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1
Ito, T., N. Udaka, T. Yazawa, K. Okudela, H. Hayashi, T. Sudo, F. Guillemot, R. Kageyama, and H. Kitamura. "Basic helix-loop-helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium." Development 127, no. 18 (September 15, 2000): 3913–21. http://dx.doi.org/10.1242/dev.127.18.3913.
Повний текст джерелаАнотація:
To clarify the mechanisms that regulate neuroendocrine differentiation of fetal lung epithelia, we have studied the expression of the mammalian homologs of achaete-scute complex (Mash1) (Ascl1 - Mouse Genome Informatics); hairy and enhancer of split1 (Hes1); and the expression of Notch/Notch-ligand system in the fetal and adult mouse lungs, and in the lungs of Mash1- or Hes1-deficient mice. Immunohistochemical studies revealed that Mash1-positive cells seemed to belong to pulmonary neuroendocrine cells (PNEC) and their precursors. In mice deficient for Mash1, no PNEC were detected. Hes1-positive cells belong to non-neuroendocrine cells. In the mice deficient in Hes1, in which Mash1 mRNA was upregulated, PNEC appeared precociously, and the number of PNEC was markedly increased. NeuroD (Neurod1 - Mouse Genome Informatics) expression in the lung was detected in the adult, and was enhanced in the fetal lungs of Hes1-null mice. Expression of Notch1, Notch2, Notch3 and Notch4 mRNAs in the mouse lung increased with age, and Notch1 mRNA was expressed in a Hes1-dependent manner. Notch1, Notch2 and Notch3 were immunohistochemically detected in non-neuroendocrine cells. Moreover, analyses of the lungs from the gene-targeted mice suggested that expression of Delta-like 1 (Dll1 - Mouse Genome Informatics) mRNA depends on Mash1. Thus, the neuroendocrine differentiation depends on basic helix-loop-helix factors, and Notch/Notch-ligand pathways may be involved in determining the cell differentiation fate in fetal airway epithelium.
2
Chytil, F. "The lungs and vitamin A." American Journal of Physiology-Lung Cellular and Molecular Physiology 262, no. 5 (May 1, 1992): L517—L527. http://dx.doi.org/10.1152/ajplung.1992.262.5.l517.
Повний текст джерелаАнотація:
Evidence is reviewed supporting the view that vitamin A (retinol) and its metabolite, retinoic acid, called natural retinoids, are major factors involved in differentiation and in maturation of the lungs. This conclusion is based on morphological observation that lack of this dietary micronutrient causes keratinizing squamous metaplasia of the bronchopulmonary tree that can be reversed by refeeding the animal with retinol. In addition to these observations suggesting an indirect participation of retinol and/or retinoic acid in the differentiation of this organ, more direct evidence is presented that this vitamin is involved in pulmonary gene expression. Adult as well as fetal lungs accumulate retinyl esters, the storage form of vitamin A, contain specific retinol- and retinoic acid-binding proteins and, more importantly, express several isoforms of nuclear retinoic acid receptors. These proteins are involved in activation and repression of specific genes regulated by retinoic acid. That retinol and/or retinoic acid may be involved in lung maturation is suggested by experimental results showing depletion of lung retinyl esters at birth, by significant alterations in the levels of the cellular retinoic acid-binding protein during lung maturation and, more importantly, by reduction in the morbidity of prematurely born human neonates who are given vitamin A because they are susceptible to bronchopulmonary dysplasia.
3
Besnard, V., S. E. Wert, K. H. Kaestner, and J. A. Whitsett. "Stage-specific regulation of respiratory epithelial cell differentiation by Foxa1." American Journal of Physiology-Lung Cellular and Molecular Physiology 289, no. 5 (November 2005): L750—L759. http://dx.doi.org/10.1152/ajplung.00151.2005.
Повний текст джерелаАнотація:
Foxa1 is a member of the winged helix family of transcription factors that is expressed in epithelial cells of the conducting airways and in alveolar type II cells of the lung. To determine the role of Foxa1 during lung morphogenesis, histology and gene expression were assessed in lungs from Foxa1−/− gene-targeted mice from embryonic day (E) 16.5 to postnatal day (PN) 13. Deletion of Foxa1 perturbed maturation of the respiratory epithelium at precise times during lung morphogenesis. While dilatation of peripheral lung saccules was delayed in Foxa1−/− mice at E16.5, sacculation was unperturbed later in development (E17.5–E18.5). At PN5, alveolarization was markedly delayed in Foxa1−/− mice; however, by PN13 lung histology was comparable to wild-type controls. Clara cell secretory protein (CCSP), prosurfactant protein (SP)-C, and SP-B protein content and immunostaining were decreased in Foxa1−/− mice between E16.5 and E18.5 but normalized after birth. Timing and sites of expression of thyroid transcription factor-1, Foxj1, and β-tubulin were unaltered in lungs of Foxa1−/− mice. In vitro, Foxa1 regulated the activity of CCSP and SP-A, SP-B, SP-C, and SP-D promoters as assessed by luciferase reporter assays in HeLa, H441, and MLE15 cells. Although Foxa1 regulates respiratory epithelial differentiation and structural maturation of the lung at precise developmental periods, the delay in maturation is subsequently compensated at times to enable respiratory function and restore normal lung structure after birth.
4
BRODY, J. "Alveolar cell differentiation markers in human lungs." Journal of Molecular and Cellular Cardiology 21 (February 1989): 161–64. http://dx.doi.org/10.1016/0022-2828(89)90852-3.
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Meierovics, Anda I., and Siobhán C. Cowley. "MAIT cells promote inflammatory monocyte differentiation into dendritic cells during pulmonary intracellular infection." Journal of Experimental Medicine 213, no. 12 (October 31, 2016): 2793–809. http://dx.doi.org/10.1084/jem.20160637.
Повний текст джерелаАнотація:
Mucosa-associated invariant T (MAIT) cells are a unique innate T cell subset that is necessary for rapid recruitment of activated CD4+ T cells to the lungs after pulmonary F. tularensis LVS infection. Here, we investigated the mechanisms behind this effect. We provide evidence to show that MAIT cells promote early differentiation of CCR2-dependent monocytes into monocyte-derived DCs (Mo-DCs) in the lungs after F. tularensis LVS pulmonary infection. Adoptive transfer of Mo-DCs to MAIT cell–deficient mice (MR1−/− mice) rescued their defect in the recruitment of activated CD4+ T cells to the lungs. We further demonstrate that MAIT cell–dependent GM-CSF production stimulated monocyte differentiation in vitro, and that in vivo production of GM-CSF was delayed in the lungs of MR1−/− mice. Finally, GM-CSF–deficient mice exhibited a defect in monocyte differentiation into Mo-DCs that was phenotypically similar to MR1−/− mice. Overall, our data demonstrate that MAIT cells promote early pulmonary GM-CSF production, which drives the differentiation of inflammatory monocytes into Mo-DCs. Further, this delayed differentiation of Mo-DCs in MR1−/− mice was responsible for the delayed recruitment of activated CD4+ T cells to the lungs. These findings establish a novel mechanism by which MAIT cells function to promote both innate and adaptive immune responses.
6
Li, Changgong, Susan M. Smith, Neil Peinado, Feng Gao, Wei Li, Matt K. Lee, Beiyun Zhou, et al. "WNT5a-ROR Signaling Is Essential for Alveologenesis." Cells 9, no. 2 (February 7, 2020): 384. http://dx.doi.org/10.3390/cells9020384.
Повний текст джерелаАнотація:
WNT5a is a mainly “non-canonical” WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5aCAG) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5aCAG phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5aCAG lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.
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Raslan, Ahmed A., Youn Jeong Oh, Yong Ri Jin, and Jeong Kyo Yoon. "R-Spondin2, a Positive Canonical WNT Signaling Regulator, Controls the Expansion and Differentiation of Distal Lung Epithelial Stem/Progenitor Cells in Mice." International Journal of Molecular Sciences 23, no. 6 (March 13, 2022): 3089. http://dx.doi.org/10.3390/ijms23063089.
Повний текст джерелаАнотація:
The lungs have a remarkable ability to regenerate damaged tissues caused by acute injury. Many lung diseases, especially chronic lung diseases, are associated with a reduced or disrupted regeneration potential of the lungs. Therefore, understanding the underlying mechanisms of the regenerative capacity of the lungs offers the potential to identify novel therapeutic targets for these diseases. R-spondin2, a co-activator of WNT/β-catenin signaling, plays an important role in embryonic murine lung development. However, the role of Rspo2 in adult lung homeostasis and regeneration remains unknown. The aim of this study is to determine Rspo2 function in distal lung stem/progenitor cells and adult lung regeneration. In this study, we found that robust Rspo2 expression was detected in different epithelial cells, including airway club cells and alveolar type 2 (AT2) cells in the adult lungs. However, Rspo2 expression significantly decreased during the first week after naphthalene-induced airway injury and was restored by day 14 post-injury. In ex vivo 3D organoid culture, recombinant RSPO2 promoted the colony formation and differentiation of both club and AT2 cells through the activation of canonical WNT signaling. In contrast, Rspo2 ablation in club and AT2 cells significantly disrupted their expansion capacity in the ex vivo 3D organoid culture. Furthermore, mice lacking Rspo2 showed significant defects in airway regeneration after naphthalene-induced injury. Our results strongly suggest that RSPO2 plays a key role in the adult lung epithelial stem/progenitor cells during homeostasis and regeneration, and therefore, it may be a potential therapeutic target for chronic lung diseases with reduced regenerative capability.
8
Lai, Jen-Feng, Lucas J. Thompson, and Steven F. Ziegler. "TSLP drives acute TH2-cell differentiation in lungs." Journal of Allergy and Clinical Immunology 146, no. 6 (December 2020): 1406–18. http://dx.doi.org/10.1016/j.jaci.2020.03.032.
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Alabed, Mashael, Asma Sultana Shaik, Narjes Saheb Sharif-Askari, Fatemeh Saheb Sharif-Askari, Shirin Hafezi, Bushra Mdkhana, Elaref Ratemi, Saleh Al-Muhsen, Qutayba Hamid, and Rabih Halwani. "Enhanced Infiltration of Central Memory T Cells to the Lung Tissue during Allergic Lung Inflammation." International Archives of Allergy and Immunology 183, no. 2 (October 20, 2021): 127–41. http://dx.doi.org/10.1159/000518835.
Повний текст джерелаАнотація:
Memory T cells play a central role in regulating inflammatory responses during asthma. However, tissue distribution of effector memory (T<sub>EM</sub>) and central memory (T<sub>CM</sub>) T-cell subtypes, their differentiation, and their contribution to the persistence of lung tissue inflammation during asthma are not well understood. Interestingly, an increase in survival and persistence of memory T cells was reported in asthmatic lungs, which may suggest a shift toward the more persistent T<sub>CM</sub> phenotype. In this report, we investigated the differential distribution of memory T-cell subtypes during allergic lung inflammation and the mechanism regulating that. Using an OVA-sensitized asthma mouse model, we observed a significant increase in the frequency of T<sub>CM</sub> cells in inflamed lungs compared to healthy controls. Interestingly, adoptive transfer techniques confirmed substantial infiltration of T<sub>CM</sub> cells to lung tissues during allergic airway inflammation. Expression levels of T<sub>CM</sub> homing receptors, CD34 and GlyCAM-1, were also significantly upregulated in the lung tissues of OVA-sensitized mice, which may facilitate the increased T<sub>CM</sub> infiltration into inflamed lungs. Moreover, a substantial increase in the relative expression of T<sub>CM</sub> profile-associated genes (EOMES, BCL-6, ID3, TCF-7, BCL-2, BIM, and BMI-1) was noted for T<sub>EM</sub> cells during lung inflammation, suggesting a shift for T<sub>EM</sub> into the T<sub>CM</sub> state. To our knowledge, this is the first study to report an increased infiltration of T<sub>CM</sub> cells into inflamed lung tissues and to suggest differentiation of T<sub>EM</sub> to T<sub>CM</sub> cells in these tissues. Therapeutic interference at T<sub>CM</sub> infiltration or differentiations could constitute an alternative treatment approach for lung inflammation.
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Bedoya, Felipe, Guang-Shing Cheng, Abigail Leibow, Nardine Zakhary, Katherine Weissler, Victoria Garcia, Elizabeth Kropf, et al. "Viral antigen induces differentiation of Foxp3+ natural regulatory T cells in influenza virus-infected mice (P1043)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 139.11. http://dx.doi.org/10.4049/jimmunol.190.supp.139.11.
Повний текст джерелаАнотація:
Abstract We have examined the formation, participation and functional specialization of virus-reactive Foxp3+ regulatory T cells (Tregs) in a mouse model of influenza virus infection. “Natural” Tregs generated intra-thymically based on interactions with a self-peptide proliferated in response to a homologous viral antigen in the lungs, and to a lesser extent in the lung-draining mediastinal LN (medLN), of virus-infected mice. By contrast, conventional CD4+ T cells with identical TCR specificity underwent little or no conversion to become “adaptive” Tregs. The virus-reactive Tregs in the medLN and the lungs of infected mice upregulated a variety of molecules associated with Treg activation, and also acquired expression of molecules (T-bet, Blimp-1 and IL-10) that confer functional specialization to Tregs. Notably, however, the phenotypes of the T-bet+ Tregs obtained from these sites were distinct, since Tregs isolated from the lungs expressed significantly higher levels of T-bet, Blimp-1 and IL-10 than did Tregs from the medLN. Adoptive transfer of antigen-reactive Tregs led to decreased proliferation of anti-viral CD4+ and CD8+ effector T cells in the lungs of infected hosts, while depletion of Tregs had a reciprocal effect. These studies demonstrate that thymically-generated Tregs can become activated by a pathogen-derived peptide and acquire discrete T-bet+ Treg phenotypes while participating in and modulating an antiviral immune response.
11
Tulo, Sukanta Kumar, Satyavratan Govindarajan, Palaniappan Ramu, and Ramakrishnan Swaminathan. "SHAPE CHARACTERIZATION OF MEDIASTINUM IN TUBERCULOSIS CHEST RADIOGRAPHS USING LEVEL SET SEGMENTATION." Biomedical Sciences Instrumentation 57, no. 2 (April 1, 2021): 212–18. http://dx.doi.org/10.34107/yhpn9422.04212.
Повний текст джерелаАнотація:
Mediastinum is considered as one of the substantial anatomical regions for the gross diagnosis of several chest related pathologies. The geometric variations of the mediastinum in Chest Radiographs (CXRs) could be utilised as potential image markers in the early detection of Tuberculosis (TB). This study attempts to segment mediastinum in CXRs using level sets for the shape characterization of TB conditions. The CXR images for this study are considered from a public database. An edge-based distance regularized level set evolution is employed to segment the lungs followed by a region-based Chan-Vese model that extracts mediastinum region. Features such as mediastinum area and lungs area are extracted from the segmented images. Further, mediastinum to lungs area ratio is calculated. Statistical analysis is performed on the features to differentiate normal and TB images. Results show that the proposed segmentation approach is able to segment the lungs and extract the mediastinum in CXRs. It is found that features namely mediastinum area and mediastinum to lungs area ratio are statistically significant in the differentiation of TB. Larger mediastinum area is observed in TB images as compared to normal. The performance of lung field segmentation is also observed to be in line with the literature. The mediastinum segmentation approach in CXRs obtains to be a novel method as compared to the existing methods. As the proposed approach based on mediastinum image analysis provides better shape characterization, the study could be clinically useful in the differentiation of TB conditions.
12
Larson, Janet E., Joseph B. Delcarpio, Michelle M. Farberman, Susan L. Morrow, and J. Craig Cohen. "CFTR modulates lung secretory cell proliferation and differentiation." American Journal of Physiology-Lung Cellular and Molecular Physiology 279, no. 2 (August 1, 2000): L333—L341. http://dx.doi.org/10.1152/ajplung.2000.279.2.l333.
Повний текст джерелаАнотація:
We have permanently reversed the lethal phenotype in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-deficient (knockout) mouse after in utero gene therapy with an adenovirus containing the cftr gene. The gene transfer targeted somatic stem cells in the developing lung and intestine, and these epithelial surfaces demonstrated permanent developmental changes after treatment. The survival statistics from the progeny of heterozygote-heterozygote matings after in utero cftr gene treatment demonstrated an increased mortality in the homozygous normal pups, indicating that overexpression during development was detrimental. The lungs of these pups revealed accelerated secretory cell proliferation and differentiation. The extent of proliferation and differentiation in the secretory cells of the lung parenchyma after in utero transfer of the cftr gene was evaluated with morphometric and biochemical analyses. These studies provide further support of the regulatory role of the cftr gene in the development of the secretory epithelium.
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Hayu, Tri Pangesti, and Ayly Soekanto. "Pengaruh Pemaparan Uap Anti Nyamuk Elektrik yang Mengandung Allathrin terhadap Berat dan Warna Paru-ParuTikusi." Jurnal Ilmiah Kedokteran Wijaya Kusuma 5, no. 1 (February 13, 2018): 26. http://dx.doi.org/10.30742/jikw.v5i1.3.
Повний текст джерелаАнотація:
Lungs as place where the gases exchange inside the body is related to enviroment sorrounding. Usage of electric mosquito repellent that contained allethrin on certain period can inflict lung’s abnormalities.The aim to this research is to find the effect of fumes exposure from the electric mosquito repellent that contained allethrin to weight and colour of rat’s lungs. The research was experimental laboratory. 24 male rats strain Wistar that devided into 4 groups, which were group 1 control (P0) without exposure, group 2 (P1) exposed 4 hours a day, group 3 (P2) exposed 6 hours a day and group 4 (P3) exposed 8 hours a day. In 30 th day, the rats terminated in the order to taken their lungs organ by operation. The purpose of taken the lungs was analyzed lung’s weight and alteration of its colour. The acquired data process by Anova test for weight analysis, and Kruskal Wallis test for colour change analysis, respectively with significant value (α < 0,05). The result of anova test is (α = 0.004) and kruskal wallis test is (α = 0,001), that to mean there are significan differentiation in group. Conclusion of this research : there was an effects of fumes exposure of electric mosquito repellent that contain allethrin against the weight and colour of the rat’s lungs. That effect on the lungs occour because collaps of the alveolus or lungs.
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Yao, Jiayi, Pierre J. Guihard, Xiuju Wu, Ana M. Blazquez-Medela, Melissa J. Spencer, Medet Jumabay, Peter Tontonoz, Alan M. Fogelman, Kristina I. Boström, and Yucheng Yao. "Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation." Journal of Cell Biology 216, no. 10 (August 24, 2017): 3369–85. http://dx.doi.org/10.1083/jcb.201612122.
Повний текст джерелаАнотація:
The vascular endothelium is critical for induction of appropriate lineage differentiation in organogenesis. In this study, we report that dysfunctional pulmonary endothelium, resulting from the loss of matrix Gla protein (MGP), causes ectopic hepatic differentiation in the pulmonary epithelium. We demonstrate uncontrolled induction of the hepatic growth factor (HGF) caused by dysregulated cross talk between pulmonary endothelium and epithelium in Mgp-null lungs. Elevated HGF induced hepatocyte nuclear factor 4 α (Hnf4a), which competed with NK2 homeobox 1 (Nkx2.1) for binding to forkhead box A2 (Foxa2) to drive hepatic differentiation in Mgp-null airway progenitor cells. Limiting endothelial HGF reduced Hnf4a, abolished interference of Hnf4a with Foxa2, and reduced hepatic differentiation in Mgp-null lungs. Together, our results suggest that endothelial–epithelial interactions, maintained by MGP, are essential in pulmonary cell differentiation.
15
Xie, Ke, Yu-sen Chai, Shi-hui Lin, Fang Xu, and Chuan-jiang Wang. "Luteolin Regulates the Differentiation of Regulatory T Cells and Activates IL-10-Dependent Macrophage Polarization against Acute Lung Injury." Journal of Immunology Research 2021 (January 18, 2021): 1–12. http://dx.doi.org/10.1155/2021/8883962.
Повний текст джерелаАнотація:
Objectives. Inflammatory disease characterized by clinical destructive respiratory disorder is called acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Studies have shown that luteolin exerts anti-inflammatory effects by increasing regulatory T cells (Tregs). In this study, we aimed to determine the effects of luteolin on ALI/ARDS and Treg differentiation. Methods. In this paper, we used cecal ligation puncture (CLP) to generate an ALI mouse model to determine the effects of luteolin on ALI/ARDS. Lung tissues were stained for interleukin- (IL-) 17A and myeloperoxidase (MPO) by immunohistochemical analysis. The levels of Treg-related cytokines in serum and bronchoalveolar lavage fluid (BALF) of mice were detected. The protein levels of NF-κB p65 in lung tissues were measured. Macrophage phenotypes in lung tissues were measured using immunofluorescence. The proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells (PBMCs) was quantified. Furthermore, in vitro, we evaluated the effects of luteolin on Treg differentiation, and the effects of IL-10 immune regulation on macrophage polarization were examined. Results. Luteolin alleviated lung injury and suppressed uncontrolled inflammation and downregulated IL-17A, MPO, and NF-κB in the lungs of CLP-induced mouse models. At this time, luteolin upregulated the level of IL-10 in serum and BALF and the frequency of CD4+CD25+FOXP3+ Tregs in PBMCs and splenic mononuclear cells of CLP mice. Luteolin treatment decreased the proportion of M1 macrophages and increased the proportion of M2 macrophages in lungs of CLP-induced mouse models. In vitro, administration of luteolin significantly induced Treg differentiation, and IL-10 promoted the polarization of M2 macrophages but reduced the polarization of M1 macrophages. Conclusions. Luteolin alleviated lung injury and suppressed uncontrolled inflammation by inducing the differentiation of CD4+CD25+FOXP3+ Tregs and upregulating the expression of IL-10. Furthermore, the anti-inflammatory cytokine IL-10 promoted polarization of M2 macrophages in vitro. Luteolin-induced Treg differentiation from naïve CD4+ T cells may be a potential mechanism for regulating IL-10 production.
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Biswas, Deblina, Anshu Kumari, George C. K. Chen, Srivathsan Vasudevan, Sharad Gupta, Supriya Shukla, and Umesh K. Garg. "Quantitative Differentiation of Pneumonia from Normal Lungs: Diagnostic Assessment Using Photoacoustic Spectral Response." Applied Spectroscopy 71, no. 11 (September 8, 2017): 2532–37. http://dx.doi.org/10.1177/0003702817708320.
Повний текст джерелаАнотація:
Pneumonia is an acute lung infection that takes life of many young children in developing countries. Early stage (red hepatization) detection of pneumonia would be pragmatic to control mortality rate. Detection of this disease at early stages demands the knowledge of pathology, making it difficult to screen noninvasively. We propose photoacoustic spectral response (PASR), a noninvasive elasticity-dependent technique for early stage pneumonia detection. We report the quantitative red hepatization detection of pneumonia through median frequency, spectral energy, and variance. Significant contrast in spectral parameters due to change in sample elasticity is found. The tissue-mimicking phantom study illustrates a 39% increase in median frequency for 1.5 times the change in density. On applying to formalin-fixed pneumonia-affected goat lungs, it provides a distinct change in spectral parameters between pneumonia affected areas and normal lungs. The obtained PASR results were found to be highly correlating to standard histopathology. The proposed technique therefore has potential to be a regular diagnostic tool for early pneumonia detection.
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Cornez, Isabelle, Sowmya Parampalli Yajnanarayana, Natascha Hermann-Kleiter, Stefan Ulrich Schmidt, Peter Brossart, Natalio Garbi, Gottfried Baier, and Dominik Wolf. "The E3 Ubiquitin Ligase Cbl-b Limits Nascent Th9 Differentiation." Blood 126, no. 23 (December 3, 2015): 2222. http://dx.doi.org/10.1182/blood.v126.23.2222.2222.
Повний текст джерелаАнотація:
Abstract Introduction: Th9 cells are critical mediators of allergy and anti-cancer immunity. The E3 ubiquitin ligase Cbl-b modulates T cell activation via regulation of the T cell receptor (TCR) activation threshold as well as by inducing TGF-β sensitivity, which is a critical differentiation factor for Th9 differentiation. Even though some evidence shows that Cbl-b impairs Th9 differentiation by targeting IL-4 dependent STAT6 activation, a complete suppression of Th9 differentiation in the absence of both STAT6 and Cbl-b is not achieved, implying the involvement of additional mechanisms. In this study, we evaluate the role of Cbl-b in early stages of TGF-β dependent Th9 differentiation. Methods: Th9 cells were generated from WT and cblb-deficient naïve CD4+ T cells. After maximum 3 days in presence of IL-4, TGF-β and anti-IFN-γ antibodies, differentiation was determined by the quantification of cytokines, mainly IL-9, and that of the two required transcription factors for Th9 differentiation, namely IRF4 and PU.1. Microarray assay revealed gene candidates that were further validated by mRNA and protein expression analysis. The functional role of Cbl-b was tested in a Th9-mediated murine lung allergy model, in which mice were challenged by intratracheal injections of house dust mite (HDM) extracts. Results: cblb-deficient naïve T cells more efficiently differentiate into Th9 cells after 3 days in culture, express in parallel PU.1 more intensively compared to WT Th9 cells, while retaining similar expression levels of IRF4, another important Th9 differentiation factor. Increased IL-9 level is not based on cblb -deficient T cell hyperproliferation, as we show an increased IL-9 production per cell by using combination of CFSE with intracellular IL-9 staining. Microarray analysis revealed that RUNX1, a known transcriptional modulator of PU.1, is more rapidly down-regulated in cblb-deficient Th9 cells compared to WT Th9 cells. Accordingly, knocking down RUNX1 by siRNA in naïve CD4+ T cells and subsequently differentiating them into Th9 cells, also induces higher IL-9 expression at the mRNA and protein levels in RUNX1-depleted Th9 cells compared to control scrambled siRNA-nucleofected Th9 cells. In the HDM murine allergy model, cblb-deficient mice have a higher lung inflammation as mirrored by increased eosinophils in the BAL and in the lungs, as well as by increased IgE production in the blood. These are also paralleled by an increased IL-9 expression level in the lungs of the allergic cblb -deficient mice. Conclusions: Cbl-b critically limits Th9 differentiation and may thus be a potential target to modify Th9 cell generation in allergy or cancer. Future studies will validate the molecular link that exists between Cbl-b and the RUNX1-dependent IL-9 expression as well as the in vivo significance of increased Th9 cell differentiation in cblb-deficient animal models of lung inflammation and cancer. Disclosures No relevant conflicts of interest to declare.
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Molinar-Rode, R., R. J. Smeyne, T. Curran, and J. I. Morgan. "Regulation of proto-oncogene expression in adult and developing lungs." Molecular and Cellular Biology 13, no. 6 (June 1993): 3213–20. http://dx.doi.org/10.1128/mcb.13.6.3213-3220.1993.
Повний текст джерелаАнотація:
Activation of immediate-early gene expression has been associated with mitogenesis, differentiation, nerve cell depolarization, and recently, terminal differentiation processes and programmed cell death. Previous evidence also suggested that immediate-early genes play a role in the physiology of the lungs (J. I. Morgan, D. R. Cohen, J. L. Hempstead, and T. Curran, Science 237:192-197, 1987). Therefore, we analyzed c-fos expression in adult and developing lung tissues. Seizures elicited by chemoconvulsants induced expression of mRNA for c-fos, c-jun, and junB and Fos-like immunoreactivity in lung tissue. The use of pharmacological antagonists and adrenalectomy indicated that this increased expression was neurogenic. Interestingly, by using a fos-lacZ transgenic mouse, it was shown that Fos-LacZ expression in response to seizure occurred preferentially in clusters of epithelial cells at the poles of the bronchioles. This was the same location of Fos-LacZ expression detected during early lung development. These data imply that pharmacological induction of immediate-early gene expression in adult mice recapitulates an embryological program of gene expression.
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Molinar-Rode, R., R. J. Smeyne, T. Curran, and J. I. Morgan. "Regulation of proto-oncogene expression in adult and developing lungs." Molecular and Cellular Biology 13, no. 6 (June 1993): 3213–20. http://dx.doi.org/10.1128/mcb.13.6.3213.
Повний текст джерелаАнотація:
Activation of immediate-early gene expression has been associated with mitogenesis, differentiation, nerve cell depolarization, and recently, terminal differentiation processes and programmed cell death. Previous evidence also suggested that immediate-early genes play a role in the physiology of the lungs (J. I. Morgan, D. R. Cohen, J. L. Hempstead, and T. Curran, Science 237:192-197, 1987). Therefore, we analyzed c-fos expression in adult and developing lung tissues. Seizures elicited by chemoconvulsants induced expression of mRNA for c-fos, c-jun, and junB and Fos-like immunoreactivity in lung tissue. The use of pharmacological antagonists and adrenalectomy indicated that this increased expression was neurogenic. Interestingly, by using a fos-lacZ transgenic mouse, it was shown that Fos-LacZ expression in response to seizure occurred preferentially in clusters of epithelial cells at the poles of the bronchioles. This was the same location of Fos-LacZ expression detected during early lung development. These data imply that pharmacological induction of immediate-early gene expression in adult mice recapitulates an embryological program of gene expression.
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Dovat, Sinisa, Kirk A. Gilbert, Lidija Petrovic-Dovat, and D. Eugene Rannels. "Targeted identification of zinc finger genes expressed in rat lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 275, no. 1 (July 1, 1998): L30—L37. http://dx.doi.org/10.1152/ajplung.1998.275.1.l30.
Повний текст джерелаАнотація:
Control of alveolar cell growth and differentiation after pneumonectomy likely involves changes in expression of regulatory genes, including those encoding zinc finger (ZF) proteins. To explore this premise, total RNA from the lungs of control and pneumonectomized rats was reverse transcribed; PCRs were performed with degenerate primers corresponding to amino acid sequences HTGEKP and CPECGK(N), which are evolutionarily conserved among ZF genes. Reaction products corresponding to three and four ZF units were isolated and cloned. Sixteen clones were sequenced and found to represent rat lung ZF genes: six clones were highly similar or identical to known ZF genes and ten clones showed lower homology to known ZF genes and thus appear to represent new members of the ZF family. Northern analysis demonstrated differential expression of some ZF genes after pneumonectomy. Thus a PCR-based strategy with primers derived from evolutionarily conserved ZF protein sequences efficiently identifies ZF genes expressed in lung, some of which may play a role in cellular growth and differentiation.
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Archavachotikul, Kwanchai, Teriggi J. Ciccone, Mala R. Chinoy, Heber C. Nielsen, and Maryann V. Volpe. "Thyroid hormone affects embryonic mouse lung branching morphogenesis and cellular differentiation." American Journal of Physiology-Lung Cellular and Molecular Physiology 282, no. 3 (March 1, 2002): L359—L369. http://dx.doi.org/10.1152/ajplung.00400.2000.
Повний текст джерелаАнотація:
Although thyroid hormone (T3) influences epithelial cell differentiation during late fetal lung development, its effects on early lung morphogenesis are unknown. We hypothesized that T3 would alter embryonic lung airway branching and temporal-spatial differentiation of the lung epithelium and mesenchyme. Gestational day 11.5 embryonic mouse lungs were cultured for 72 h in BGJb serum-free medium without or with added T3 (0.2, 2.0, 10.0, or 100 nM). Evaluation of terminal bud counts showed a dose- and time-dependent decrease in branching morphogenesis. Cell proliferation was also significantly decreased with higher doses of T3. Morphometric analysis of lung histology showed that T3 caused a dose-dependent decrease in mesenchyme and increase in cuboidal epithelia and airway space. Immunocytochemistry showed that with T3 treatment, Nkx2.1 and surfactant protein SP-C proteins became progressively localized to cuboidal epithelial cells and mesenchymal expression of Hoxb5 was reduced, a pattern resembling late fetal lung development. We conclude that exogenous T3 treatment during early lung development accelerated epithelial and mesenchymal cell differentiation at the expense of premature reduction in new branch formation and lung growth.
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Lanzke, Nadine, Mario Menk, Clarissa von Haefen, Lilit Sargsyan, Bianca Scharf, Klaus-Dieter Wernecke, and Claudia D. Spies. "Ethanol-Induced Alterations of T Cells and Cytokines after Surgery in a Murine Infection Model." International Journal of Inflammation 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/1067598.
Повний текст джерелаАнотація:
Background. Interactions between alcohol, infection, and surgery and their effect on differentiation and functionality of T helper cells are not yet completely understood. We hypothesized that alcohol and surgery disturb differentiation of T helper cells and contribute to an impaired immune response.Methods. Mice were treated with alcohol for two weeks. Saline treatment served as control. Clinical performance and weight were assessed. On day 14, a median laparotomy was performed and animals were challenged withKlebsiella pneumoniaeintranasally. Bacterial load was determined in lungs and blood. T helper cell subpopulations and the released cytokines were assessed in lungs, spleens, and plasma. Key transcription factors of T cell differentiation were evaluated.Results. Alcohol significantly impaired clinical appearance and body weight of animals with postsurgical infection(p<0.05). Bacterial load was significantly higher after alcohol treatment(p<0.05). T helper cell subsets and released cytokine levels were significantly altered in lung, but not in spleen. Expression of transcription factors of T helper cell lineage commitment did not translate into different counts of T helper cells.Conclusions. Alcohol and surgery lead to significant cellular and functional modulations of T helper cells during postsurgical infection. These effects may contribute to an impaired immune response after surgery.
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Beal, Allison, Hilda Ramon, George Worthen, and Paula Oliver. "The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines (175.11)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 175.11. http://dx.doi.org/10.4049/jimmunol.188.supp.175.11.
Повний текст джерелаАнотація:
Abstract Ndfip1 is an adaptor that promotes polyubiquitylation by the E3 ubiquitin ligase Itch. Mice that lack either Ndfip1 or Itch develop a severe TH2-mediated inflammatory disease at sites of environmental antigen exposure, including the lung. Here we demonstrate that lungs from Ndfip1-/- mice showed increased numbers of neutrophils and TH17 cells. This was not because Ndfip1-/- T cells are intrinsically biased towards TH17 differentiation. In fact, fewer Ndfip1-/- T cells differentiated into TH17 cells in vitro due to the overproduction of IL-4 production. Rather, TH17 differentiation in vivo was increased in Ndfip1-/- mice due to elevated numbers of IL-6 producing eosinophils. Interestingly, mice lacking both Ndfip1 and IL-4 had levels of IL-6 comparable to WT controls and these Ndfip1-/- IL-4-/- mice had fewer TH17 cells in their lungs compared to Ndfip1-/- IL-4+/+ mice. These results indicate that TH2 inflammation, such as that observed in Ndfip1-/- mice, can increase TH17 differentiation by recruiting IL-6 producing eosinophils into secondary lymphoid organs and tissues. This may explain why TH17 cells develop within an ongoing TH2 inflammatory response, such as asthma.
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Bellusci, S., R. Henderson, G. Winnier, T. Oikawa, and B. L. Hogan. "Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis." Development 122, no. 6 (June 1, 1996): 1693–702. http://dx.doi.org/10.1242/dev.122.6.1693.
Повний текст джерелаАнотація:
Epithelial-mesenchymal interactions are critical for the branching and differentiation of the lung, but the mechanisms involved are still unclear. To investigate this problem in mouse embryonic lung, we have studied the temporal and spatial expression of genes implicated in the morphogenesis of other organs. At 11.5 days p.c., hepatocyte nuclear factor-3beta (Hnf-3beta) is expressed uniformly throughout the epithelium, while Wnt-2 expression is confined to the distal mesenchyme. Sonic hedgehog (Shh) transcripts are found throughout the epithelium, with high levels in the distal tips of the terminal buds, while bone morphogenetic protein-4 (Bmp-4) transcripts are localized at high levels in the distal tips of the epithelium, with lower levels in the adjacent mesenchyme. Epithelial expression is also seen for Bmp-7, but transcripts are less dramatically upregulated at the distal tips. The Type I Bone morphogenetic protein receptor gene (Bmpr/Tfr-11/Brk-1) is expressed at low levels in the epithelium and in the distal mesenchyme. To investigate the role of Bmp-4 in lung development, we have misexpressed the gene throughout the distal epithelium of transgenic lungs using a surfactant protein C enhancer/promoter. From 15.5 days p.c., transgenic lungs are smaller than normal, with grossly distended terminal buds and, at birth, contain large air-filled sacs which do not support normal lung function. Labeling with BrdU reveals an inhibition of epithelia] proliferation in 15.5 days p.c. transgenic lungs. A small but significant stimulation of proliferation of mesenchymal cells is also observed, but this is accompanied by an increase in cell death. In situ hybridization with riboprobes for the proximal airway marker, CC10, and the distal airway marker, SP-C, shows normal differentiation of bronchiolar Clara cells but a reduction in the number of differentiated Type II cells in transgenic lungs. A model is proposed for the role of BMP4 and other signalling molecules in embryonic lung morphogenesis.
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Chang, Liming, Meihua Zhang, Qiheng Chen, Jiongyu Liu, Wei Zhu, and Jianping Jiang. "From Water to Land: The Structural Construction and Molecular Switches in Lungs during Metamorphosis of Microhyla fissipes." Biology 11, no. 4 (March 30, 2022): 528. http://dx.doi.org/10.3390/biology11040528.
Повний текст джерелаАнотація:
Most anurans must undergo metamorphosis to adapt to terrestrial life. This process enhances the air-breathing ability of the lungs to cope with the change in oxygen medium from water to air. Revealing the structural construction and molecular switches of lung organogenesis is essential to understanding the realization of the air-breathing function. In this study, histology and transcriptomics were conducted in combination to explore these issues in Microhyla fissipes’ lungs during metamorphosis. During the pro-metamorphic phase, histological structural improvement of the alveolar wall is accompanied by robust substrate metabolism and protein turnover. The lungs, at the metamorphic climax phase, are characterized by an increased number of cilia in the alveolar epithelial cells and collagenous fibers in the connective tissues, corresponding to the transcriptional upregulation of cilia and extracellular matrix-related genes. Post-metamorphic lungs strengthen their contracting function, as suggested by the thickened muscle layer and the upregulated expression of genes involved in muscle contraction. The blood–gas barrier is fully developed in adult lungs, the transcriptional features of which are tissue growth and regulation of differentiation and immunity. Importantly, significant transcriptional switches of pulmonary surfactant protein and hemoglobin facilitate air breathing. Our results illuminated four key steps of lung development for amphibians to transition from water to land.
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Anis, Mursalin M., Scott A. Fulton, Scott M. Reba, Clifford V. Harding, and W. Henry Boom. "Modulation of Naive CD4+ T-Cell Responses to an Airway Antigen during Pulmonary Mycobacterial Infection." Infection and Immunity 75, no. 5 (February 12, 2007): 2260–68. http://dx.doi.org/10.1128/iai.01709-06.
Повний текст джерелаАнотація:
ABSTRACT During pulmonary mycobacterial infection, there is increased trafficking of dendritic cells from the lungs to the draining lymph nodes. We hypothesized that ongoing mycobacterial infection would modulate recruitment and activation of antigen-specific naive CD4+ T cells after airway antigen challenge. BALB/c mice were infected by aerosol with Mycobacterium bovis BCG. At peak bacterial burden in the lungs (4 to 6 weeks postinfection), carboxy-fluorescein diacetate succinimidyl ester-labeled naive ovalbumin-specific DO11.10 T cells were adoptively transferred into infected and uninfected mice. Recipient mice were challenged intranasally with soluble ovalbumin (OVA), and OVA-specific T-cell responses were measured in the lungs, draining mediastinal lymph nodes (MLN), and spleens. OVA challenge resulted in increased activation and proliferation of OVA-specific T cells in the draining MLN of both infected and uninfected mice. However, only BCG-infected mice had prominent OVA-specific T-cell activation, proliferation, and Th1 differentiation in the lungs. BCG infection caused greater distribution of airway OVA to pulmonary dendritic cells and enhanced presentation of OVA peptide by lung CD11c+ cells. Together, these data suggest that an existing pulmonary mycobacterial infection alters the phenotype of lung dendritic cells so that they can activate antigen-specific naive CD4+ T cells in the lungs in response to airway antigen challenge.
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Vuckovic, Aline, Susanne Herber-Jonat, Andreas W. Flemmer, Ina M. Ruehl, Carmela Votino, Valérie Segers, Alexandra Benachi та ін. "Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?" American Journal of Physiology-Lung Cellular and Molecular Physiology 310, № 4 (15 лютого 2016): L311—L327. http://dx.doi.org/10.1152/ajplung.00122.2015.
Повний текст джерелаАнотація:
Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined.
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Enomoto, Yasunori, Sayomi Matsushima, Kiyoshi Shibata, Yoichiro Aoshima, Haruna Yagi, Shiori Meguro, Hideya Kawasaki, et al. "LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis." Clinical Science 132, no. 14 (July 31, 2018): 1565–80. http://dx.doi.org/10.1042/cs20180435.
Повний текст джерелаАнотація:
Although differentiation of lung fibroblasts into α-smooth muscle actin (αSMA)-positive myofibroblasts is important in the progression of idiopathic pulmonary fibrosis (IPF), few biomarkers reflecting the fibrotic process have been discovered. We performed microarray analyses between FACS-sorted steady-state fibroblasts (lineage (CD45, TER-119, CD324, CD31, LYVE-1, and CD146)-negative and PDGFRα-positive cells) from untreated mouse lungs and myofibroblasts (lineage-negative, Sca-1-negative, and CD49e-positive cells) from bleomycin-treated mouse lungs. Amongst several genes up-regulated in the FACS-sorted myofibroblasts, we focussed on Ltbp2, the gene encoding latent transforming growth factor-β (TGF-β) binding protein-2 (LTBP2), because of the signal similarity to Acta2, which encodes αSMA, in the clustering analysis. The up-regulation was reproduced at the mRNA and protein levels in human lung myofibroblasts induced by TGF-β1. LTBP2 staining in IPF lungs was broadly positive in the fibrotic interstitium, mainly as an extracellular matrix (ECM) protein; however, some of the αSMA-positive myofibroblasts were also stained. Serum LTBP2 concentrations, evaluated using ELISA, in IPF patients were significantly higher than those in healthy volunteers (mean: 21.4 compared with 12.4 ng/ml) and showed a negative correlation with % predicted forced vital capacity (r = −0.369). The Cox hazard model demonstrated that serum LTBP2 could predict the prognosis of IPF patients (hazard ratio for death by respiratory events: 1.040, 95% confidence interval: 1.026–1.054), which was validated using the bootstrap method with 1000-fold replication. LTBP2 is a potential prognostic blood biomarker that may reflect the level of differentiation of lung fibroblasts into myofibroblasts in IPF.
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Piairo, Paulina, Rute S. Moura, Maria João Baptista, Jorge Correia-Pinto, and Cristina Nogueira-Silva. "STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia." Cellular Physiology and Biochemistry 45, no. 1 (December 22, 2017): 1–14. http://dx.doi.org/10.1159/000486218.
Повний текст джерелаАнотація:
Background: Congenital diaphragmatic hernia (CDH) is a life-threatening developmental anomaly, intrinsically combining severe pulmonary hypoplasia and hypertension. During development, signal transducers and activators of transcription (STAT) are utilized to elicit cell growth, differentiation, and survival. Methods: We used the nitrofen-induced CDH rat model. At selected gestational time points, lungs were divided into two experimental groups, i.e., control or CDH. We performed immunohistochemistry and western blotting analysis to investigate the developmental expression profile of the complete family of STATs (STAT1-6), plus specific STATs activation (p-STAT3, p-STAT6) and regulation by SOCS (SOCS3) in normal lungs against those of diseased lungs. The normal fetal lung explants were treated with piceatannol (STAT3 inhibitor) in vitro followed by morphometrical analysis. Results: Molecular profiling of STATs during the lung development revealed distinct early and late expression signatures. Experimental CDH altered the STATs expression, activation, and regulation in the fetal lungs. In particular, STAT3 and STAT6 were persistently over-expressed and early over-activated. Piceatannol treatment dose-dependently stimulated the fetal lung growth. Conclusion: These findings suggest that STATs play an important role during normal fetal lung development and CDH pathogenesis. Moreover, functionally targeting STAT signaling modulates fetal lung growth, which highlights that STAT3 and STAT6 signaling might be promising therapeutic targets in reducing or preventing pulmonary hypoplasia in CDH.
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Meneghetti, A., W. V. Cardoso, J. S. Brody, and M. C. Williams. "Epithelial marker genes are expressed in cultured embryonic rat lung and in vivo with similar spatial and temporal patterns." Journal of Histochemistry & Cytochemistry 44, no. 10 (October 1996): 1173–82. http://dx.doi.org/10.1177/44.10.8813083.
Повний текст джерелаАнотація:
Explants of embryonic lung are often used to characterize lung growth, bronchial tree pattern, and cell differentiation. Most investigators culture lungs for 3-7 days in defined media lacking, e.g., added growth factors or hormones. If growth and differentiation are comparable to that in vivo, these cultures show considerable promise for identifying developmental regulatory molecules and target genes, and for elucidating molecular responses. We used in situ hybridization and RT-PCR to compare times and sites of expression of mRNAs of six epithelial genes in cultured and uncultured fetal rat lungs. These genes, expressed in distal lung of adult rats, are surfactant proteins (SP) A, B, and C; LAR, a receptor-type tyrosine phosphatase; Clara cell secretory protein (CC10, CCSP); and T1alpha. SP-A, SF-B, LAR, and CC10 are expressed by both Clara and Type II cells in adult animals. SP-C and T1alpha are unique markers for Type II and Type I cells, respectively. SP-C, LAR, and T1alpha are expressed before the lung is explanted (Day 13.5); SP-A, -B, and CC10 mRNAs are first detected later. The onset of expression is similar in vivo and in vitro. Although the patterns of expression differ for each mRNA, their sites of expression in culture match those in vivo relative to the bronchial tree. The explanted embryonic lung appears to be an excellent experimental model.
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Coleman, C., J. Zhao, M. Gupta, S. Buckley, J. D. Tefft, C. W. Wuenschell, P. Minoo, K. D. Anderson, and D. Warburton. "Inhibition of vascular and epithelial differentiation in murine nitrofen-induced diaphragmatic hernia." American Journal of Physiology-Lung Cellular and Molecular Physiology 274, no. 4 (April 1, 1998): L636—L646. http://dx.doi.org/10.1152/ajplung.1998.274.4.l636.
Повний текст джерелаАнотація:
Neonates with congenital diaphragmatic hernia (DH) die of pulmonary hypoplasia and persistent pulmonary hypertension. We used immunohistochemical localization of α-smooth muscle actin (α-SMA), platelet endothelial cell adhesion molecule (PECAM)-1, thyroid transcription factor (TTF)-1, surfactant protein (SP) A, SP-C, and competitive RT-PCR quantitation of TTF-1, SP-A, SP-C, and α-SMA mRNA expression to characterize the epithelial and vascular phenotype of lungs from ICR fetal mice with a nitrofen-induced DH. Nitrofen (25 mg) was gavage fed to pregnant mice on day 8 of gestation. Fetal mice were delivered on day 17. The diaphragm was examined for a defect, and the lungs were either fixed, sectioned, and immunostained or processed for mRNA isolation. In comparison with control lungs, DH lungs showed increased expression of α-SMA mRNA, fewer and more muscular arterioles (α-SMA), less well-developed capillary networks (PECAM-1), delayed epithelial development marked by a persistence of TTF-1 in the periphery, and decreased SP-A mRNA and SP-A expression. These data suggest that in the murine nitrofen-induced DH, as in human congenital DH, pulmonary insufficiency is due to an inhibition of peripheral pulmonary development including terminal airway and vascular morphogenesis.
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Song, MeiJuan, Qi Lv, XiuWei Zhang, Juan Cao, ShuLi Sun, PeiXin Xiao, ShiKe Hou, et al. "Dynamic Tracking Human Mesenchymal Stem Cells Tropism following Smoke Inhalation Injury in NOD/SCID Mice." Stem Cells International 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/1691856.
Повний текст джерелаАнотація:
Multiple preclinical evidences have supported the potential value of mesenchymal stem cells (MSCs) for treatment of acute lung injury (ALI). However, few studies focus on the dynamic tropism of MSCs in animals with acute lung injury. In this study, we track systemically transplanted human bone marrow-derived mesenchymal stem cells (hBMSCs) in NOD/SCID mice with smoke inhalation injury (SII) through bioluminescence imaging (BLI). The results showed that hBMSCs systemically delivered into healthy NOD/SCID mouse initially reside in the lungs and then partially translocate to the abdomen after 24 h. Compared with the uninjured control group treated with hBMSCs, higher numbers of hBMSCs were found in the lungs of the SII NOD/SCID mice. In both the uninjured and SII mice, the BLI signals in the lungs steadily decreased over time and disappeared by 5 days after treatment. hBMSCs significantly attenuated lung injury, elevated the levels of KGF, decreased the levels of TNF-αin BALF, and inhibited inflammatory cell infiltration in the mice with SII. In conclusion, our findings demonstrated that more systemically infused hBMSCs localized to the lungs in mice with SII. hBMSC xenografts repaired smoke inhalation-induced lung injury in mice. This repair was maybe due to the effect of anti-inflammatory and secreting KGF of hMSCs but not associated with the differentiation of the hBMSCs into alveolar epithelial cells.
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Chapoval, Svetlana P., Ann E. Kelly-Welch, Elizabeth Smith, and Achsah D. Keegan. "Complex role of STAT6 in allergic airway inflammation (39.11)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S27. http://dx.doi.org/10.4049/jimmunol.178.supp.39.11.
Повний текст джерелаАнотація:
Abstract STAT6 plays a critical role in Th2 cell differentiation and in allergic lung inflammation. Using a chimeric mouse model, we observed alternative lung pathology in STAT6 KO mice even when WT bone marrow or Th2 cells were provided. Thus, we hypothesized that STAT6 contributes to inflammation in a complex manner. To detail STAT6 function, WT and STAT6 KO mice were subjected to OVA priming and challenges. Broncho-alveolar lavage (BAL) cell composition, lung histology, and FACS analysis of digested lungs were assessed 48h after the last challenge. As expected, eosinophils composed a majority of BAL cells in WT mice and less than 2% in STAT6 KO mice. The OVA-induced inflammation in STAT6 KO lungs was composed mainly of macrophages with small fractions of neutrophils and lymphocytes. The OVA-treated WT lungs showed strong although divergent expression of F4/80, Mac-2, and CD11b molecules; this was significantly reduced in STAT6 KO mice. However, the numbers of dendritic cells, B cells, CD4+ and CD8+ T cells in the lungs of OVA-treated mice were unaffected by STAT6 deficiency. Interestingly, STAT6 KO mice showed enhanced basal airway reactivity to methacholine and numbers of Mac-2+ cells as compared to WT mice, suggesting that STAT6 deficiency altered lung homeostasis. Taken together, our studies demonstrate STAT6-dependent and –independent features of asthma phenotype which may impact treatments targeting STAT6. (AI38985)
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Das, Sushant Kumar, Dong Jun Yang, Jin Liang Wang, Chuan Zhang, and Han Feng Yang. "Non-Gaussian diffusion imaging for malignant and benign pulmonary nodule differentiation: a preliminary study." Acta Radiologica 58, no. 1 (July 19, 2016): 19–26. http://dx.doi.org/10.1177/0284185116639763.
Повний текст джерелаАнотація:
Background Diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) has demonstrated inconsistent results in pulmonary nodule differentiation. Diffusion kurtosis imaging (DKI), which quantifies non-Gaussian diffusion, is believed to better characterize tissue micro-structure than conventional DWI. Purpose To assess the feasibility of DKI in human lungs and to compare its diagnostic value with standard DWI in differentiating malignancies from benign pulmonary nodules. Material and Methods Thirty-five pulmonary nodules in 32 consecutive patients were evaluated by DKI by using 3b-values of 0, 500, and 1000 s/mm2 and conventional DWI with b values of 0 and 800 s/mm2. Two observers independently evaluated and compared diagnostic accuracy of mean kurtosis (MK) and ADC values in differentiating malignancies from benign pulmonary nodules. The intra- and inter-observer repeatability (intra-class correlation coefficient [ICC]) were also assessed for each derived measures. Results The diagnostic accuracy, and the area under curve (AUC) in differentiating malignancies from benign pulmonary nodule, were not significantly higher for MK (Obs. 1a: 85.70%, 0.87; Obs. 1b: 80.00%, 0.80; and Obs. 2: 82.80%, 0.91) as compared to ADC (Obs. 1a: 77.14%, 0.81; Obs. 1b: 80.00%, 0.85; and Obs. 2: 77.14%, 0.85 respectively). The intra- and inter-observer agreement (ICC) for malignant and benign lesions was substantial for each reading. Conclusion The initial results of this study indicate the feasibility of DKI in human lungs. However, there was no significant benefit of DKI derived MK values over ADC for malignant and benign pulmonary nodule differentiation.
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Shan, Lin, Jon C. Aster, Jeffrey Sklar, and Mary E. Sunday. "Notch-1 regulates pulmonary neuroendocrine cell differentiation in cell lines and in transgenic mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 2 (February 2007): L500—L509. http://dx.doi.org/10.1152/ajplung.00052.2006.
Повний текст джерелаАнотація:
The notch gene family encodes transmembrane receptors that regulate cell differentiation by interacting with surface ligands on adjacent cells. Previously, we demonstrated that tumor necrosis factor-α (TNF) induces neuroendocrine (NE) cell differentiation in H82, but not H526, undifferentiated small cell lung carcinoma lines. We now test the hypothesis that TNF mediates NE cell differentiation in part by altering Notch gene expression. First, using RT-PCR, we determined that TNF treatment of H82, but not H526, transiently decreases notch-1 mRNA in parallel with induction of gene expression for the NE-specific marker DOPA decarboxylase (DDC). Second, we treated H82 and H526 with notch-1 antisense vs. sense oligodeoxynucleotides. Using quantitative RT-PCR and Western analyses we demonstrate that DDC mRNA and protein are increased in H82 by notch-1 antisense, whereas notch-1 mRNA and activated Notch-1 protein are decreased. mRNA for Hes1, a transcription factor downstream from activated Notch, is also decreased by Notch-1 antisense in H82 but not H526. After 7 days of Notch-1 antisense treatment, neural cell adhesion molecule (NCAM) immunoreactivity is induced in H82 but not H526. Third, we generated transgenic mice bearing notch-1 driven by the neural/NE-specific calcitonin promoter, which express activated Notch-1 in developing lung epithelium. Newborn NotchCal mouse lungs have high levels of hes1 mRNA, reflecting increased activated Notch, compared with wild-type. NotchCal lungs have decreased CGRP-positive NE cells, decreased protein gene product 9.5 (PGP9.5)-positive NE cells, and decreased gastrin-releasing peptide (GRP), CGRP, and DDC mRNA levels compared with normal littermates. Cumulatively, these observations provide further support for a role for Notch-1 signaling in regulating pulmonary NE cell differentiation.
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Shan, Ming, Han-Fang Cheng, David Corry, and Farrah Kheradmand. "Lung antigen presenting cells in human emphysema (93.21)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 93.21. http://dx.doi.org/10.4049/jimmunol.184.supp.93.21.
Повний текст джерелаАнотація:
Abstract Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.
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Yoo, Jae-Kwang, Eleanor Fish, and Thomas Braciale. "A novel mechanism regulating anti-viral humoral response: interplay between IL-21, LAPC and TFH in anti-IAV humoral response. (P6174)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 189.2. http://dx.doi.org/10.4049/jimmunol.190.supp.189.2.
Повний текст джерелаАнотація:
Abstract The humoral immune response to most respiratory virus infections plays a prominent role in virus clearance and is essential for resistance to reinfection. T follicular helper (TFH) cells are believed to support the development both of a potent primary antibody response and of the germinal center response critical for memory B cell development. Using a model of primary murine influenza A virus (IAV) infection, we demonstrate that a novel APC, the LAPC (Late-activator APC), promotes the TFH response in the draining LNs (dLNs) of the IAV-infected lungs. LAPCs migrate from the infected lungs to the dLN “late,” i.e., 6 d after infection, which is concomitant with TFH differentiation. LAPC migration is CXCR3-CXCL9-dependent, and LAPC triggering of TFH cell development requires ICOS-ICOSL-dependent signaling. In IAV infection, the host immune system control this LAPC-mediated TFH differentiation via IL-21.We have demonstrated that IL-21, a well known TFH differentiation inducing factor, produced by NK T-cells in the dLN acts on lymph node resident T cells to stimulate TNF-α release by the T-cells. TNF-α in turn stimulates dLN resident dendritic cells to secrete CXCL9, a potent chemotactic stimulus for migration of CXCR3 expressing lung resident LAPC into the dLN. It is then the migrant LAPC which acts to modulate TFH differentiation during respiratory viral infection. Our results reveal a novel and previously unsuspected mechanism for regulating anti-viral TFH and humoral responses.
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Yang, Guang, Maurice D. Hinson, Jessica E. Bordner, Qing S. Lin, Amal P. Fernando, Ping La, Clyde J. Wright та Phyllis A. Dennery. "Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells". American Journal of Physiology-Lung Cellular and Molecular Physiology 301, № 2 (серпень 2011): L187—L196. http://dx.doi.org/10.1152/ajplung.00082.2011.
Повний текст джерелаАнотація:
Postnatal lung development requires proliferation and differentiation of specific cell types at precise times to promote proper alveolar formation. Hyperoxic exposure can disrupt alveolarization by inhibiting cell growth; however, it is not fully understood how this is mediated. The transcription factor CCAAT/enhancer binding protein-α (C/EBPα) is highly expressed in the lung and plays a role in cell proliferation and differentiation in many tissues. After 72 h of hyperoxia, C/EBPα expression was significantly enhanced in the lungs of newborn mice. The increased C/EBPα protein was predominantly located in alveolar type II cells. Silencing of C/EBPα with a transpulmonary injection of C/EBPα small interfering RNA (siRNA) prior to hyperoxic exposure reduced expression of markers of type I cell and differentiation typically observed after hyperoxia but did not rescue the altered lung morphology at 72 h. Nevertheless, when C/EBPα hyperoxia-exposed siRNA-injected mice were allowed to recover for 2 wk in room air, lung epithelial cell proliferation was increased and lung morphology was restored compared with hyperoxia-exposed control siRNA-injected mice. These data suggest that C/EBPα is an important regulator of postnatal alveolar epithelial cell proliferation and differentiation during injury and repair.
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Rotin, D., B. J. Goldstein, and C. A. Fladd. "Expression of the tyrosine phosphatase LAR-PTP2 is developmentally regulated in lung epithelia." American Journal of Physiology-Lung Cellular and Molecular Physiology 267, no. 3 (September 1, 1994): L263—L270. http://dx.doi.org/10.1152/ajplung.1994.267.3.l263.
Повний текст джерелаАнотація:
The role of tyrosine kinases in regulating cell proliferation, differentiation, and development has been well documented. In contrast, little is known about the role of protein tyrosine phosphatases (PTPs) in mammalian development. To identify PTPs that may be involved in lung development, we have isolated (by polymerase chain reaction) from rat fetal alveolar epithelial cells a cDNA fragment which was identified as the recently cloned tyrosine phosphatase LAR-PTP2. Analysis of tissue expression of LAR-PTP2 identified a approximately 7.5-kb message in the lung, which is also expressed weakly in brain, and an alternatively spliced approximately 6.0-kb message (LAR-PTP2B) expressed in brain. In the fetal lung, LAR-PTP2 was preferentially expressed in lung epithelial (but not fibroblast) cells grown briefly in primary culture, and its expression was tightly regulated during lung development, peaking at 20 days of gestational age (term = 22 days), when mature alveolar type II epithelium first appears. Accordingly, immunoblot analysis revealed high expression of endogenous LAR-PTP2 protein in alveolar epithelial cells from 21-day gestation fetuses. LAR-PTP2 was also expressed in lungs of newborn rats, but transcripts (and protein) were barely detectable in adult lungs and in the nonproliferating adult alveolar type II cells. Interestingly, expression was restored in the transformed adult type II-like A549 cells. These results suggest that LAR-PTP2 may play a role in the proliferation and/or differentiation of epithelial cells during lung development.
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Liu, Yuru, Ruxana T. Sadikot, Guy R. Adami, Vladimir V. Kalinichenko, Srikanth Pendyala, Viswanathan Natarajan, You-yang Zhao, and Asrar B. Malik. "FoxM1 mediates the progenitor function of type II epithelial cells in repairing alveolar injury induced by Pseudomonas aeruginosa." Journal of Experimental Medicine 208, no. 7 (June 27, 2011): 1473–84. http://dx.doi.org/10.1084/jem.20102041.
Повний текст джерелаАнотація:
The alveolar epithelium is composed of the flat type I cells comprising 95% of the gas-exchange surface area and cuboidal type II cells comprising the rest. Type II cells are described as facultative progenitor cells based on their ability to proliferate and trans-differentiate into type I cells. In this study, we observed that pneumonia induced by intratracheal instillation of Pseudomonas aeruginosa (PA) in mice increased the expression of the forkhead transcription factor FoxM1 in type II cells coincidentally with the induction of alveolar epithelial barrier repair. FoxM1 was preferentially expressed in the Sca-1+ subpopulation of progenitor type II cells. In mice lacking FoxM1 specifically in type II cells, type II cells showed decreased proliferation and impaired trans-differentiation into type I cells. Lungs of these mice also displayed defective alveolar barrier repair after injury. Expression of FoxM1 in the knockout mouse lungs partially rescued the defective trans-differentiation phenotype. Thus, expression of FoxM1 in type II cells is essential for their proliferation and transition into type I cells and for restoring alveolar barrier homeostasis after PA-induced lung injury.
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Shrestha, Amrit Kumar, Matthew L. Bettini, Renuka T. Menon, Vashisht Y. N. Gopal, Shixia Huang, Dean P. Edwards, Mohan Pammi, Roberto Barrios, and Binoy Shivanna. "Consequences of early postnatal lipopolysaccharide exposure on developing lungs in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 1 (January 1, 2019): L229—L244. http://dx.doi.org/10.1152/ajplung.00560.2017.
Повний текст джерелаАнотація:
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infants that is characterized by interrupted lung development. Postnatal sepsis causes BPD, yet the contributory mechanisms are unclear. To address this gap, studies have used lipopolysaccharide (LPS) during the alveolar phase of lung development. However, the lungs of infants who develop BPD are still in the saccular phase of development, and the effects of LPS during this phase are poorly characterized. We hypothesized that chronic LPS exposure during the saccular phase disrupts lung development by mechanisms that promote inflammation and prevent optimal lung development and repair. Wild-type C57BL6J mice were intraperitoneally administered 3, 6, or 10 mg/kg of LPS or a vehicle once daily on postnatal days (PNDs) 3–5. The lungs were collected for proteomic and genomic analyses and flow cytometric detection on PND6. The impact of LPS on lung development, cell proliferation, and apoptosis was determined on PND7. Finally, we determined differences in the LPS effects between the saccular and alveolar lungs. LPS decreased the survival and growth rate and lung development in a dose-dependent manner. These effects were associated with a decreased expression of proteins regulating cell proliferation and differentiation and increased expression of those mediating inflammation. While the lung macrophage population of LPS-treated mice increased, the T-regulatory cell population decreased. Furthermore, LPS-induced inflammatory and apoptotic response and interruption of cell proliferation and alveolarization was greater in alveolar than in saccular lungs. Collectively, the data support our hypothesis and reveal several potential therapeutic targets for sepsis-mediated BPD in infants.
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Zhao, Lihua, Meishuang Li, Zhibao Yin, Limin Lv, Meng Zhou, Yixi Wang, Manling Zhang, et al. "Development of a Lung Vacancy Mouse Model through CRISPR/Cas9-Mediated Deletion of Thyroid Transcription Factor 1 Exon 2." Cells 11, no. 23 (December 1, 2022): 3874. http://dx.doi.org/10.3390/cells11233874.
Повний текст джерелаАнотація:
A developmental niche vacancy in host embryos is necessary for stem cell complementation-based organ regeneration (SCOG). Thyroid transcription factor 1 (TTF-1) is a tissue-specific transcription factor that regulates the embryonic development and differentiation of the thyroid and, more importantly, lungs; thus, it has been considered as a master gene to knockout in order to develop a lung vacancy host. TTF-1 knockout mice were originally produced by inserting a stop codon in Exon 3 of the gene (E3stop) through embryonic stem cell-based homologous recombination. The main problems of utilizing E3stop host embryos for lung SCOG are that these animals all have a tracheoesophageal fistula (TEF), which cannot be corrected by donor stem cells, and most of them have monolateral sac-like lungs. To improve the mouse model towards achieving SCOG-based lung generation, in this project, we used the CRISPR/Cas9 tool to remove Exon 2 of the gene by zygote microinjection and successfully produced TTF-1 knockout (E2del) mice. Similar to E3stop, E2del mice are birth-lethal due to retarded lung development with sac-like lungs and only a rudimentary bronchial tree, increased basal cells but without alveolar type II cells and blood vessels, and abnormal thyroid development. Unlike E3stop, 57% of the E2del embryos presented type I tracheal agenesis (TA, a kind of human congenital malformation) with a shortened trachea and clear separations of the trachea and esophagus, while the remaining 43% had TEF. Furthermore, all the E2del mice had bilateral sac-like lungs. Both TA and bilateral sac-like lungs are preferred in SCOG. Our work presents a new strategy for producing SCOG host embryos that may be useful for lung regeneration.
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Cohen, Pazit Y., Raphael Breuer, Philip Zisman, and Shulamit B. Wallach-Dayan. "Bleomycin-Treated Chimeric Thy1-Deficient Mice with Thy1-Deficient Myofibroblasts and Thy-Positive Lymphocytes Resolve Inflammation without Affecting the Fibrotic Response." Mediators of Inflammation 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/942179.
Повний текст джерелаАнотація:
Lung fibrosis is characterized by abnormal accumulation of fibroblasts in the interstitium of the alveolar space. Two populations of myofibroblasts, distinguished by Thy1 expression, are detected in human and murine lungs. Accumulation of Thy1-negative (Thy1−) myofibroblasts was shown in the lungs of humans with idiopathic pulmonary fibrosis (IPF) and of bleomycin-treated mice. We aimed to identify genetic changes in lung myofibroblasts following Thy1 crosslinking and assess the impact of specific lung myofibroblast Thy1-deficiency, in vivo, in bleomycin-injured mouse lungs. Thy1 increased in mouse lung lymphocytes following bleomycin injury but decreased in myofibroblasts when fibrosis was at the highest point (14 days), as assessed by immunohistochemistry. Using gene chip analysis, we detected that myofibroblast Thy1 crosslinking mediates downregulation of genes promoting cell proliferation, survival, and differentiation, and reduces production of extracellular matrix (ECM) components, while concurrently mediating the upregulation of genes known to foster inflammation and immunological functions. Chimeric Thy1-deficient mice with Thy1+lymphocytes and Thy1−myofibroblasts showed fibrosis similar to wild-type mice and an increased number of CD4/CD25 regulatory T cells, with a concomitant decrease in inflammation. Lung myofibroblasts downregulate Thy1 expression to increase their proliferation but to diminish the in vivo inflammatory milieu. Inflammation is not essential for evolution of fibrosis as was previously stated.
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Clark, Jean C., Jay W. Tichelaar, Susan E. Wert, Nobuyuki Itoh, Anne-Karina T. Perl, Mildred T. Stahlman, and Jeffrey A. Whitsett. "FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo." American Journal of Physiology-Lung Cellular and Molecular Physiology 280, no. 4 (April 1, 2001): L705—L715. http://dx.doi.org/10.1152/ajplung.2001.280.4.l705.
Повний текст джерелаАнотація:
Transgenic mice in which fibroblast growth factor (FGF)-10 was expressed in the lungs of fetal and postnatal mice were generated with a doxycycline-inducible system controlled by surfactant protein (SP) C or Clara cell secretory protein (CCSP) promoter elements. Expression of FGF-10 mRNA in the fetal lung caused adenomatous malformations, perturbed branching morphogenesis, and caused respiratory failure at birth. When expressed after birth, FGF-10 caused multifocal pulmonary tumors. FGF-10-induced tumors were highly differentiated papillary and lepidic pulmonary adenomas. Epithelial cells lining the tumors stained intensely for thyroid transcription factor (TTF)-1 and SP-C but not CCSP, indicating that FGF-10 enhanced differentiation of cells to a peripheral alveolar type II cell phenotype. Withdrawal from doxycycline caused rapid regression of the tumors associated with rapid loss of the differentiation markers TTF-1, SP-B, and proSP-C. FGF-10 disrupted lung morphogenesis and induced multifocal pulmonary tumors in vivo and caused reversible type II cell differentiation of the respiratory epithelium.
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Colvin, Jennifer S., Andrew C. White, Stephen J. Pratt, and David M. Ornitz. "Lung hypoplasia and neonatal death inFgf9-null mice identify this gene as an essential regulator of lung mesenchyme." Development 128, no. 11 (June 1, 2001): 2095–106. http://dx.doi.org/10.1242/dev.128.11.2095.
Повний текст джерелаАнотація:
Mammalian lung develops as an evagination of ventral gut endoderm into the underlying mesenchyme. Iterative epithelial branching, regulated by the surrounding mesenchyme, generates an elaborate network of airways from the initial lung bud. Fibroblast growth factors (FGFs) often mediate epithelial-mesenchymal interactions and mesenchymal Fgf10 is essential for epithelial branching in the developing lung. However, no FGF has been shown to regulate lung mesenchyme. In embryonic lung, Fgf9 is detected in airway epithelium and visceral pleura at E10.5, but is restricted to the pleura by E12.5. We report that mice homozygous for a targeted disruption of Fgf9 exhibit lung hypoplasia and early postnatal death. Fgf9−/− lungs exhibit reduced mesenchyme and decreased branching of airways, but show significant distal airspace formation and pneumocyte differentiation. Our results suggest that Fgf9 affects lung size by stimulating mesenchymal proliferation. The reduction in the amount of mesenchyme in Fgf9−/− lungs limits expression of mesenchymal Fgf10. We suggest a model whereby FGF9 signaling from the epithelium and reciprocal FGF10 signaling from the mesenchyme coordinately regulate epithelial airway branching and organ size during lung embryogenesis.
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Wang, J., B. Campos, M. A. Kaetzel, and J. R. Dedman. "Expression of a calmodulin inhibitor peptide in progenitor alveolar type II cells disrupts lung development." American Journal of Physiology-Lung Cellular and Molecular Physiology 271, no. 2 (August 1, 1996): L245—L250. http://dx.doi.org/10.1152/ajplung.1996.271.2.l245.
Повний текст джерелаАнотація:
Calmodulin (CaM) is a major intracellular Ca2+ mediator protein involved in cell growth and differentiation. To evaluate calmodulin function in lung, it was necessary to construct a gene that encodes a high-affinity calmodulin binding peptide, since chemically synthesized calmodulin inhibitors lack binding and targeting specificity. This calmodulin inhibitor peptide gene was targeted to type II epithelial cells in transgenic mice using the human surfactant protein C promoter. Neutralization of calmodulin function in progenitor type II epithelial pneumocytes alters epithelial cell growth and differentiation, which prevents branching morphogenesis of the bronchial tree. Newborn transgenic animals have undeveloped lungs. This study indicates that type II lung epithelial cells require functional CaM for proliferation and development. The targeting of specific inhibitor peptides to a single lung cell type is an approach to evaluate the role of calmodulin, the ubiquitous calcium-dependent regulator protein, in lung development and disease.
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Vasilescu, Dragoş M., Christine Klinge, Lars Knudsen, Leilei Yin, Ge Wang, Ewald R. Weibel, Matthias Ochs, and Eric A. Hoffman. "Stereological assessment of mouse lung parenchyma via nondestructive, multiscale micro-CT imaging validated by light microscopic histology." Journal of Applied Physiology 114, no. 6 (March 15, 2013): 716–24. http://dx.doi.org/10.1152/japplphysiol.00855.2012.
Повний текст джерелаАнотація:
Quantitative assessment of the lung microstructure using standard stereological methods such as volume fractions of tissue, alveolar surface area, or number of alveoli, are essential for understanding the state of normal and diseased lung. These measures are traditionally obtained from histological sections of the lung tissue, a process that ultimately destroys the three-dimensional (3-D) anatomy of the tissue. In comparison, a novel X-ray-based imaging method that allows nondestructive sectioning and imaging of fixed lungs at multiple resolutions can overcome this limitation. Scanning of the whole lung at high resolution and subsequent regional sampling at ultrahigh resolution without physically dissecting the organ allows the application of design-based stereology for assessment of the whole lung structure. Here we validate multiple stereological estimates performed on micro–computed tomography (μCT) images by comparing them with those obtained via conventional histology on the same mouse lungs. We explore and discuss the potentials and limitations of the two approaches. Histological examination offers higher resolution and the qualitative differentiation of tissues by staining, but ultimately loses 3-D tissue relationships, whereas μCT allows for the integration of morphometric data with the spatial complexity of lung structure. However, μCT has limited resolution satisfactory for the sterological estimates presented in this study but not for differentiation of tissues. We conclude that introducing stereological methods in μCT studies adds value by providing quantitative information on internal structures while not curtailing more complex approaches to the study of lung architecture in the context of physiological or pathological studies.
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Ong, Tan, Ler, Gunaratne, Choi, Seet, and Chow. "Insights into Early Recovery from Influenza Pneumonia by Spatial and Temporal Quantification of Putative Lung Regenerating Cells and by Lung Proteomics." Cells 8, no. 9 (August 26, 2019): 975. http://dx.doi.org/10.3390/cells8090975.
Повний текст джерелаАнотація:
During influenza pneumonia, the alveolar epithelial cells of the lungs are targeted by the influenza virus. The distal airway stem cells (DASCs) and proliferating alveolar type II (AT2) cells are reported to be putative lung repair cells. However, their relative spatial and temporal distribution is still unknown during influenza-induced acute lung injury. Here, we investigated the distribution of these cells, and concurrently performed global proteomic analysis of the infected lungs to elucidate and link the cellular and molecular events during influenza pneumonia recovery. BALB/c mice were infected with a sub-lethal dose of influenza H1N1 virus. From 5 to 25 days post-infection (dpi), mouse lungs were subjected to histopathologic and immunofluorescence analysis to probe for global distribution of lung repair cells (using P63 and KRT5 markers for DASCs; SPC and PCNA markers for AT2 cells). At 7 and 15 dpi, infected mouse lungs were also subjected to protein mass spectrometry for relative protein quantification. DASCs appeared only in the damaged area of the lung from 7 dpi onwards, reaching a peak at 21 dpi, and persisted until 25 dpi. However, no differentiation of DASCs to AT2 cells was observed by 25 dpi. In contrast, AT2 cells began proliferating from 7 dpi to replenish their population, especially within the boundary area between damaged and undamaged areas of the infected lungs. Mass spectrometry and gene ontology analysis revealed prominent innate immune responses at 7 dpi, which shifted towards adaptive immune responses by 15 dpi. Hence, proliferating AT2 cells but not DASCs contribute to AT2 cell regeneration following transition from innate to adaptive immune responses during the early phase of recovery from influenza pneumonia up to 25 dpi.
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Popova, N. V., and L. Rossi. "Nitrosomethylurea disturbs differentiation of mouse embryonic lungs in organ cultures." Russian Journal of Developmental Biology 31, no. 3 (May 2000): 166–70. http://dx.doi.org/10.1007/bf02758821.
Повний текст джерела
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OBERT, MARTIN, STEFANIE HAGNER, GABRIELE A. KROMBACH, SELCUK INAN, and HARALD RENZ. "FRACTAL GEOMETRY ENABLES CLASSIFICATION OF DIFFERENT LUNG MORPHOLOGIES IN A MODEL OF EXPERIMENTAL ASTHMA." Fractals 23, no. 03 (July 31, 2015): 1550024. http://dx.doi.org/10.1142/s0218348x15500243.
Повний текст джерелаАнотація:
Animal models represent the basis of our current understanding of the pathophysiology of asthma and are of central importance in the preclinical development of drug therapies. The characterization of irregular lung shapes is a major issue in radiological imaging of mice in these models. The aim of this study was to find out whether differences in lung morphology can be described by fractal geometry. Healthy and asthmatic mouse groups, before and after an acute asthma attack induced by methacholine, were studied. In vivo flat-panel-based high-resolution Computed Tomography (CT) was used for mice's thorax imaging. The digital image data of the mice's lungs were segmented from the surrounding tissue. After that, the lungs were divided by image gray-level thresholds into two additional subsets. One subset contained basically the air transporting bronchial system. The other subset corresponds mainly to the blood vessel system. We estimated the fractal dimension of all sets of the different mouse groups using the mass radius relation (mrr). We found that the air transporting subset of the bronchial lung tissue enables a complete and significant differentiation between all four mouse groups (mean D of control mice before methacholine treatment: 2.64 ± 0.06; after treatment: 2.76 ± 0.03; asthma mice before methacholine treatment: 2.37 ± 0.16; after treatment: 2.71 ± 0.03; p < 0.05). We conclude that the concept of fractal geometry allows a well-defined, quantitative numerical and objective differentiation of lung shapes — applicable most likely also in human asthma diagnostics.