corrêa, Deborah, Micheline R. Silveira, Cynthia M. Borges, Danielle G. Souza, and Mauro M. Teixeira. "Changes in Pulmonary Function and Parasite Burden in Rats Infected with Strongyloides venezuelensis Concomitant with Induction of Allergic Airway Inflammation." Infection and Immunity 71, no. 5 (May 2003): 2607–14. http://dx.doi.org/10.1128/iai.71.5.2607-2614.2003.
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ABSTRACT The prevalence of allergic diseases such as asthma has increased markedly over the past few decades. To evaluate the possible mutual influence of helminth infection and allergy, the combined effects of experimental allergic airway inflammation and infection with Strongyloides venezuelensis on various parasitological and inflammatory indices were evaluated in the rat. A challenge of immunized rats with aerosolized ovalbumin (OVA) resulted in eosinophilic inflammation that peaked 48 h after the challenge and was accompanied by airway hyperresponsiveness (AHR) to an intravenous acetylcholine challenge. S. venezuelensis infection concomitant with an OVA challenge of immunized rats resulted in prolonged pulmonary inflammation with increased eosinophil infiltration in bronchoalveolar lavage fluid but not in the lung tissue. These rats also showed a significant parasite burden reduction, especially during parasite migration through the lungs. However, the fecundity rates of worms that reached the intestine were similar in allergic and nonallergic animals. Despite airway inflammation, the increased responsiveness of the airways in the experimental asthma model was suppressed during parasite migration through the lungs (2 days). In contrast, parasite-induced AHR was unchanged 5 days after infection in immunized and challenged rats. In conclusion, infection with S. venezuelensis interfered with the onset of AHR following an antigen challenge of immunized rats. The ability of parasites to switch off functional airway responses is therapeutically relevant because we may learn from parasites how to modulate lung function and, hence, the AHR characteristic of asthmatic patients.
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Maritz, G. S., H. L. Matthews, and J. Aalbers. "Maternal copper supplementation protects the neonatal rat lung against the adverse effects of maternal nicotine exposure." Reproduction, Fertility and Development 12, no. 2 (2000): 97. http://dx.doi.org/10.1071/rd98127.
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Maternal nicotine exposure interferes with the extracellular formation of the connective tissue frame-work of the neonatal lung, a process that is dependent on copper-dependent lysyl oxidase. It has been shown that, during the phase of lung development associated with alveolarization, maternal nicotine exposure resulted in a reduction in the copper content and thus conceivably in the activity of lysyl oxidase of the neonatal lung. Therefore the aims of this study were (a) to determine the effects of maternal nicotine exposure during gestation and lactation on neonatal lung development, and (b) to establish whether maternal copper supplementation during gestation and lactation prevented the effect of maternal nicotine exposure on neonatal lung development. Pregnant rats were randomly divided into four groups: the control group received saline; the second group received 1 mg nicotine (kg bodyweight)–1 day–1 subcutaneously; the third group received 1 mg copper (kg bodyweight)–1 day–1; and the fourth group received both nicotine and copper in the same quantities as the previous two groups. Lung tissue of 14- and 42-day-old rat pups were processed for light microscopy. Maternal nicotine exposure during gestation and lactation resulted in (a) decreased alveolar number, (b) reduced internal surface area and (c) increased alveolar volume. Copper supplementation during gestation and lactation prevented the adverse effects of maternal nicotine exposure during gestation and lactation on the development of the alveolar region of the rat lung.
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Jin, Yi, Bernadette Chen, Thomas J. Calvert, Louis G. Chicoine, Yusen Liu, and Leif D. Nelin. "Chronic hypoxia decreases arterial and venous compliance in isolated perfused rat lungs: an effect that is reversed by exogenous l-arginine." American Journal of Physiology-Heart and Circulatory Physiology 304, no. 2 (January 15, 2013): H195—H205. http://dx.doi.org/10.1152/ajpheart.00188.2012.
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Chronic hypoxia (CH)-induced pulmonary hypertension is characterized by vasoconstriction and vascular remodeling, leading to right ventricular dysfunction. Given the role of arterial compliance ( Ca) in right ventricular work, a decrease in Ca would add to right ventricular work. Nitric oxide (NO) is a potent vasodilator made by NO synthases from l-arginine (l-Arg). However, little is known of the effect of l-Arg on vascular compliance ( Cv) in the lung. We hypothesized that exposure to CH would decrease Ca and that this effect would be reversed by exogenous l-Arg. Sprague-Dawley rats were exposed to either normoxia or CH for 14 days; the lungs were then isolated and perfused. Vascular occlusions were performed and modeled using a three-compliance, two-resistor model. Pressure-flow curves were generated, and a distensible vessel model was used to estimate distensibility and a vascular resistance parameter ( R0). Hypoxia resulted in the expected increase in arterial resistance ( Ra) as well as a decrease in both Ca and Cv. l-Arg had little effect on Ra, Ca, or Cv in isolated lungs from normoxic animals. l-Arg decreased Ra in lungs from CH rats and redistributed compliance to approximately that found in normoxic lungs. CH increased R0, and l-Arg reversed this increase in R0. l-Arg increased exhaled NO, and inhibition of l-Arg uptake attenuated the l-Arg-induced increase in exhaled NO. These data demonstrate that the CH-induced decrease in Ca was reversed by l-Arg, suggesting that l-Arg may improve CH-induced right ventricular dysfunction.
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Vignali, Dario A. A., S. N. Klaus, Q. D. Bickle, and M. G. Taylor. "Histological examination of the cellular reactions around schistosomula of Schistosoma mansoni in the lungs of sublethally irradiated and unirradiated, immune and control rats." Parasitology 98, no. 1 (February 1989): 57–65. http://dx.doi.org/10.1017/s0031182000059680.
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SummaryHistopathological data on the cellular reactions (foci) around Schistosoma mansoni schistosomula in the lungs of both irradiated (750 rad) and unirradiated, passively immunized and normal rats were consistent with the idea that a significant proportion of immune-mediated attrition in passively immunized rats occurs in the lungs. In unirradiated rats, immune serum elicited an enhanced (i.e. larger) and accelerated (i.e. more rapidly developing) inflammatory cellular infiltration around lung-stage parasites when administered 5 days post-infection, when the parasites were already in the lungs. This demonstrated the antigenicity of lung-stage schistosomula and their potential as targets for immune attack. In irradiated rats, innate immunity was decreased as judged by an increase in the number of worms recovered by portal perfusion, and was accompanied by an overall decreased percentage of trapped parasites compared with unirradiated controls, suggesting that trapping in the lungs is involved in innate, as well as acquired immunity. In contrast to the results in unirradiated rats, passive transfer of immune serum into irradiated recipients did not result in larger lung foci than in the NRS-recipients. However, there was evidence of an accelerated response resulting in an essentially similar ratio of trapped parasites (VRS- compared with NRS-recipients) in irradiated rats, as compared with unirradiated rats, reflecting the similar levels of resistance manifested in both groups of rats. This also lent credence to the notion that it was the speed of immune recognition of the migrating schistosomula and the establishment of trapping foci that were of greater importance rather than the size of the enveloping granulomata. Investigations into the cellular composition of the foci surrounding trapped parasites in unirradiated rats revealed a predominance of mononuclear cells, with equal proportions of lymphocytes and macrophages. Eosinophils represented less than 3% of the cellular composition of the foci and were typically distant from the parasites themselves, arguing against their role in specific immunity in this model. Irradiation of recipient rats resulted in a corresponding increase in the percentage of macrophages in lung foci.
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Lai-Fook, S. J., and M. R. Kaplowitz. "Pleural space thickness in situ by light microscopy in five mammalian species." Journal of Applied Physiology 59, no. 2 (August 1, 1985): 603–10. http://dx.doi.org/10.1152/jappl.1985.59.2.603.
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The thickness of the pleural space was measured by a focusing method using a light microscope (X157, 2.5-micron depth of focus). In anesthetized animals, thin transparent parietal pleural windows were made by dissection of intercostal muscle. Multiple postmortem measurements were made of the combined thickness of the pleural space and the window by focusing in sequence on the lung surface and on 1- to 2-micron tantulum particles sprayed on the window. The window thickness was measured after creating a pneumothorax and retracting the lungs. In supine rabbits the pleural space measured at various heights on the costal surface was of uniform thickness (16 micron) except for a thicker region (62 micron) located within 3 mm of the most dependent part of the lung. The thicker region reverted to the uniform thickness after it was placed in a nondependent position by inverting the animal from the supine to prone position, indicating fluid drainage by gravity. In the prone position near midchest, pleural space thickness (t) averaged 6.9 micron in the mouse, 10.2 in the rat, 17.2 in the rabbit, 18.3 in the cat, and 23.6 in the dog. Animals of larger body mass (M, kg) had a wider pleural space: t = 13.1 X M0.20. There was no contact between the two pleurae, indicating that fluid lubrication facilitates sliding between the lung and chest wall. Based on the t vs. M relationship and estimates of the viscous flow of pleural liquid, pleural fluid exchange rate would be proportional to body mass and the work of sliding as a fraction of the work of breathing would be smaller in larger animals.
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Hardiany, N. S., A. A. Asa, D. Safirina, and W. Mulyawan. "The Effect of Intermittent Hypobaric Hypoxia Exposure on Reduced-Glutathione Level in Rat Lung and Renal Tissues." Advanced Science Letters 24, no. 8 (August 1, 2018): 6249–51. http://dx.doi.org/10.1166/asl.2018.12704.
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Hypobaric hypoxia is basically a hypoxia condition experienced in high altitude commonly during flight, that increase reactive oxygen species (ROS). When hypoxia hypobaric does not undergo continuation or in other word, intermittent, it will cause adaptation response in a form of protection mode into ROS. Moreover, ROS could be eliminated by reduced-glutathione (GSH) as an endogenous non enzymatic antioxidant. Therefore, the aim of this study was to analyze the effects of intermittent hypobaric hypoxia exposure on GSH level in rat lung and renal tissue. Lung and renal samples were collected from 6–8 weeks old male Sprague-Dawley rats weighing 150–200 g, previously exposed 1–4 times to intermittent hypobaric hypoxia in 35,000 ft (1 minute), 25.000 ft (5 minute) and 18,000 ft altitude (25 minute). Afterwards, GSH level was calculated from lung and renal extracts using the Ellman’s method. In lung tissues, GSH level was decreased in hypoxia 1×, 2×, 3×, 4× treatment, and were significant between the control–hypoxia 3×, control–hypoxia 4×, hypoxia 1×–hypoxia 3× and hypoxia 1×–hypoxia 4×. On the contrary, GSH level was increased in renal tissues on hypoxia 1× and hypoxia 2× treatment compared to control. Nevertheless, GSH level was decreased after 3× treatment and found almost stabilized at 4× treatment of hypoxia in renal tissues. Intermittent hypobaric hypoxia exposure affect GSH in rat lung and renal tissues with varying level as an adaptive response system.
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Vranje, Slađana, Zvezdana Rajkovača, and Dražana Srdić. "THE WORK OF THE CLINIC FOR LUNG DISEASES DURING THE TWO YEARS OF THE PANDEMIC COVID 19." Respiratio 10,11,12, no. 1,2,3 (June 3, 2022): 398–403. http://dx.doi.org/10.26601/rsp.aprs.22.14.
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Pojava bolesti COVID 19 dovela je do velikih promjena u životima ljudi, zahtijevala promjene u organizaciji rada, te izazvala veliki pritisak na rad i funkcionisanje zdravstvenog sistema. Sve zdravstvene ustanove u svijetu, pa i Klinika za plućne bolesti, kao dio UKC Republike Srpske, su prilagodile svoj način rada novonastaloj situaciji. Cilj rada je prikazati odgovor Klinike za plućne bolesti izazovima medicinske struke koje sa sobom donosi pojava bolesti COVID 19. Retrospektivna studija podataka dobijenih iz informacionog sistema o pacijentima koji su liječeni u Klinici za plućne bolesti tokom 2019.godine, godina prije pandemije, i u periodu pandemije, od januara 2020. godine do 31. marta 2022. godine. Broj hospitalizovanih pacijenata 2019. je iznosio 4233, 2020.godine 4246, 2021. godine 4581 pacijent dok je sa 31. martom ove godine broj hospitalizovanih pacijenata 1113. Broj pacijenata liječenih 2020. godine od COVID 19 iznosio je 964, 2021. godine 1244 dok je za prva tri mjeseca 2022.godine hospitalizovanih zbog COVID 19 bio 169. Polna strukturi oboljelih od COVID 19 i 2020.godine i 2021.godine bila je ista procentualno, odnosno, zastupljenost muškog pola bila je 62%a ženskog 38%, a za posmatrani period 2022.godine zastupljenost muškog pola bila je 53% a ženskog 47%. Prema starosnoj dobi procentualno su najviše zastupljeni stariji od 65 godina, 2020.godine ih je bilo 62%, 2021.godine 70% a za prva tri mjeseca 2022.godine 81%. Profesionalni rad, pravovremeno regaovanje od strane rukovodstva UKC Republike Srpske, poštovanje epidemioloških mjera, stalna saradnja i zajednički rad svih medicinskih i nemedicinskihradnikaKlinike za plućne bolesti i UKC Republike Srpske omogućili su da se prevaziđu svi problemi, omogući nesmetan rad i pruži pomoćonim kojim je to u to vrijeme bilo potrebno.
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López-Yerena, Anallely, Anna Vallverdú-Queralt, Rosa M. Lamuela-Raventós, and Elvira Escribano-Ferrer. "LC-ESI-LTQ-Orbitrap-MS for Profiling the Distribution of Oleacein and Its Metabolites in Rat Tissues." Antioxidants 10, no. 7 (July 5, 2021): 1083. http://dx.doi.org/10.3390/antiox10071083.
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The purpose of this work was to study the distribution of oleacein (OLEA) and its metabolites in rat plasma and different tissues, namely brain, heart, kidney, liver, lung, small intestine, spleen, stomach, skin, and thyroid, following the acute intake of a refined olive oil containing 0.3 mg/mL of OLEA. For this purpose, a distribution kinetics study was carried out. The plasma and tissues were collected at 1, 2, and 4.5 h after the intervention, and analyzed by LC-ESI-LTQ-Orbitrap-MS. Unmetabolized OLEA was detected in the stomach, small intestine, liver, plasma and, most notably, the heart. This finding may be useful for the development of new applications of OLEA for cardiovascular disease prevention. Noteworthy are also the high levels of hydroxytyrosol (OH-TY) and OLEA + CH3 found in the small intestine, liver, and plasma, and the detection of nine OLEA metabolites, five of them arising from conjugation reactions. Liver, heart, spleen, and lungs were the target tissues where the metabolites were most distributed. However, it is important to note that OH-TY, in our experimental conditions, was not detected in any target tissue (heart, spleen, thyroids, lungs, brain, and skin). These results shed further light on the metabolism and tissue distribution of OLEA and contribute to understanding the mechanisms underlying its effect in human health.
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Rodrigues, Pedro L., Nuno F. Rodrigues, Duarte Duque, Sara Granja, Jorge Correia-Pinto, and João L. Vilaça. "Automated Image Analysis of Lung Branching Morphogenesis from Microscopic Images of Fetal Rat Explants." Computational and Mathematical Methods in Medicine 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/820214.
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Background.Regulating mechanisms of branching morphogenesis of fetal lung rat explants have been an essential tool for molecular research. This work presents a new methodology to accurately quantify the epithelial, outer contour, and peripheral airway buds of lung explants during cellular development from microscopic images.Methods.The outer contour was defined using an adaptive and multiscale threshold algorithm whose level was automatically calculated based on an entropy maximization criterion. The inner lung epithelium was defined by a clustering procedure that groups small image regions according to the minimum description length principle and local statistical properties. Finally, the number of peripheral buds was counted as the skeleton branched ends from a skeletonized image of the lung inner epithelia.Results.The time for lung branching morphometric analysis was reduced in 98% in contrast to the manual method. Best results were obtained in the first two days of cellular development, with lesser standard deviations. Nonsignificant differences were found between the automatic and manual results in all culture days.Conclusions.The proposed method introduces a series of advantages related to its intuitive use and accuracy, making the technique suitable to images with different lighting characteristics and allowing a reliable comparison between different researchers.
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Sabet, Mojgan, Ziad Tarazi, Jonathan Parkinson, Kade Roberts, Philip Thompson, Roger Nation, Tony Velkov, et al. "707. QPX9003: Pharmacology of a Novel Polymyxin in Mice and Rats." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S319. http://dx.doi.org/10.1093/ofid/ofz360.775.
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Abstract Background Currently available polymyxins are limited by toxicity and poor efficacy at tolerated doses. We have developed a new series of polymyxin derivatives with improved safety profiles and in vitro potency against major MDR bacteria. The following describes studies on the in vivo antimicrobial activity and toxicity of QPX9003 in mice and rats. Methods Mouse studies. The minimum lethal dose (MLD by IV bolus) and nephrotoxicity (6 IP doses administered 2 hours apart) of QPX9003 and polymyxin B (PMB) were determined in Swiss mice. For the neutropenic mouse thigh infection using A. baumannii, Swiss mice were infected with ~106 CFU/thigh. Doses were administered IP at various intervals starting 2-hour post-infection and continued over 24 hours. Rat studies. For the rat lung infection model, Sprague-Dawley rats were infected with ~107 CFU/lung. QPX9003 and PMB were administered IV every 4 hours starting 2 hours post-infection and continued over 24 hours. Bacteria. For both infection models, animals were infected with A. baumannii AB1016 (QPX9003 MIC of 0.5 mg/L and PMB MIC of 1.0 mg/L). Untreated control groups were sacrificed at the start of treatment and both untreated and treated groups were sacrificed 24 hours after the start of treatment, infected tissues harvested, homogenized, and plated to determine colony counts. Results QPX9003 had reduced acute toxicity and nephrotoxicity compared with PMB in mice. QPX9003 showed better bacterial killing of A. baumannii than PMB at similar plasma exposures in both the mouse thigh model (−0.41 vs. +0.83 log CFU/thigh) and rat lung infection model (−1.10 vs. +1.44 log CFU/lung). Conclusion QPX9003 was less acutely toxic, less nephrotoxic, and was more efficacious in mouse and rat infection models compared with PMB. QPX9003 is a promising new polymyxin. (This work was supported in part by federal funds from the National Institutes of Allergy and Infectious Diseases [R01AI098771], and the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under OTA number HHSO100201600026C). Disclosures All authors: No reported disclosures.
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Jacob, R. E., K. R. Minard, G. Laicher, and C. Timchalk. "3D 3He diffusion MRI as a local in vivo morphometric tool to evaluate emphysematous rat lungs." Journal of Applied Physiology 105, no. 4 (October 2008): 1291–300. http://dx.doi.org/10.1152/japplphysiol.90375.2008.
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In this work, we investigate 3He magnetic resonance imaging as a noninvasive morphometric tool to assess emphysematous disease state on a local level. Emphysema was induced intratracheally in rats with 25 U/100 g body wt of porcine pancreatic elastase dissolved in 200 μl saline. Rats were then paired with saline-dosed controls. Nine three-dimensional (3D) 3He diffusion-weighted images were acquired at 1, 2, or 3 wk postdose, after which the lungs were harvested and prepared for histological analysis. Recently introduced indexes sensitive to the heterogeneity of the air space size distribution were calculated. These indexes, D1 and D2, were derived from the moments of the mean equivalent airway diameters. Averaged over the entire lung, it is shown that the average 3He diffusivity ( Dave) correlates well with histology ( R = 0.85, P < 0.0001). By matching small (0.046 cm2) regions in 3He images with corresponding regions in histological slices, Dave correlates significantly with both D 1 and D 2 ( R = 0.88 and R = 0.90, respectively, with P < 0.0001). It is concluded that 3He MRI is a viable noninvasive morphometric tool for localized in vivo emphysema assessment.
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Papp, Michael, Xiaopeng Li, Jiaju Zhuang, Rongqi Wang, and Bruce D. Uhal. "Angiotensin receptor subtype AT1 mediates alveolar epithelial cell apoptosis in response to ANG II." American Journal of Physiology-Lung Cellular and Molecular Physiology 282, no. 4 (April 1, 2002): L713—L718. http://dx.doi.org/10.1152/ajplung.00103.2001.
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Previous work from this laboratory demonstrated induction of apoptosis in lung alveolar epithelial cells (AEC) by purified angiotensin II (ANG II) and expression of mRNAs for both ANG II receptor subtypes AT1 and AT2(Wang R, Zagariya A, Ibarra-Sunga O, Gidea C, Ang E, Deshmukh S, Chaudhary G, Baraboutis J, Filippatos G, and Uhal BD. Am J Physiol Lung Cell Mol Physiol 276: L885–L889, 1999.). The present study was designed to determine the ANG II receptor subtype mediating AEC apoptosis in response to ANG II. Apoptosis was induced with purified ANG II applied to the human lung AEC-derived carcinoma cell line A549 or to primary AEC isolated from Wistar rats. In both cell types, the AT1-selective receptor antagonists L-158809 or losartan inhibited ANG II-induced apoptosis by 90% at concentrations of 10−8 M and 10−7 M, respectively. The inhibition was concentration dependent with IC50 of 10−12 M and 10−11 M on the primary rat AEC. In contrast, the AT2-selective antagonists PD-123319 or PD-126055 could not block ANG II-induced apoptosis in either cell type. In primary rat AEC, apoptosis in response to ANG II was blunted in a dose-dependent manner by the protein kinase C inhibitor chelerythrine but not by the tyrosine phosphatase inhibitor sodium orthovanadate. Together, these data indicate that AEC apoptosis in response to ANG II is mediated by receptor subtype AT1, despite the expression of mRNAs for both AT1 and AT2.
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Harris, William Thomas, and Farruk Kabir. "2058 miRNA manipulation to improve CFTR correction in cystic fibrosis." Journal of Clinical and Translational Science 2, S1 (June 2018): 20. http://dx.doi.org/10.1017/cts.2018.96.
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OBJECTIVES/SPECIFIC AIMS: CFTR is the mutant protein that causes cystic fibrosis (CF), a fatal respiratory diseases affecting 1 in 3500 children. CFTR modulators are small molecules that directly address mutant CFTR function. Improving correction of the F508del CFTR mutation (affecting 90% of CF patients) is one of the most pressing unmet needs in CF. Currently available F508del therapeutics only marginally improve CF, In vitro, we have identified a miRNA that impairs utility of CFTR directed therapies. miR-145 is upregulated by TGF-β (a genetic modifier of CF lung disease) with a direct binding site on the 3’-untranslated region of CFTR mRNA. Binding of miR-145 to CFTR destabilizes mRNA transcript and impedes protein translation. Overexpression of miR-145 abolishes benefit of F508del CFTR correction. Antagonists to miR-145 block TGF-β suppression of CFTR function and augment response to CFTR correction. This project evaluate in vivo impact of TGF-beta and miRNA manipulation on CFTR functional readouts including nasal potential difference (NPD) and short circuit current (Isc) across tracheal explants in addition to standard biochemical measures. METHODS/STUDY POPULATION: Wild-type Sprague-Dawley rats were inoculated with an adenoviral vector containing bioactive TGF-beta or sham at 1×109 pfu/animal placed in the left nares. Seven days post-inoculation, functional, and biochemical measures were conducted. NPD was measured with a microelectrode placed in the left nare and grounded the tail. The nare was sequentially perfused with standard Ringer’s solution, amiloride (to block the ENaC sodium channel), low chloride Ringer’s (to stimulate chloride efflux), forskolin (to open the CFTR channel) and CFTRinh-172 (to block the CFTR channel. Tracheal explants were harvested, microdissected, and placed on modified Ussing chambers. RESULTS/ANTICIPATED RESULTS: We have inoculated WT rats with bioactive TGF-β Versus sham delivered by intranasal inoculation of an adenoviral vector. Functional readout of CFTR function is by Isc across tracheal epithelia and NPD. Lung homogenates are analyzed for TGF-β signaling, miRNA expression, and CFTR transcripts. Both tracheal explants and NPD indicate TGF-β stimulation diminishes CFTR function in vivo. In tracheal explants, TGF-β exposure diminishes CFTR response to forskolin-stimulation by 75%. Loss of current after CFTR inhibition (CFTRinh-172) is halved. By nasal PD, TGF-β inoculation similarly halves the bioelectric response to low chloride and forskolin stimulation. Evaluation by qPCR reveals a strong increase in TGF-β signaling demarcated by PAI-1, prompting a reduction in CFTR mRNA. miR-145 is expressed highly in rat pulmonary tissue, but no change in overall miR-145 levels was detected between TGF-β and sham exposed rats. This finding reflects what we have observed in human lungs, with a localized increased miR-145 expression in CF epithelia, but similarly high levels of miR-145 in both CF and non-CF whole lung homogenates. Although expressed at lower levels than miR-145, we did find increased expression in TGF-β relevant miR-101, miR-494, and miR-144 that have a predicted binding site on rat 3’-UTR in TGF-β exposed Versus sham lungs. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data indicate the relevance of TGF-β stimulation to suppress CFTR synthesis and function in vivo. Future work will evaluate whether these additional miRNA with CFTR binding sites may mediate TGF-β suppression of CFTR in the rat model, and the utility of miRNA manipulation to augment F508del CFTR correction.
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Boukhvalova, Marina S., Gregory A. Prince, and Jorge C. G. Blanco. "Respiratory Syncytial Virus Infects and Abortively Replicates in the Lungs in Spite of Preexisting Immunity." Journal of Virology 81, no. 17 (June 27, 2007): 9443–50. http://dx.doi.org/10.1128/jvi.00102-07.
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ABSTRACT Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and viral pneumonia in young children and a serious health risk in immunocompromised individuals and the elderly. Immunity to RSV is not completely understood. In this work, we established a method for monitoring RSV infection by real-time PCR and applied this method for analysis of RSV replication in vivo in the cotton rat model in naïve animals and in animals rendered immune to RSV by prior RSV infection. We found that even though no virus could be isolated from the lungs of RSV-challenged immune animals, RSV infection in fact took place and an accumulation of viral RNA transcripts was observed. This type of replication, therefore, can be termed “abortive,” as RSV is capable of entering the cells in the lungs of immune animals, yet the production of progeny viruses is impaired. Similar patterns of RSV gene expression gradient were observed between naïve and reinfected animals, indicating that the skewing of mRNA gradient of viral gene expression, a mechanism documented during latent infection by other viruses, is not likely to be responsible for abortive replication of RSV during reinfection. We found that passive administration of antibodies to RSV prevents productive infection normally accompanied by viral release in the lung, but it does not prevent abortive replication of the virus. To the best of our knowledge, this is the first evidence of abortive replication of RSV in vivo.
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Ge, Peng, Yalan Luo, Qi Yang, Haiyun Wen, Jin Liu, Yibo Zhang, Xuanchi Dong, et al. "Ferroptosis in Rat Lung Tissue during Severe Acute Pancreatitis-Associated Acute Lung Injury: Protection of Qingyi Decoction." Oxidative Medicine and Cellular Longevity 2023 (February 11, 2023): 1–22. http://dx.doi.org/10.1155/2023/5827613.
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Qingyi decoction (QYD) has anti-inflammatory pharmacological properties and substantial therapeutic benefits on severe acute pancreatitis (SAP) in clinical practice. However, its protective mechanism against SAP-associated acute lung injury (ALI) remains unclear. In this study, we screened the active ingredients of QYD from the perspective of network pharmacology to identify its core targets and signaling pathways against SAP-associated ALI. Rescue experiments were used to determine the relationship between QYD and ferroptosis. Then, metabolomics and 16s rDNA sequencing were used to identify differential metabolites and microbes in lung tissue. Correlation analysis was utilized to explore the relationship between core targets, signaling pathways, metabolic phenotypes, and microbial flora, sorting out the potential molecular network of QYD against SAP-associated lung ALI. Inflammatory damage was caused by SAP in the rat lung. QYD could effectively alleviate lung injury, improve respiratory function, and significantly reduce serum inflammatory factor levels in SAP rats. Network pharmacology and molecular docking identified three key targets: ALDH2, AnxA1, and ICAM-1. Mechanistically, QYD may inhibit ferroptosis by promoting the ALDH2 expression and suppress neutrophil infiltration by blocking the cleavage of intact AnxA1 and downregulating ICAM-1 expression. Ferroptosis activator counteracts the pulmonary protective effect of QYD in SAP rats. In addition, seven significant differential metabolites were identified in lung tissues. QYD relatively improved the lung microbiome’s abundance in SAP rats. Further correlation analysis determined the correlation between ferroptosis, differential metabolites, and differential microbes. In this work, the network pharmacology, metabolomics, and 16s rDNA sequencing were integrated to uncover the mechanism of QYD against SAP-associated ALI. This novel integrated method may play an important role in future research on traditional Chinese medicine.
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Shih, Jin-Yuan, Akira Inoue, Rebecca Cheng, Rocio Varea, and Sang-We Kim. "Does Pemetrexed Work in Targetable, Nonsquamous Non-Small-Cell Lung Cancer? A Narrative Review." Cancers 12, no. 9 (September 17, 2020): 2658. http://dx.doi.org/10.3390/cancers12092658.
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Pemetrexed is currently mainly considered for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) negative for gene mutations/rearrangements (wild-type disease (WTD)). This narrative review aimed to highlight the role of pemetrexed in the treatment of onco-driven nonsquamous advanced NSCLC by reviewing published clinical studies. For epidermal growth factor receptor (EGFR) mutations, patient survival following first-line pemetrexed–platinum was longer than for WTD. Later-line pemetrexed-based treatment after tyrosine kinase inhibitor (TKI) failure provided greater benefits than non-pemetrexed regimens. First- and later-line pemetrexed-based therapy also provided survival benefits in patients with anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearrangements. In patients with rearranged during transfection (RET) proto-oncogene rearrangements, survival with pemetrexed was similar to that in ALK- and ROS1-positive patients and longer than that in patients with Kirsten rat sarcoma (KRAS) virus proto-oncogene mutations or WTD, although the available studies were limited. For Erb-b2 receptor tyrosine kinase 2 (ERRB2) mutations, first-line pemetrexed showed outcomes similar to those for EGFR and KRAS alterations. Data on pemetrexed in patients with KRAS mutations or MNNG HOS-transforming (MET) expression were limited. Pemetrexed could be an option for first- and second-line treatment for TKI failure in nonsquamous advanced NSCLC with select targetable driver mutations.
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PÉREZ-SERRANO, J., J. MARTÍNEZ, P. REGAL, W. E. BERNADINA, and F. RODRÍGUEZ-CAABEIRO. "Prior immunity to Trichinella spiralis prevents (re)occurrence of an explicit stress response in intestines but not in mesenteric lymph nodes, heart and lungs from reinfected rats." Parasitology 121, no. 5 (November 2000): 565–73. http://dx.doi.org/10.1017/s003118209900671x.
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We recently showed that, in our Trichinella spiralis rat model, first exposure, but not re-exposure to infective-stage larvae evoked heat shock responses in 4 test organs. Our work, however, failed to implicate either early complete clearance of challenge muscle larvae (ML), or rapid elimination of newborn larvae (NBL) in the phenomenon noted in reinfected rats. This study clarifies that issue using 2 established facts in T. spiralis biology and anti-T. spiralis immunology. That is, adult worms injure gut cells and immune destruction of NBL requires release of material also toxic to host cells. To approach the above problem we analysed relevant and irrelevant rat organs for increased heat shock protein (HSP) production at 1, 7, 14, 20 and 27 p.i. during first and second infections. Organs examined were intestines, mesenteric lymph nodes (MLN), heart and lungs. Using densitometric analyses of immunoblots, increased HSP expression was detected on day 7 in intestines from both primary and secondary-infected rats albeit that the change in the latter was just short of significant. Interestingly, MLN only exhibited increased HSP levels in the reinfected rat model with increased HSP levels persisting for 1 week. A lasting shock response was detected in reinfected rats; in contrast, first exposure resulted in shock responses being evident in lungs at either day 7 or day 14, only. These findings suggest that (i) in immune rats, a few challenge ML develop into adults, produce NBLwhich are trapped within MLN, and (ii) that anti-T. spiralis and/or anti-NBL immunity is associated with an, as yet, uncomprehended stress to host's heart tissues.
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Li, Xiaopeng, Maria Molina-Molina, Amal Abdul-Hafez, Jose Ramirez, Anna Serrano-Mollar, Antonio Xaubet, and Bruce D. Uhal. "Extravascular sources of lung angiotensin peptide synthesis in idiopathic pulmonary fibrosis." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 5 (November 2006): L887—L895. http://dx.doi.org/10.1152/ajplung.00432.2005.
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Previous work from this laboratory demonstrated de novo synthesis of angiotensin (ANG) peptides by apoptotic pulmonary alveolar epithelial cells (AEC) and by lung myofibroblasts in vitro and in bleomycin-treated rats. To determine whether these same cell types also synthesize ANG peptides de novo within the fibrotic human lung in situ, we subjected paraffin sections of normal and fibrotic (idiopathic pulmonary fibrosis, IPF) human lung to immunohistochemistry (IHC) and in situ hybridization to detect ANG peptides and angiotensinogen (AGT) mRNA. These were analyzed both alone and in combination with cell-specific markers of AEC [monoclonal antibody (MAb) MNF-116] and myofibroblasts [α-smooth muscle actin (α-SMA) MAb] and an in situ DNA end labeling (ISEL) method to detect apoptosis. In normal human lung, IHC detected AGT protein in smooth muscle underlying normal bronchi and vessels, but not elsewhere. Real-time RT-PCR and Western blotting revealed that AGT mRNA and protein were 21-fold and 3.6-fold more abundant, respectively, in IPF lung biopsies relative to biopsies of normal human lung (both P < 0.05). In IPF lung, both AGT protein and mRNA were detected in AEC that double-labeled with MAb MNF-116 and with ISEL, suggesting AGT expression by apoptotic epithelia in situ. AGT protein and mRNA also colocalized to myofibroblast foci detected by α-SMA MAb, but AGT mRNA was not detected in smooth muscle. These data are consistent with earlier data from isolated human lung cells in vitro and bleomycin-induced rat lung fibrosis models, and they suggest that apoptotic AEC and myofibroblasts constitute key sources of locally derived ANG peptides in the IPF lung.
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Fritsch, P., N. Dudoignon, K. Guillet, G. Rateau, and J. Delforge. "Influence de la distribution de dose sur le risque d'apparition de cancers pulmonaires après inhalation d'oxydes d'actinides." Canadian Journal of Physiology and Pharmacology 80, no. 7 (July 1, 2002): 722–26. http://dx.doi.org/10.1139/y02-098.
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The aim of this work was to estimate risk of lung tumour occurrence after inhalation of actinide oxides from published studies and rat studies in progress. For the same delivered dose, the risk increases when homogeneity of irradiation increases, i.e., the number of particles deposited after inhalation increases (small particles and (or) low specific alpha activity). The doseeffect relationships reported appear linear up to a few gray, depending on the aerosol considered, and then the slope decreases. This slope, which corresponds with the risk, can vary over one order of magnitude depending on the aerosol used. An effective threshold at about 1 Gy was not observed for the most homogeneous dose distributions. A dosimetric and biological approach is proposed to provide a more realistic risk estimate.Key words: actinide oxides, inhalation, lung tumour, alpha irradiation, dosimetry.
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Oesch, F., E. Fabian, and Robert Landsiedel. "Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models." Archives of Toxicology 93, no. 12 (October 31, 2019): 3419–89. http://dx.doi.org/10.1007/s00204-019-02602-7.
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Abstract The xenobiotic metabolism in the lung, an organ of first entry of xenobiotics into the organism, is crucial for inhaled compounds entering this organ intentionally (e.g. drugs) and unintentionally (e.g. work place and environmental compounds). Additionally, local metabolism by enzymes preferentially or exclusively occurring in the lung is important for favorable or toxic effects of xenobiotics entering the organism also by routes other than by inhalation. The data collected in this review show that generally activities of cytochromes P450 are low in the lung of all investigated species and in vitro models. Other oxidoreductases may turn out to be more important, but are largely not investigated. Phase II enzymes are generally much higher with the exception of UGT glucuronosyltransferases which are generally very low. Insofar as data are available the xenobiotic metabolism in the lung of monkeys comes closed to that in the human lung; however, very few data are available for this comparison. Second best rate the mouse and rat lung, followed by the rabbit. Of the human in vitro model primary cells in culture, such as alveolar macrophages and alveolar type II cells as well as the A549 cell line appear quite acceptable. However, (1) this generalization represents a temporary oversimplification born from the lack of more comparable data; (2) the relative suitability of individual species/models is different for different enzymes; (3) when more data become available, the conclusions derived from these comparisons quite possibly may change.
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Mickler, Elizabeth A., Huaxin Zhou, Tzu L. Phang, Mark W. Geraci, Robert S. Stearman, and Catherine R. Sears. "Low-Coverage Whole Genome Sequencing Using Laser Capture Microscopy with Combined Digital Droplet PCR: An Effective Tool to Study Copy Number and Kras Mutations in Early Lung Adenocarcinoma Development." International Journal of Molecular Sciences 22, no. 21 (November 6, 2021): 12034. http://dx.doi.org/10.3390/ijms222112034.
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Defining detailed genomic characterization of early tumor progression is critical to identifying key regulators and pathways in carcinogenesis as potentially druggable targets. In human lung cancer, work to characterize early cancer development has mainly focused on squamous cancer, as the earliest lesions are more proximal in the airways and often accessible by repeated bronchoscopy. Adenocarcinomas are typically located distally in the lung, limiting accessibility for biopsy of pre-malignant and early stages. Mouse lung cancer models recapitulate many human genomic features and provide a model for tumorigenesis with pre-malignant atypical adenomatous hyperplasia and in situ adenocarcinomas often developing contemporaneously within the same animal. Here, we combined tissue characterization and collection by laser capture microscopy (LCM) with digital droplet PCR (ddPCR) and low-coverage whole genome sequencing (LC-WGS). ddPCR can be used to identify specific missense mutations in Kras (Kirsten rat sarcoma viral oncogene homolog, here focused on Kras Q61) and estimate the percentage of mutation predominance. LC-WGS is a cost-effective method to infer localized copy number alterations (CNAs) across the genome using low-input DNA. Combining these methods, the histological stage of lung cancer can be correlated with appearance of Kras mutations and CNAs. The utility of this approach is adaptable to other mouse models of human cancer.
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Itter, G., W. Jung, B. A. Schoelkens, and W. Linz. "The isolated working heart model in infarcted rat hearts." Laboratory Animals 39, no. 2 (April 1, 2005): 178–93. http://dx.doi.org/10.1258/0023677053739738.
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Congestive heart failure (CHF) is one of the most common causes of death in western countries. The aim of this study was to establish and validate the working heart model in rat hearts with CHF. In the rat model the animals show parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure. The focus of attention was the evaluation of cardiodynamics (e.g.contractility) in the isolated 'working heart' model. The geometric properties of the left ventricle were measured by planimetry (stereology). Formulae available in the past for determining certain parameters in the working heart model (e.g.external heart work) have to be fitted to the circumstances of the infarcted rat hearts with its different organ properties. CHF was induced in Wistar Kyoto (WKY/NHsd) and spontaneously hypertensive rats (SHR/NHsd) by creating a permanent (8 week) occlusion of the left coronary artery, 2 mm distal to the origin from the aorta, by a modified technique (Itter et al. 2004). This resulted in a large infarction of the free left ventricular wall. We were able to establish and adapt a new and predictive working heart model in spontaneously hypertensive rat hearts with myocardial infarction (MI) 8–12 weeks after coronary artery ligation. At this stage the WKY rat did not show any symptoms of CHF. The SHR rat represented characteristic parameters and symptoms that could be extrapolated to the clinical situation of patients with end-stage heart failure (NYHA III–IV). Upon inspection, severe clinical symptoms of CHF such as dyspnoea, subcutaneous oedema, palebluish limbs and impaired motion were prominent. On necropsy the SHR showed lung oedema, hydrothorax, large dilated left and right ventricular chambers and hypertrophy of the septum. In the working heart model the infarcted animals showed reduced heart power, diminished contractility and enhanced heart work, much more so in the SHR/NHsd than in the Wistar Kyoto rat (WKY/NHsd). The aim for the future is to find a causal therapy of heart failure treatment. At present, only palliative therapy is possible for patients with heart failure. For this reason the working heart model in CHF rat hearts should provide a valuable method for early testing of new therapeutic approaches for patients with CHF.
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Tomonaga, Taisuke, Hiroto Izumi, Yukiko Yoshiura, Chinatsu Nishida, Kazuhiro Yatera, and Yasuo Morimoto. "Examination of Surfactant Protein D as a Biomarker for Evaluating Pulmonary Toxicity of Nanomaterials in Rat." International Journal of Molecular Sciences 22, no. 9 (April 28, 2021): 4635. http://dx.doi.org/10.3390/ijms22094635.
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This work studies the relationship between lung inflammation caused by nanomaterials and surfactant protein D (SP-D) kinetics and investigates whether SP-D can be a biomarker of the pulmonary toxicity of nanomaterials. Nanomaterials of nickel oxide and cerium dioxide were classified as having high toxicity, nanomaterials of two types of titanium dioxides and zinc oxide were classified as having low toxicity, and rat biological samples obtained from 3 days to 6 months after intratracheal instillation of those nanomaterials and micron-particles of crystalline silica were used. There were different tendencies of increase between the high- and low-toxicity materials in the concentration of SP-D in bronchoalveolar-lavage fluid (BALF) and serum and in the expression of the SP-D gene in the lung tissue. An analysis of the receiver operating characteristics for the toxicity of the nanomaterials by SP-D in BALF and serum showed a high accuracy of discrimination from 1 week to 3 or 6 months after exposure. These data suggest that the differences in the expression of SP-D in BALF and serum depended on the level of lung inflammation caused by the nanomaterials and that SP-D can be biomarkers for evaluating the pulmonary toxicity of nanomaterials.
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Raoul, William, Bernadette Chailley-Heu, Anne-Marie Barlier-Mur, Christophe Delacourt, Bernard Maître, and Jacques R. Bourbon. "Effects of vascular endothelial growth factor on isolated fetal alveolar type II cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 286, no. 6 (June 2004): L1293—L1301. http://dx.doi.org/10.1152/ajplung.00157.2003.
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Previous investigations gained from in vivo or lung explant studies suggested that VEGF is an autocrine proliferation and maturation factor for developing alveolar type II cells. The objective of this work was to determine whether VEGF exerted its growth and maturation effects directly on isolated type II cells. These were isolated from 19-day fetal rat lung and cultured in defined medium. The presence of VEGF receptor-2 was assessed in cultured cells at the pre- and posttranslational levels. Recombinant VEGF165, formerly found to be active on lung explants, failed to enhance type II cell proliferation estimated by thymidine and 5-bromo-2′-deoxy-uridine incorporation. It increased choline incorporation in saturated phosphatidylcholine by 27% but did not increase phospholipid surfactant pool size. VEGF (100 ng/ml) left unchanged the transcript level of surfactant proteins (SP)-A, SP-C, and SP-D but increased SP-B transcripts to four times the control steady-state level. VEGF slightly retarded, but did not prevent, the in vitro transdifferentiation of type II into type I cells, as assessed by immunolabeling of the type I cell marker T1α. We conclude that, with the exception of SP-B expression, which appears to be controlled directly, the previously observed effects of this VEGF isoform on type II cells are likely to be exerted indirectly through reciprocal paracrine interactions involving other lung cell types.
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Chagnon, Frédéric, Alexandra Bourgouin, Réjean Lebel, Marc-André Bonin, Eric Marsault, Martin Lepage, and Olivier Lesur. "Smart imaging of acute lung injury: exploration of myeloperoxidase activity using in vivo endoscopic confocal fluorescence microscopy." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 6 (September 15, 2015): L543—L551. http://dx.doi.org/10.1152/ajplung.00289.2014.
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The pathophysiology of acute lung injury (ALI) is well characterized, but its real-time assessment at bedside remains a challenge. When patients do not improve after 1 wk despite supportive therapies, physicians have to consider open lung biopsy (OLB) to identify the process(es) at play. Sustained inflammation and inadequate repair are often observed in this context. OLB is neither easy to perform in a critical setting nor exempt from complications. Herein, we explore intravital endoscopic confocal fluorescence microscopy (ECFM) of the lung in vivo combined with the use of fluorescent smart probe(s) activated by myeloperoxidase (MPO). MPO is a granular enzyme expressed by polymorphonuclear neutrophils (PMNs) and alveolar macrophages (AMs), catalyzing the synthesis of hypoclorous acid, a by-product of hydrogen peroxide. Activation of these probes was first validated in vitro in relevant cells (i.e., AMs and PMNs) and on MPO-non-expressing cells (as negative controls) and then tested in vivo using three rat models of ALI and real-time intravital imaging with ECFM. Semiquantitative image analyses revealed that in vivo probe-related cellular/background fluorescence was associated with corresponding enhanced lung enzymatic activity and was partly prevented by specific MPO inhibition. Additional ex vivo phenotyping was performed, confirming that fluorescent cells were neutrophil elastase+(PMNs) or CD68+(AMs). This work is a first step toward “virtual biopsy” of ALI without OLB.