Journal articles on the topic 'Airway eosinophilia'
To see the other types of publications on this topic, follow the link: Airway eosinophilia.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Airway eosinophilia.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Johansson, Kristina Britt Charlotte, Carina Malmhäll, Patricia Ramos-Ramírez, and Madeleine Rådinger. "IL-33 elicits IL-5 dependent eosinophilia in vivo." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 194.8. http://dx.doi.org/10.4049/jimmunol.198.supp.194.8.
Full textAbstract:
Abstract Introduction Interleukin (IL)-33 plays important roles in the immunopathogenesis of allergy and asthma. It acts by promoting IL-5 and IL-13 secretion from IL-33 responsive type 2 innate lymphoid cells (ILC2s) or directly activates eosinophils and mast cells. IL-5 is crucial in eosinophilic inflammation by controlling differentiation and survival of eosinophils in the bone marrow as well as release and recruitment of eosinophils to the airways. While ILC2s have emerged as important producers of IL-5 in airways, the cellular source of IL-5 in the bone marrow is less explored. In this study we tested the hypothesis that IL-33 induced airway eosinophilia is an IL-5 dependent process in which ILC2s produce IL-5 locally in the bone marrow. Methods IL-5 production by bone marrow ILC2s was analyzed by intracellular flow cytometry in a murine model of IL-33 induced airway eosinophilia. Results Intranasal IL-33 administration resulted in eosinophil infiltration in airways and increased eosinophils in bone marrow. It was accompanied by a dramatic induction of eotaxin-2 in airways, indicating eosinophil recruitment to the tissue. IL-5+ ILC2s as well as expression of the IL-33 receptor on ILC2s increased in the bone marrow in response to IL-33 administration. Importantly, airway and bone marrow eosinophils were greatly reduced in mice pre-treated with anti-IL-5 antibodies followed by intranasal IL-33. Conclusion Our results demonstrate that IL-33 elicits IL-5 dependent eosinophilia in vivo, where ILC2s represent a local source of IL-5 in the bone marrow.
2
Cusack, Ruth P., Christiane E. Whetstone, Yanqing Xie, Maral Ranjbar, and Gail M. Gauvreau. "Regulation of Eosinophilia in Asthma—New Therapeutic Approaches for Asthma Treatment." Cells 10, no. 4 (April 6, 2021): 817. http://dx.doi.org/10.3390/cells10040817.
Full textAbstract:
Asthma is a complex and chronic inflammatory disease of the airways, characterized by variable and recurring symptoms, reversible airflow obstruction, bronchospasm, and airway eosinophilia. As the pathophysiology of asthma is becoming clearer, the identification of new valuable drug targets is emerging. IL-5 is one of these such targets because it is the major cytokine supporting eosinophilia and is responsible for terminal differentiation of human eosinophils, regulating eosinophil proliferation, differentiation, maturation, migration, and prevention of cellular apoptosis. Blockade of the IL-5 pathway has been shown to be efficacious for the treatment of eosinophilic asthma. However, several other inflammatory pathways have been shown to support eosinophilia, including IL-13, the alarmin cytokines TSLP and IL-33, and the IL-3/5/GM-CSF axis. These and other alternate pathways leading to airway eosinophilia will be described, and the efficacy of therapeutics that have been developed to block these pathways will be evaluated.
3
Oliver, Brian, Katrina Tonga, David Darley, Sandra Rutting, Xin Zhang, Hui Chen, and Gang Wang. "COPD treatment choices based on blood eosinophils: are we there yet?" Breathe 15, no. 4 (December 2019): 318–23. http://dx.doi.org/10.1183/20734735.0254-2019.
Full textAbstract:
Eosinophils are increasingly being recognised as an important characteristic feature of COPD. Patients with COPD and eosinophilic inflammation tend to respond to steroid therapy; however, many questions remain regarding the optimum measurement. Eosinophilic inflammation may be defined based on various sampling techniques, including eosinophil levels in blood, sputum, bronchoalveolar lavage or biopsy, which leads to inconsistencies in its definition. Blood eosinophils may increase in conjunction with sputum eosinophils during COPD exacerbations and therefore may be a good surrogate marker of airway eosinophilic inflammation. However, the timing of the blood eosinophil measurement, the stability of the eosinophil count and the threshold used in different studies are variable. The use of blood eosinophil count to direct biological therapies in COPD has also had variable outcomes. Eosinophilic inflammation has an important role in COPD management; however, its use as the optimum biomarker still needs further investigation.Key pointsEosinophilia may play a significant role in the pathogenesis of COPD.Eosinophilic inflammation in COPD can be steroid responsive; however, eosinophilic inflammation is variable, and caution needs to be taken with measurements and the thresholds used.The long-term effects of reducing eosinophil levels in COPD is unclear.Educational aimsTo explore current knowledge of eosinophils in COPD.To explore the relationship between eosinophilia and corticosteroid use.To understand the limitations of assessing and using eosinophilia in COPD.
4
Broide, David, Jurgan Schwarze, Helen Tighe, Tim Gifford, Minh-Duc Nguyen, Siamak Malek, John Van Uden, Elena Martin-Orozco, Erwin W. Gelfand, and Eyal Raz. "Immunostimulatory DNA Sequences Inhibit IL-5, Eosinophilic Inflammation, and Airway Hyperresponsiveness in Mice." Journal of Immunology 161, no. 12 (December 15, 1998): 7054–62. http://dx.doi.org/10.4049/jimmunol.161.12.7054.
Full textAbstract:
Abstract We have used a mouse model of allergen-induced airway hyperresponsiveness to demonstrate that immunostimulatory DNA sequences (ISS) containing a CpG DNA motif significantly inhibit airway eosinophilia and reduce responsiveness to inhaled methacholine. ISS not only inhibited eosinophilia of the airway (by 93%) and lung parenchyma (91%), but also significantly inhibited blood eosinophilia (86%), suggesting that ISS was exerting a significant effect on the bone marrow production of eosinophils. The inhibition of the bone marrow production of eosinophils by 58% was associated with a significant inhibition of T cell-derived cytokine generation (IL-5, granulocyte-macrophage CSF, and IL-3). ISS exerted this inhibitory effect on T cell cytokine production indirectly by stimulating monocytes/macrophages and NK cells to generate IL-12 and IFNs. The onset of the ISS effect on reducing the number of tissue eosinophils was both immediate (within 1 day of administration) and sustained (lasted 6 days), and was not due to ISS directly inducing eosinophil apoptosis. ISS was effective in inhibiting eosinophilic airway inflammation when administered either systemically (i.p.), or mucosally (i.e., intranasally or intratracheally). Interestingly, a single dose of ISS inhibited airway eosinophilia as effectively as daily injections of corticosteroids for 7 days. Moreover, while both ISS and corticosteroids inhibited IL-5 generation, only ISS was able to induce allergen-specific IFN-γ production and redirect the immune system toward a Th1 response. Thus, systemic or mucosal administration of ISS before allergen exposure could provide a novel form of active immunotherapy in allergic diseases.
5
Salter, Brittany M., Xiaotian Ju, and Roma Sehmi. "Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma." Cells 10, no. 2 (February 16, 2021): 412. http://dx.doi.org/10.3390/cells10020412.
Full textAbstract:
Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.
6
Vucevic, Danijela, Tatjana Radosavljevic, and Gordana Djordjevic-Denic. "The role of eosinophilic leukocytes in pathogenesis of bronchial asthma." Jugoslovenska medicinska biohemija 23, no. 4 (2004): 333–41. http://dx.doi.org/10.2298/jmh0404333v.
Full textAbstract:
Pathogenesis of bronchial asthma has not been completely understood. Eosinophilic leukocytes accumulate in high numbers in the lungs, blood and sputum of asthmatic patients. Peripheral blood eosinophilia has been identified as a risk factor for the development of airway obstruction. Prominent eosinophilic inflammatory infiltrate in the bronchial mucosa and correlation between eosinophil numbers and disease severity supports the hypothesis that eosinophils are central inflammatory cells capable of inducing pathophysiological features of asthma. Activated eosinophils secrete a wide range of preformed and newly generated mediators that damage the bronchial epithelium, contract smooth muscle, increase mucous secretion and cause vasodilatation. There is ample evidence that oxidants generation is increased during an asthma exacerbation. Many investigations indicate that airway and blood eosinophils produce more oxidants in asthmatic patients compared with control subjects.
7
Drake, Matthew G., Gregory D. Scott, Emily D. Blum, Katherine M. Lebold, Zhenying Nie, James J. Lee, Allison D. Fryer, Richard W. Costello, and David B. Jacoby. "Eosinophils increase airway sensory nerve density in mice and in human asthma." Science Translational Medicine 10, no. 457 (September 5, 2018): eaar8477. http://dx.doi.org/10.1126/scitranslmed.aar8477.
Full textAbstract:
In asthma, airway nerve dysfunction leads to excessive bronchoconstriction and cough. It is well established that eosinophils alter nerve function and that airway eosinophilia is present in 50 to 60% of asthmatics. However, the effects of eosinophils on airway nerve structure have not been established. We tested whether eosinophils alter airway nerve structure and measured the physiological consequences of those changes. Our results in humans with and without eosinophilic asthma showed that airway innervation and substance P expression were increased in moderate persistent asthmatics compared to mild intermittent asthmatics and healthy subjects. Increased innervation was associated with a lack of bronchodilator responsiveness and increased irritant sensitivity. In a mouse model of eosinophilic airway inflammation, the increase in nerve density and airway hyperresponsiveness were mediated by eosinophils. Our results implicate airway nerve remodeling as a key mechanism for increased irritant sensitivity and exaggerated airway responsiveness in eosinophilic asthma.
8
Schwarze, Jürgen, Grzegorz Cieslewicz, Anthony Joetham, Toshihide Ikemura, Eckard Hamelmann, and Erwin W. Gelfand. "CD8 T Cells Are Essential in the Development of Respiratory Syncytial Virus-Induced Lung Eosinophilia and Airway Hyperresponsiveness." Journal of Immunology 162, no. 7 (April 1, 1999): 4207–11. http://dx.doi.org/10.4049/jimmunol.162.7.4207.
Full textAbstract:
Abstract Viral respiratory infections can cause bronchial hyperresponsiveness and exacerbate asthma. In mice, respiratory syncytial virus (RSV) infection results in airway hyperresponsiveness (AHR) and eosinophil influx into the airways. The immune cell requirements for these responses to RSV infection are not well defined. To delineate the role of CD8 T cells in the development of RSV-induced AHR and lung eosinophilia, we tested the ability of mice depleted of CD8 T cells to develop these symptoms of RSV infection. BALB/c mice were depleted of CD8 T cells using anti-CD8 Ab treatment before intranasal administration of infectious RSV. Six days postinfection, airway responsiveness to inhaled methacholine was assessed by barometric body plethysmography, and numbers of lung eosinophils and levels of IFN-γ, IL-4, and IL-5 in bronchoalveolar lavage fluid were monitored. RSV infection resulted in airway eosinophilia and AHR in control mice, but not in CD8-depleted animals. Further, whereas RSV-infected mice secreted increased amounts of IL-5 into the airways as compared with noninfected controls, no IL-5 was detectable in both bronchoalveolar lavage fluid and culture supernatants from CD8-depleted animals. Treatment of CD8-depleted mice with IL-5 fully restored both lung eosinophilia and AHR. We conclude that CD8 T cells are essential for the influx of eosinophils into the lung and the development of AHR in response to RSV infection.
9
Rajavelu, Priya, Madhavi Rayapudi, Matthew Moffitt, Akanksha Mishra, and Anil Mishra. "Significance of para-esophageal lymph nodes in food or aeroallergen-induced iNKT cell-mediated experimental eosinophilic esophagitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 302, no. 7 (April 1, 2012): G645—G654. http://dx.doi.org/10.1152/ajpgi.00223.2011.
Full textAbstract:
Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder driven by food hypersensitivity; however, the specific foods and mechanisms involved are unclear. In patients with EoE, we have found that hypersensitivities to corn and peanuts are the most common. Accordingly, we sensitized and exposed mice either intranasally or intragastrically with corn or peanut extract or saline. Esophageal eosinophilia, the genes of eosinophil-directed cytokines, and allergen-induced antibodies were examined in mice challenged with corn or peanut extract or saline. A high number of esophageal lamina propria eosinophils as well as eosinophilic microabscesses, intraepithelial eosinophils, extracellular eosinophilic granules, thickened and disrupted epithelial mucosa, and mast cell hyperplasia were observed in the esophagus of peanut or corn allergen-challenged mice. Mechanistic analysis indicated that para-esophageal lymph nodes might be critical in the trafficking of eosinophils to the esophagus and in EoE association to airway eosinophilia. Furthermore, experimentation with gene-targeted mice revealed that peanut allergen-induced EoE was dependent on eotaxin and invariant natural killer T (iNKT) cells, as CD1d and eotaxin-1/2 gene-deficient mice were protected from disease induction. Thus we provide evidence that para-esophageal lymph nodes are involved in food- or aeroallergen-induced eosinophilia and patchy EoE pathogenesis, likely a mechanism dependent on eotaxins and iNKT cells.
10
Brussino, L., E. Heffler, C. Bucca, S. Nicola, and G. Rolla. "Eosinophils Target Therapy for Severe Asthma: Critical Points." BioMed Research International 2018 (October 25, 2018): 1–6. http://dx.doi.org/10.1155/2018/7582057.
Full textAbstract:
Asthma is a chronic and heterogeneous disease, which is defined as severe disease whenever it requires treatment with a high dose of inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming ‘‘uncontrolled’’ or if it remains ‘‘uncontrolled’’ despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma, which is characterized by sputum eosinophilia, associated with mild to moderate increase in blood eosinophil count, frequently adult-onset, and associated with chronic rhinosinusitis with nasal polyps in half of the cases. Eosinophilic asthma is driven by T2 inflammation, characterized, among the others, by interleukin-5 production. IL-5 plays a key role in the differentiation, survival, migration, and activation of eosinophils, and it has become an appealing therapeutic target for eosinophilic asthma. In recent years two monoclonal antibodies (mepolizumab and reslizumab) directed against IL-5 and one monoclonal antibody directed against the alpha-subunit of the IL-5 receptor (benralizumab) have been developed. All these IL-5 target drugs have been shown to reduce the number of exacerbation in patients with severe asthma selected on the basis of peripheral blood eosinophil count. There are still a number of unresolved issues related to the anti-IL5 strategy in eosinophilic asthma, which are here reviewed. These issues include the effects of such therapy on airway obstruction and asthmatic symptoms, the level of baseline eosinophils that predicts a response to treatment, the relationship between blood and airway eosinophilia, and, perhaps most importantly, how to elucidate the pathogenetic role played by eosinophils in the individual patient with severe eosinophilic asthma.
11
Doyle, Alfred D., Manali Mukherjee, William E. LeSuer, Tyler B. Bittner, Saif M. Pasha, Justin J. Frere, Joseph L. Neely, et al. "Eosinophil-derived IL-13 promotes emphysema." European Respiratory Journal 53, no. 5 (February 6, 2019): 1801291. http://dx.doi.org/10.1183/13993003.01291-2018.
Full textAbstract:
The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.
12
Mo, Yuqing, Kan Zhang, Yuchen Feng, Lingling Yi, Yuxia Liang, Wenliang Wu, Jianping Zhao, et al. "Epithelial SERPINB10, a novel marker of airway eosinophilia in asthma, contributes to allergic airway inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 1 (January 1, 2019): L245—L254. http://dx.doi.org/10.1152/ajplung.00362.2017.
Full textAbstract:
Serine peptidase inhibitor, clade B, member 10 (SERPINB10) expression is increased in IL-13-stimulated human bronchial epithelial cells and in a murine model of allergic airway inflammation. However, the role of SERPINB10 in asthma remains unknown. We examined the association between epithelial SERPINB10 expression and airway eosinophilia in subjects with asthma and the role of Serpinb10 in allergic airway inflammation in an animal model. Epithelial SERPINB10 mRNA and protein expression were markedly increased in subjects with asthma ( n = 60) compared with healthy controls ( n = 25). Epithelial SERPINB10 mRNA levels were significantly correlated with airway hyperresponsiveness (AHR) and three parameters reflecting airway eosinophilia including the percentage of sputum eosinophils, the number of eosinophils in bronchial submucosa, and fraction of exhaled nitric oxide in subjects with asthma. Moreover, epithelial SERPINB10 expression was strongly correlated with the epithelial gene signature ( CLCA1, POSTN, and SERPINB2) for type 2 status. In normal human bronchial epithelial cells cultured at air-liquid interface, knockdown of SERPINB10 suppressed IL-13-stimulated periostin (encoded by POSTN) and CCL26 (eotaxin-3) expression by inhibiting the activation of p38 MAPK. Epithelial CCL26 mRNA levels were correlated with SERPINB10 expression in subjects with asthma. Airway knockdown of Serpinb10 alleviated AHR, airway eosinophilia and the expression of periostin and Ccl26 in a murine model of allergic airway disease. Taken together, epithelial SERPINB10 is a novel marker for airway eosinophilia in asthma. Epithelial SERPINB10 contributes to allergic airway eosinophilic inflammation, at least in part, by regulating the expression of periostin and CCL26.
13
Gundel, R. H., M. E. Gerritsen, G. J. Gleich, and C. D. Wegner. "Repeated antigen inhalation results in a prolonged airway eosinophilia and airway hyperresponsiveness in primates." Journal of Applied Physiology 68, no. 2 (February 1, 1990): 779–86. http://dx.doi.org/10.1152/jappl.1990.68.2.779.
Full textAbstract:
The effects of repeated antigen inhalation on airway cellular composition and airway responsiveness were examined in primates. Airway cellular composition was assessed by bronchoalveolar lavage (BAL), and airway responsiveness was measured as the bronchoconstrictor response to cumulative methacholine dose-response determinations over the course of a 10-wk study. Control animals, exposed to repeated vehicle inhalation challenges, were tested in parallel with the antigen-challenged group. Repeated antigen inhalation resulted in a prolonged inflammatory reaction characterized by a large increase in airway eosinophils (3 +/- 1 to 59 +/- 15%, P less than 0.01). Airway eosinophilia was associated with an increase in airway responsiveness as indicated by a leftward shift in the methacholine dose-response curves, an increase in the slope of the dose-response curves, and a decrease in PC100 values (the dose of methacholine required to cause a 100% increase in lung resistance). The number of BAL eosinophils and the level of eosinophil major basic protein in BAL correlated significantly with methacholine PC100 values (r = 0.61, P less than 0.01 and r = 0.64, P less than 0.01, respectively). Histological examination of lung biopsy samples taken at week 10 of the study demonstrated a striking infiltration of eosinophils in the antigen-challenged animals. These results support earlier observations that demonstrated an association between increases in airway eosinophils and increases in airway responsiveness and suggest that eosinophils are involved in the pathogenesis of hyperresponsive airways.
14
Humbles, Alison A., Dolores M. Conroy, Sylvie Marleau, Sara M. Rankin, Roger T. Palframan, Amanda E. I. Proudfoot, Timothy N. C. Wells, et al. "Kinetics of Eotaxin Generation and Its Relationship to Eosinophil Accumulation in Allergic Airways Disease: Analysis in a Guinea Pig Model In Vivo." Journal of Experimental Medicine 186, no. 4 (August 18, 1997): 601–12. http://dx.doi.org/10.1084/jem.186.4.601.
Full textAbstract:
Challenge of the airways of sensitized guinea pigs with aerosolized ovalbumin resulted in an early phase of microvascular protein leakage and a delayed phase of eosinophil accumulation in the airway lumen, as measured using bronchoalveolar lavage (BAL). Immunoreactive eotaxin levels rose in airway tissue and BAL fluid to a peak at 6 h falling to low levels by 12 h. Eosinophil numbers in the tissue correlated with eotaxin levels until 6 h but eosinophils persisted until the last measurement time point at 24 h. In contrast, few eosinophils appeared in BAL over the first 12 h, major trafficking through the airway epithelium occurring at 12–24 h when eotaxin levels were low. Constitutive eotaxin was present in BAL fluid. Both constitutive and allergen-induced eosinophil chemoattractant activity in BAL fluid was neutralized by an antibody to eotaxin. Allergen-induced eotaxin appeared to be mainly in airway epithelium and macrophages, as detected by immunostaining. Allergen challenge of the lung resulted in a rapid release of bone marrow eosinophils into the blood. An antibody to IL-5 suppressed bone marrow eosinophil release and lung eosinophilia, without affecting lung eotaxin levels. Thus, IL-5 and eotaxin appear to cooperate in mediating a rapid transfer of eosinophils from the bone marrow to the lung in response to allergen challenge.
15
Tjota, Melissa, Ayodeji Adegunsoye, and Aliya Husain. "Association of Submucosal Eosinophilia With Blood and Bronchoalveolar Lavage Eosinophilia in Adults With Severe Refractory Asthma." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S118. http://dx.doi.org/10.1093/ajcp/aqz122.003.
Full textAbstract:
Abstract Objectives Asthma is a chronic inflammatory disease of the lungs, and for individuals with persistently uncontrolled symptoms despite maximal medical therapy, an endobronchial biopsy and bronchoalveolar lavage (BAL) may be obtained to guide therapy. Given the invasive nature of this procedure, most patients obtain blood eosinophil counts. The goal of this study was to compare blood, BAL, and biopsy eosinophils to identify whether there is a correlation between these various approaches. Methods A retrospective study was conducted in adult patients (n = 220) who had been seen in the Refractory Obstructive Lung Disease clinic over a 10-year period (2008-2017). All the patients had been clinically diagnosed with severe refractory asthma. Clinical data were obtained through review of the electronic medical records. Results Patients with submucosal eosinophilia had a greater prevalence of intraepithelial eosinophils (50.9% vs 2.3%, P < .001), intraepithelial neutrophils (36.7% vs 9.3%, P < .001), and intraepithelial lymphocytes (52.5% vs 18.6%, P < .001). In contrast, no significant differences were noted between the samples with submucosal eosinophilia present versus submucosal eosinophilia absent for polymorphonuclear leukocyte (PMN) percent, lymphocyte percent, or macrophage percent in BAL. There was a significant difference in eosinophil percentage between the two groups (8.7% vs 1.1%, P = .004). When submucosal eosinophilia was divided into mild (1-10 eosinophils/HPF), moderate (11-20 eosinophils/HPF), and severe (>20 eosinophils/HPF), mean eosinophilia trended more with eosinophilia in the BAL than with the peripheral blood. There was poor correlation (r = 0.31, P = .0001) between eosinophil levels in the blood and BAL. Conclusion Compared to BAL, histopathologic data may more accurately characterize the underlying pathophysiology in severe asthmatics by providing a more detailed quantification of the airway inflammatory infiltrates. Moreover, blood eosinophilia may not be as representative of airway inflammation in patients with severe refractory asthma given the poor correlation between eosinophil levels in the blood and BAL.
16
Henry, Peter J., Tracy S. Mann, Angela C. D'Aprile, Glenn J. Self, and Roy G. Goldie. "An endothelin receptor antagonist, SB-217242, inhibits airway hyperresponsiveness in allergic mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 283, no. 5 (November 1, 2002): L1072—L1078. http://dx.doi.org/10.1152/ajplung.00076.2002.
Full textAbstract:
Within the airways, endothelin-1 (ET-1) can exert a range of prominent effects, including airway smooth muscle contraction, bronchial obstruction, airway wall edema, and airway remodeling. ET-1 also possesses proinflammatory properties and contributes to the late-phase response in allergic airways. However, there is no direct evidence for the contribution of endogenous ET-1 to airway hyperresponsiveness in allergic airways. Allergic inflammation induced in mice by sensitization and challenge with the house dust mite allergen Der P1 was associated with elevated levels of ET-1 within the lung, increased numbers of eosinophils within bronchoalveolar lavage fluid and tissue sections, and development of airway hyperresponsiveness to methacholine ( P < 0.05, n = 6 mice per group). Treatment of allergic mice with an endothelin receptor antagonist, SB-217242 (30 mg · kg−1· day−1), during allergen challenge markedly inhibited airway eosinophilia (bronchoalveolar lavage fluid and tissue) and development of airway hyperresponsiveness. These findings provide direct evidence for a mediator role for ET-1 in development of airway hyperresponsiveness and airway eosinophilia in Der P1-sensitized mice after antigen challenge.
17
Schwarze, Jürgen, Grzegorz Cieslewicz, Eckard Hamelmann, Anthony Joetham, Leonard D. Shultz, Marinus C. Lamers, and Erwin W. Gelfand. "IL-5 and Eosinophils Are Essential for the Development of Airway Hyperresponsiveness Following Acute Respiratory Syncytial Virus Infection." Journal of Immunology 162, no. 5 (March 1, 1999): 2997–3004. http://dx.doi.org/10.4049/jimmunol.162.5.2997.
Full textAbstract:
Abstract Viral respiratory infections can cause bronchial hyperresponsiveness and exacerbate asthma. In mice, respiratory syncytial virus (RSV) infection, which induces an immune response dominated by IFN-γ, results in airway hyperresponsiveness (AHR) and eosinophil influx into the airways, both of which are prevented by pretreatment with anti-IL-5 Ab. To delineate the role of IL-5, IL-4, and IFN-γ in the development of RSV-induced AHR and lung eosinophilia, we tested the ability of mice deficient in each of these cytokines to develop these symptoms of RSV infection. Mice deficient in either IL-5, IL-4, or IFN-γ were administered infectious RSV intranasally, and 6 days later, airway responsiveness to inhaled methacholine was assessed by barometric body plethysmography, and numbers of lung eosinophils and production of IFN-γ, IL-4, and IL-5 by mononuclear cells from peribronchial lymph nodes were monitored. RSV infection resulted in airway eosinophilia and AHR in both IL-4- and IFN-γ-deficient mice, but not in IL-5-deficient mice. Reconstitution of IL-5-deficient mice with IL-5 restored these responses and enhanced the responses in IL-4-deficient mice. Anti-VLA-4 (very late Ag-4) treatment prevented lung eosinophilia and AHR following RSV infection and IL-5 reconstitution. We conclude that in response to RSV, IL-5 is essential for the influx of eosinophils into the lung and that eosinophils in turn are critical for the development of AHR. IFN-γ and IL-4 are not essential for these responses to RSV infection.
18
Zhang, Kan, Yuxia Liang, Yuchen Feng, Wenliang Wu, Huilan Zhang, Jianguo He, Qinghua Hu, et al. "Decreased epithelial and sputum miR-221-3p associates with airway eosinophilic inflammation and CXCL17 expression in asthma." American Journal of Physiology-Lung Cellular and Molecular Physiology 315, no. 2 (August 1, 2018): L253—L264. http://dx.doi.org/10.1152/ajplung.00567.2017.
Full textAbstract:
Airway eosinophilic inflammation is a key feature of type 2 high asthma. The role of epithelial microRNA (miR) in airway eosinophilic inflammation remains unclear. We examined the expression of miR-221-3p in bronchial brushings, induced sputum, and plasma from 77 symptomatic, recently diagnosed, steroid-naive subjects with asthma and 36 healthy controls by quantitative PCR and analyzed the correlation between miR-221-3p expression and airway eosinophilia. We found that epithelial, sputum, and plasma miR-221-3p expression was significantly decreased in subjects with asthma. Epithelial miR-221-3p correlated with eosinophil in induced sputum and bronchial biopsies, fraction of exhaled nitric oxide, blood eosinophil, epithelial gene signature of type 2 status, and methacholine provocative dosage required to cause a 20% decline in forced expiratory volume in the first second in subjects with asthma. Sputum miR-221-3p also correlated with airway eosinophilia and was partially restored after inhaled corticosteroid treatment. Inhibition of miR-221-3p expression suppressed chemokine (C-C motif) ligand (CCL) 24 (eotaxin-2), CCL26 (eotaxin-3), and periostin (POSTN) expression in BEAS-2B bronchial epithelial cells. We verified that chemokine (C-X-C motif) ligand (CXCL) 17, an anti-inflammatory chemokine, is a target of miR-221-3p, and epithelial CXCL17 expression significantly increased in asthma. CXCL17 inhibited CCL24, CCL26, and POSTN expression via the p38 MAPK pathway. Airway overexpression of miR-221-3p exacerbated airway eosinophilic inflammation, suppressed CXCL17 expression, and enhanced CCL24, CCL26, and POSTN expression in house dust mite-challenged mice. Taken together, epithelial and sputum miR-221-3p are novel biomarkers for airway eosinophilic inflammation in asthma. Decreased epithelial miR-221-3p may protect against airway eosinophilic inflammation by upregulating anti-inflammatory chemokine CXCL17.
19
Hall, Laurie R., Rajeev K. Mehlotra, Alan W. Higgins, Musa A. Haxhiu, and Eric Pearlman. "An Essential Role for Interleukin-5 and Eosinophils in Helminth-Induced Airway Hyperresponsiveness." Infection and Immunity 66, no. 9 (September 1, 1998): 4425–30. http://dx.doi.org/10.1128/iai.66.9.4425-4430.1998.
Full textAbstract:
ABSTRACT Infection with the parasitic helminth Brugia malayi can result in development of a severe asthmatic response termed tropical pulmonary eosinophilia. This disease, thought to result from a host inflammatory response to blood parasites which become trapped in the lung microvasculature, is characterized by a profound eosinophilic infiltration into the lungs. Recruitment of eosinophils also correlates with the development of airway hyperresponsiveness (AHR) to cholinergic agonists and severe asthmatic symptoms. Our studies examined the role of interleukin-5 (IL-5) in helminth-induced pulmonary eosinophilia and AHR. C57BL/6 mice immunized with killed B. malayi microfilariae and challenged intravenously with live microfilariae exhibit many of the characteristics of human disease, including peripheral and pulmonary eosinophilia. Cells recovered by bronchoalveolar lavage of sensitized mice consisted of 3.8% eosinophils on day 1 postchallenge and 84% on day 10. Extracellular major basic protein was present on the surface of airway epithelial cells as early as day 1 and continued to be evident after 8 days, indicating sustained activation and degranulation of eosinophils in the lung. These histologic changes correlated with the development of AHR to carbachol. In contrast to immunocompetent mice, immunization and challenge with B. malayi in IL-5−/− mice did not induce peripheral or pulmonary eosinophilia, and these mice failed to show AHR in response to cholinergic agonists. Taken together, these data indicate that IL-5 and eosinophils are required for the induction of AHR by filarial helminths.
20
Boulares, Hamid, Yasuhiro Suzuki, Amarjit Naura, Mustapha Oumouna, Rahul Datta, and Chetan Hans. "PARP-1 and iNOS relationship in allergen-induced lung inflammation: dependence of iNOS expression on PARP-1 and its dispensability for eosinophil recruitment post-IL-5 production (98.1)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S192. http://dx.doi.org/10.4049/jimmunol.178.supp.98.1.
Full textAbstract:
Abstract The inducible nitric oxide synthase (iNOS) has been suggested to play an important role in the pathogenesis of asthma by contributing to eosinophilia and the ensuing oxidative damage after allergen exposure. IL-5 was shown to induce iNOS expression and that a reduction in iNOS expression reduces airway recruitment of eosinophils in response to allergen exposure. We recently showed that PARP-1 also plays a critical role in the pathogenesis of the disease by promoting eosinophil recruitment by participating in the cascade leading to IL-5 production. Here, we investigated the interrelationship between PARP-1 and iNOS in inducing eosinophilia. Our results show that iNOS gene deletion reduces eosinophil recruitment but to lesser degree as compared to PARP-1 gene deletion, suggesting a partial role for this protein in airway inflammation. PARP-1 gene deletion severely reduced iNOS expression in the airways of ovalbumin (allergen)-challenged mice and consequent nitration of target proteins and this phenomenon was closely associated with an impairment of p65 NF-κB nuclear translocation and phosphorylation of its inhibitor, I-κBα. IL-5-intranasal administration restored the eosinophilia in ovalbumin-challenged PARP-1−/− mice but did not reverse iNOS expression, suggesting that iNOS may be dispensable for eosinophil recruitment after IL-5 production. Altogether, our results further support the role of PARP-1 in the process of eosinophil recruitment during allergen-induced lung inflammation and provide evidence for a potential specific relationship between PARP-1 and iNOS. Support: NIH-HL072889 and 1P20RR18766 to HB.
21
Cohn, Lauren, Jeffrey S. Tepper, and Kim Bottomly. "Cutting Edge: IL-4-Independent Induction of Airway Hyperresponsiveness by Th2, But Not Th1, Cells." Journal of Immunology 161, no. 8 (October 15, 1998): 3813–16. http://dx.doi.org/10.4049/jimmunol.161.8.3813.
Full textAbstract:
Abstract We investigated the role of Th1 or Th2 cells in airway hyperresponsiveness (AHR), because both IFN-γ and IL-4 and IL-5-producing CD4 T cells have been identified in the airways of asthmatics. After transfer of in vitro-generated TCR transgenic Th1 or Th2 cells and exposure to inhaled Ag, Th2 cells induced AHR and airway eosinophilia, whereas Th1 cells induced neutrophilic inflammation without AHR. Next, to determine the precise effector function of IL-4 in Th2 cell-induced AHR, we transferred IL-4−/− Th2 cells into wild-type and IL-4−/− recipient mice. After exposure to inhaled Ag, both groups of mice exhibited AHR with markedly reduced airway eosinophilia. Thus, IL-4 production by Th2 cells is not essential for the induction of AHR, but is critical for the migration of eosinophils from lung tissue into the airways.
22
Schwarze, Jürgen, Mika Makela, Grzegorz Cieslewicz, Azzeddine Dakhama, Michael Lahn, Toshihide Ikemura, Anthony Joetham, and Erwin W. Gelfand. "Transfer of the Enhancing Effect of Respiratory Syncytial Virus Infection on Subsequent Allergic Airway Sensitization by T Lymphocytes." Journal of Immunology 163, no. 10 (November 15, 1999): 5729–34. http://dx.doi.org/10.4049/jimmunol.163.10.5729.
Full textAbstract:
Abstract In mice, respiratory syncytial virus (RSV) infection enhances allergic airway sensitization, resulting in lung eosinophilia and in airway hyperresponsiveness (AHR). The mechanisms by which RSV contributes to development of asthma and its effects on allergic airway sensitization in mice are not known. We tested whether these consequences of RSV infection can be adoptively transferred by T cells and whether depletion of T cell subsets prevents the effects of RSV infection on subsequent airway sensitization. Mononuclear cells, T lymphocytes, or CD4 or CD8 T cells from peribronchial lymph nodes (PBLN) of RSV-infected mice were transferred into naive BALB/c mice which were then exposed to OVA via the airways. Additionally, RSV-infected mice were depleted of CD4 or CD8 T cells following acute RSV infection but prior to airway sensitization. Following sensitization, airway responsiveness to inhaled methacholine, numbers of lung eosinophils, and levels of IFN-γ, IL-4, and IL-5 in PBLN cell cultures were monitored. Transfer of T cells from RSV-infected mice resulted in increased eosinophil influx into the lungs, increased IL-5 production, and development of AHR following airway sensitization to allergen. Transfer of CD8 but not CD4 T cells from the PBLN of RSV-infected mice also resulted in AHR following 10 days of OVA exposure. Further, depletion of CD8 T cells prevented these consequences of RSV infection while CD4 T cell depletion reduced them. We conclude that T cells, in particular CD8 T cells, are critical in mediating RSV-induced development of lung eosinophilia and AHR following allergic airway sensitization.
23
Henderson, W. R., D. B. Lewis, R. K. Albert, Y. Zhang, W. J. Lamm, G. K. Chiang, F. Jones, et al. "The importance of leukotrienes in airway inflammation in a mouse model of asthma." Journal of Experimental Medicine 184, no. 4 (October 1, 1996): 1483–94. http://dx.doi.org/10.1084/jem.184.4.1483.
Full textAbstract:
Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.
24
Cohn, Lauren, Robert J. Homer, Heather MacLeod, Markus Mohrs, Frank Brombacher, and Kim Bottomly. "Th2-Induced Airway Mucus Production Is Dependent on IL-4Rα, But Not on Eosinophils." Journal of Immunology 162, no. 10 (May 15, 1999): 6178–83. http://dx.doi.org/10.4049/jimmunol.162.10.6178.
Full textAbstract:
Abstract Mucus hyperproduction in asthma results from airway inflammation and contributes to clinical symptoms, airway obstruction, and mortality. In human asthmatics and in animal models, excess mucus production correlates with airway eosinophilia. We previously described a system in which TCR transgenic CD4 Th2 cells generated in vitro were transferred into recipient mice and activated in the respiratory tract with inhaled Ag. Th2 cells stimulated airway eosinophilia and a marked increase in mucus production, while mice that received Th1 cells exhibited airway inflammation without eosinophilia or mucus. Mucus could be induced by IL-4−/− Th2 cells at comparable levels to mucus induced by IL-4+/+ Th2 cells. In the current studies we dissect further the mechanisms of Th2-induced mucus production. When IL-4−/− Th2 cells are transferred into IL-4Rα−/− mice, mucus is not induced, and BAL eosinophilia is absent. These data suggest that in the absence of IL-4, IL-13 may be critical for Th2-induced mucus production and eosinophilia. To determine whether eosinophils are important in mucus production, IL-5−/− Th2 cells were transferred into IL-5−/− recipients. Eosinophilia was abolished, yet mucus staining in the epithelium persisted. These studies show definitively that IL-5, eosinophils, or mast cells are not essential, but signaling through IL-4Rα is critically important in Th2 cell stimulation of mucus production.
25
Kottyan, Leah C., Ann R. Collier, Khanh H. Cao, Kathryn A. Niese, Megan Hedgebeth, Caius G. Radu, Owen N. Witte, Gurjit K. Khurana Hershey, Marc E. Rothenberg, and Nives Zimmermann. "Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner." Blood 114, no. 13 (September 24, 2009): 2774–82. http://dx.doi.org/10.1182/blood-2009-05-220681.
Full textAbstract:
Abstract The microenvironment of the lung in asthma is acidic, yet the effect of acidity on inflammatory cells has not been well established. We now demonstrate that acidity inhibits eosinophil apoptosis and increases cellular viability in a dose-dependent manner between pH 7.5 and 6.0. Notably, acidity induced eosinophil cyclic adenosine 5′-monophosphate (cAMP) production and enhanced cellular viability in an adenylate cyclase–dependent manner. Furthermore, we identify G protein-coupled receptor 65 (GPR65) as the chief acid-sensing receptor expressed by eosinophils, as GPR65-deficient eosinophils were resistant to acid-induced eosinophil cAMP production and enhanced viability. Notably, GPR65−/− mice had attenuated airway eosinophilia and increased apoptosis in 2 distinct models of allergic airway disease. We conclude that eosinophil viability is increased in acidic microenvironments in a cAMP- and GPR65-dependent manner.
26
Su, Yung-Chang, Dijana Townsend, Lara J. Herrero, Ali Zaid, Michael S. Rolph, Michelle E. Gahan, Michelle A. Nelson, et al. "Dual Proinflammatory and Antiviral Properties of Pulmonary Eosinophils in Respiratory Syncytial Virus Vaccine-Enhanced Disease." Journal of Virology 89, no. 3 (November 19, 2014): 1564–78. http://dx.doi.org/10.1128/jvi.01536-14.
Full textAbstract:
ABSTRACTHuman respiratory syncytial virus (RSV) is a major cause of morbidity and severe lower respiratory tract disease in the elderly and very young, with some infants developing bronchiolitis, recurrent wheezing, and asthma following infection. Previous studies in humans and animal models have shown that vaccination with formalin-inactivated RSV (FI-RSV) leads to prominent airway eosinophilic inflammation following RSV challenge; however, the roles of pulmonary eosinophilia in the antiviral response and in disease pathogenesis are inadequately understood.In vivostudies in mice with eotaxin and/or interleukin 5 (IL-5) deficiency showed that FI-RSV vaccination did not lead to enhanced pulmonary disease, where following challenge there were reduced pulmonary eosinophilia, inflammation, Th2-type cytokine responses, and altered chemokine (TARC and CCL17) responses. In contrast to wild-type mice, RSV was recovered at high titers from the lungs of eotaxin- and/or IL-5-deficient mice. Adoptive transfer of eosinophils to FI-RSV-immunized eotaxin- and IL-5-deficient (double-deficient) mice challenged with RSV was associated with potent viral clearance that was mediated at least partly through nitric oxide. These studies show that pulmonary eosinophilia has dual outcomes: one linked to RSV-induced airway inflammation and pulmonary pathology and one with innate features that contribute to a reduction in the viral load.IMPORTANCEThis study is critical to understanding the mechanisms attributable to RSV vaccine-enhanced disease. This study addresses the hypothesis that IL-5 and eotaxin are critical in pulmonary eosinophil response related to FI-RSV vaccine-enhanced disease. The findings suggest that in addition to mediating tissue pathology, eosinophils within a Th2 environment also have antiviral activity.
27
Doran, Emma, David F. Choy, Aarti Shikotra, Claire A. Butler, Declan M. O'Rourke, James A. Johnston, Adrien Kissenpfennig, Peter Bradding, Joseph R. Arron, and Liam G. Heaney. "Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma." European Respiratory Journal 48, no. 3 (June 23, 2016): 715–25. http://dx.doi.org/10.1183/13993003.00400-2015.
Full textAbstract:
Severe asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high-dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the Janus kinase–signal transducers and activators of transcription pathway. We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, quantitative PCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating interleukin (IL)-13 signalling in vitro.SOCS1 gene expression was significantly lower in the airways of severe asthmatics compared with mild/moderate asthmatics, and was inversely associated with airway eosinophilia and other measures of T-helper type 2 (Th2) inflammation. Immunohistochemistry demonstrated SOCS1 was predominantly localised to the bronchial epithelium. SOCS1 overexpression inhibited IL-13-mediated chemokine ligand (CCL) 26 (eotaxin-3) mRNA expression in bronchial epithelial cells.Severe asthma patients with persistent airway eosinophilia and Th2 inflammation have reduced airway epithelial SOCS1 expression. SOCS1 inhibits epithelial IL-13 signalling, supporting its key role in regulating Th2-driven eosinophilia in severe asthma.
28
de Bruin, Alexander M., Miranda Buitenhuis, Koenraad F. van der Sluijs, Klaas P. J. M. van Gisbergen, Louis Boon, and Martijn A. Nolte. "Eosinophil differentiation in the bone marrow is inhibited by T cell–derived IFN-γ." Blood 116, no. 14 (October 7, 2010): 2559–69. http://dx.doi.org/10.1182/blood-2009-12-261339.
Full textAbstract:
Abstract To explore whether and how T cells can affect myelopoiesis, we investigated myeloid differentiation in a model for T cell-mediated immune activation. We found that CD70-transgenic (CD70TG) mice, which have elevated numbers of interferon-γ (IFN-γ)–producing effector T cells in the periphery and bone marrow, are almost devoid of eosinophilic granulocytes. Induction of allergic airway inflammation in these mice failed to induce eosinophilia as well as airway hyperresponsiveness. CD70TG mice also have strongly reduced numbers of eosinophil lineage-committed progenitors, whereas granulocyte/macrophage progenitors from these mice are unable to generate eosinophils in vitro. We found that granulocyte/macrophage progenitors express IFN-γR1 and that IFN-γ is sufficient to inhibit eosinophil differentiation of both murine and human progenitor cells in vitro. We demonstrate that inhibition of eosinophil development in CD70TG mice is IFN-γ–dependent and that T cell–derived IFN-γ is sufficient to inhibit eosinophil formation in vivo. Finally, we found that IFN-γ produced on anti-CD40 treatment and during viral infection can also suppress eosinophil formation in wild-type mice. These data demonstrate that IFN-γ inhibits the differentiation of myeloid progenitors to eosinophils, indicating that the adaptive immune system plays an important role in orchestrating the formation of the appropriate type of myeloid cells during immune activation.
29
Ge, Xiao Na, Sung Gil Ha, Yana G. Greenberg, Amrita Rao, Idil Bastan, Ada G. Blidner, Savita P. Rao, Gabriel A. Rabinovich, and P. Sriramarao. "Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1." Proceedings of the National Academy of Sciences 113, no. 33 (July 25, 2016): E4837—E4846. http://dx.doi.org/10.1073/pnas.1601958113.
Full textAbstract:
Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma. Allergen exposure resulted in airway recruitment of Gal-1–expressing inflammatory cells, including eosinophils, as well as increased Gal-1 in extracellular spaces in the lungs. In vitro, extracellular Gal-1 exerted divergent effects on eosinophils that were N-glycan– and dose-dependent. At concentrations ≤0.25 µM, Gal-1 increased eosinophil adhesion to vascular cell adhesion molecule-1, caused redistribution of integrin CD49d to the periphery and cell clustering, but inhibited ERK(1/2) activation and eotaxin-1–induced migration. Exposure to concentrations ≥1 µM resulted in ERK(1/2)-dependent apoptosis and disruption of the F-actin cytoskeleton. At lower concentrations, Gal-1 did not alter expression of adhesion molecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine receptor CCR3, but decreased CD49d and CCR3 was observed in eosinophils treated with higher concentrations of this lectin. In vivo, allergen-challenged Gal-1–deficient mice exhibited increased recruitment of eosinophils and CD3+ T lymphocytes in the airways as well as elevated peripheral blood and bone marrow eosinophils relative to corresponding WT mice. Further, these mice had an increased propensity to develop airway hyperresponsiveness and displayed significantly elevated levels of TNF-α in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and suppresses airway inflammation by inhibiting cell migration and promoting eosinophil apoptosis.
30
Li, Fei, Xufei Du, Fen Lan, Na Li, Chao Zhang, Chen Zhu, Xiaohui Wang, et al. "Eosinophilic inflammation promotes CCL6-dependent metastatic tumor growth." Science Advances 7, no. 22 (May 2021): eabb5943. http://dx.doi.org/10.1126/sciadv.abb5943.
Full textAbstract:
Compelling evidence suggests that inflammatory components contribute to cancer development. However, eosinophils, involved in several inflammatory diseases, were not fully explored in cancer metastasis. We show that airway inflammatory eosinophilia and colonic inflammation with eosinophil infiltration are both associated with increased metastasis in mice. Eosinophilia is responsible for increased bone metastasis in eosinophil-enriched Cd3δ-Il-5 transgenic (Il-5 Tg) mice. We also observe increased eosinophils in the malignant pleural effusion of cancer patients with pleural metastasis. Mechanistically, eosinophils promote tumor cell migration and metastasis formation through secreting C-C motif chemokine ligand 6 (CCL6). Genetic knockout of Ccl6 in Il-5 Tg mice remarkably attenuates bone metastasis. Moreover, inhibition of C-C chemokine receptor 1 (CCR1, the receptor of CCL6) in tumor cells reduces tumor cell migration and metastasis. Thus, our study identifies a CCL6-dependent prometastatic activity of eosinophils, which can be inhibited by targeting CCR1 and represent an approach to preventing metastatic disease.
31
Kanda, Akira, Kenji Kondo, Naoki Hosaka, Yoshiki Kobayashi, Dan Van Bui, Yasutaka Yun, Kensuke Suzuki, et al. "Eosinophilic Upper Airway Inflammation in a Murine Model Using an Adoptive Transfer System Induces Hyposmia and Epithelial Layer Injury with Convex Lesions." Medical Sciences 7, no. 2 (February 5, 2019): 22. http://dx.doi.org/10.3390/medsci7020022.
Full textAbstract:
Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a refractory upper airway disease, accompanied mainly by eosinophilia and/or asthma. In addition, the disease correlates with a high rate of hyposmia, following a marked infiltration of eosinophils into the inflamed site, the paranasal sinus. Although eosinophils are known to contribute to the development of hyposmia and CRSwNP pathology, the underlying mechanisms remain unclear. This study aimed to investigate whether eosinophilic upper airway inflammation induces hyposmia and CRSwNP in a murine model using an adoptive transfer system. Methods: To induce eosinophilic rhinosinusitis, splenocytes, including a high proportion (over 50%) of activated eosinophils (SPLhEos), were collected from interleukin-5 transgenic mice following double intraperitoneal injections of antigens, such as ovalbumin, house dust mite, or fungus. Activated SPLhEos with corresponding antigens were then transferred into the nasal cavity of recipient mice, which were sensitized and challenged by the corresponding antigen four times per week. Olfactory function, histopathological, and computed tomography (CT) analyses were performed 2 days after the final transfer of eosinophils. Results: Hyposmia was induced significantly in mice that received SPLhEos transfer compared with healthy and allergic mice, but it did not promote morphological alteration of the paranasal sinus. Pathological analysis revealed that epithelial layer injury and metaplasia similar to polyps, with prominent eosinophil infiltration, was induced in recipient tissue. However, there was no nasal polyp development with interstitial edema that was similar to those recognized in human chronic rhinosinusitis. Conclusions: This study supports the previously unsuspected contribution of eosinophils to CRS development in the murine model and suggests that murine-activated eosinophilic splenocytes contribute to the development of hyposmia due to more mucosal inflammation than physical airway obstruction and epithelial layer injury with convex lesions.
32
Tosca, Maria Angela, Donata Girosi, Oliviero Sacco, Roberto Bernardini, and Giorgio Ciprandi. "Steroid-sparing effect of mepolizumab in children with severe eosinophilic nonallergic asthma." Allergologia et Immunopathologia 49, no. 5 (September 1, 2021): 113–16. http://dx.doi.org/10.15586/aei.v49i5.466.
Full textAbstract:
Background: Asthma is characterized by a chronic airway inflammation, usually sustained by type 2 immunity. Bronchial and peripheral eosinophilia are biomarkers for type 2 asthma. Biologicals are the most effective treatment for severe asthma at present. Mepolizumab is an antagonist of interleukin-5 (IL-5), the most relevant cytokine involved in eosinophilia.Objective: This case report evaluated the effectiveness of mepolizumab in two girls with severe eosinophilic non-allergic asthma.Materials and methods: Two female children with severe eosinophilic nonallergic asthma were treated with mepolizumab for two years. Clinical findings, lung function, peripheral eosinophils, asthma control, and bronchial endoscopy were performed.Results: Biologicals reduced the eosinophilia, asthma exacerbations, and improved lung function in both patients. The treatment was also safe and well-tolerated.Conclusion: Mepolizumab represents an effective therapeutic option in the management of severe pediatric asthma.
33
Ge, Xiao Na, Idil Bastan, Mythili Dileepan, Yana Greenberg, Sung Gil Ha, Kaylee A. Steen, David A. Bernlohr, Savita P. Rao, and P. Sriramarao. "FABP4 regulates eosinophil recruitment and activation in allergic airway inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 315, no. 2 (August 1, 2018): L227—L240. http://dx.doi.org/10.1152/ajplung.00429.2017.
Full textAbstract:
Fatty acid binding protein 4 (FABP4), a member of a family of lipid-binding proteins, is known to play a role in inflammation by virtue of its ability to regulate intracellular events such as lipid fluxes and signaling. Studies have indicated a proinflammatory role for FABP4 in allergic asthma although its expression and function in eosinophils, the predominant inflammatory cells recruited to allergic airways, were not investigated. We examined expression of FABP4 in murine eosinophils and its role in regulating cell recruitment in vitro as well as in cockroach antigen (CRA)-induced allergic airway inflammation. CRA exposure led to airway recruitment of FABP4-expressing inflammatory cells, specifically eosinophils, in wild-type (WT) mice. FABP4 expression in eosinophils was induced by TNF-α as well as IL-4 and IL-13. FABP4-deficient eosinophils exhibited markedly decreased cell spreading/formation of leading edges on vascular cell adhesion molecule-1 and significantly decreased adhesion to intercellular adhesion molecule-1 associated with reduced β2-integrin expression relative to WT cells. Furthermore, FABP4-deficient eosinophils exhibited decreased migration, F-actin polymerization, calcium flux, and ERK(1/2) phosphorylation in response to eotaxin-1. In vivo, CRA-challenged FABP4-deficient mice exhibited attenuated eosinophilia and significantly reduced airway inflammation (improved airway reactivity, lower IL-5, IL-13, TNF-α, and cysteinyl leukotriene C4 levels, decreased airway structural changes) compared with WT mice. In conclusion, expression of FABP4 in eosinophils is induced during conditions of inflammation and plays a proinflammatory role in the development of allergic asthma by promoting eosinophil adhesion and migration and contributing to the development of various aspects of airway inflammation.
34
Li, Andrew, Hiang Ping Chan, Phyllis X. L. Gan, Mei Fong Liew, W. S. Fred Wong, and Hui-Fang Lim. "Eosinophilic endotype of chronic obstructive pulmonary disease: similarities and differences from asthma." Korean Journal of Internal Medicine 36, no. 6 (November 1, 2021): 1305–19. http://dx.doi.org/10.3904/kjim.2021.180.
Full textAbstract:
Approximately 25% to 40% of patients with chronic obstructive pulmonary disease (COPD) have the eosinophilic endotype. It is important to identify this group accurately because they are more symptomatic and are at increased risk for exacerbations and accelerated decline in forced expiratory volume in the 1st second. Importantly, this endotype is a marker of treat ment responsiveness to inhaled corticosteroid (ICS), resulting in decreased mortality risk. In this review, we highlight differences in the biology of eosinophils in COPD compared to asthma and the different definitions of the COPD eosinophilic endotype based on sputum and blood eosinophil count (BEC) with the corresponding limitations. Although BEC is useful as a biomarker for eosinophilic COPD endotype, optimal BEC cut-offs can be combined with clinical characteristics to improve its sensitivity and specificity. A targeted approach comprising airway eosinophilia and appropriate clinical and physiological features may improve identification of subgroups of patients who would benefit from biologic therapy or early use of ICS for disease modification.
35
Gavett, S. H., D. J. O'Hearn, X. Li, S. K. Huang, F. D. Finkelman, and M. Wills-Karp. "Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice." Journal of Experimental Medicine 182, no. 5 (November 1, 1995): 1527–36. http://dx.doi.org/10.1084/jem.182.5.1527.
Full textAbstract:
Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen-induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.
36
Yang, Liyan, Lauren Cohn, Dong-Hong Zhang, Robert Homer, Anuradha Ray, and Prabir Ray. "Essential Role of Nuclear Factor κB in the Induction of Eosinophilia in Allergic Airway Inflammation." Journal of Experimental Medicine 188, no. 9 (November 2, 1998): 1739–50. http://dx.doi.org/10.1084/jem.188.9.1739.
Full textAbstract:
The molecular mechanisms that contribute to an eosinophil-rich airway inflammation in asthma are unclear. A predominantly T helper 2 (Th2)-type cell response has been documented in allergic asthma. Here we show that mice deficient in the p50 subunit of nuclear factor (NF)- κB are incapable of mounting eosinophilic airway inflammation compared with wild-type mice. This deficiency was not due to a block in T cell priming or proliferation in the p50−/− mice, nor was it due to a defect in the expression of the cell adhesion molecules VCAM-1 and ICAM-1 that are required for the extravasation of eosinophils into the airways. The major defects in the p50−/− mice were the lack of production of the Th2 cytokine interleukin 5 and the chemokine eotaxin, which are crucial for proliferation and for differentiation and recruitment, respectively, of eosinophils into the asthmatic airway. Additionally, the p50−/− mice were deficient in the production of the chemokines macrophage inflammatory protein (MIP)-1α and MIP-1β that have been implicated in T cell recruitment to sites of inflammation. These results demonstrate a crucial role for NF-κB in vivo in the expression of important molecules that have been implicated in the pathogenesis of asthma.
37
Abdala-Valencia, Hiam, Julie Earwood, Shelly Bansal, Michael Jansen, George Babcock, Beth Garvy, Marsha Wills-Karp, and Joan M. Cook-Mills. "Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 5 (May 2007): L1111—L1125. http://dx.doi.org/10.1152/ajplung.00208.2006.
Full textAbstract:
Pulmonary eosinophilia is one of the most consistent hallmarks of asthma. Infiltration of eosinophils into the lung in experimental asthma is dependent on the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. Ligation of VCAM-1 activates endothelial cell NADPH oxidase, which is required for VCAM-1-dependent leukocyte migration in vitro. To examine whether endothelial-derived NADPH oxidase modulates eosinophil recruitment in vivo, mice deficient in NADPH oxidase (CYBB mice) were irradiated and received wild-type hematopoietic cells to generate chimeric CYBB mice. In response to ovalbumin (OVA) challenge, the chimeric CYBB mice had increased numbers of eosinophils bound to the endothelium as well as reduced eosinophilia in the lung tissue and bronchoalveolar lavage. This occurred independent of changes in VCAM-1 expression, cytokine/chemokine levels (IL-5, IL-10, IL-13, IFNγ, or eotaxin), or numbers of T cells, neutrophils, or mononuclear cells in the lavage fluids or lung tissue of OVA-challenged mice. Importantly, the OVA-challenged chimeric CYBB mice had reduced airway hyperresponsiveness (AHR). The AHR in OVA-challenged chimeric CYBB mice was restored by bypassing the endothelium with intratracheal administration of eosinophils. These data suggest that VCAM-1 induction of NADPH oxidase in the endothelium is necessary for the eosinophil recruitment during allergic inflammation. Moreover, these studies provide a basis for targeting VCAM-1-dependent signaling pathways in asthma therapies.
38
White, A. M., T. Yoshimura, A. W. Smith, J. Westwick, and M. L. Watson. "Airway inflammation induced by recombinant guinea pig tumor necrosis factor-alpha." American Journal of Physiology-Lung Cellular and Molecular Physiology 273, no. 3 (September 1, 1997): L524—L530. http://dx.doi.org/10.1152/ajplung.1997.273.3.l524.
Full textAbstract:
We have cloned and expressed recombinant guinea pig tumor necrosis factor-alpha (gpTNF-alpha) and examined its inflammatory activities after tracheal instillation in guinea pigs. A 1,071-bp cDNA, including the region encoding the full-length 234-amino acid gpTNF-alpha protein, was cloned from concanavalin A-stimulated guinea pig splenocytes. The 154-amino acid protein corresponding to secreted gpTNF-alpha was expressed as a fusion protein in Escherichia coli, purified by affinity chromatography, and cleaved to yield a 17-kDa protein. gpTNF-alpha had a cytotoxic effect on WEHI 164 cells and was detected by goat anti-murine tumor necrosis factor-alpha (TNF-alpha) antibody in Western blots. Intratracheal instillation of gpTNF-alpha (50-150 ng) caused pronounced and dose-dependent airway eosinophilia. Incubation of gpTNF-alpha with rabbit anti-murine TNF-alpha sera or heating the gpTNF-alpha before instillation reduced bronchoalveolar lavage (BAL) eosinophils to near control levels. Maximum BAL eosinophilia was observed at 24 h, but eosinophil numbers remained significantly above vehicle-treated animals for 72 h. Hence, gpTNF-alpha elicits a pronounced and protracted eosinophil accumulation in the guinea pig lung.
39
Antus, Balazs, and Imre Barta. "Blood Eosinophils and Exhaled Nitric Oxide: Surrogate Biomarkers of Airway Eosinophilia in Stable COPD and Exacerbation." Biomedicines 10, no. 9 (August 30, 2022): 2128. http://dx.doi.org/10.3390/biomedicines10092128.
Full textAbstract:
In recent years, tremendous efforts have been devoted to characterizing the inflammatory processes in chronic obstructive pulmonary disease (COPD) in order to provide more personalized treatment for COPD patients. While it has proved difficult to identify COPD-specific inflammatory pathways, the distinction between eosinophilic and non-eosinophilic airway inflammation has gained clinical relevance. Evidence has shown that sputum eosinophil counts are increased in a subset of COPD patients and that these patients are more responsive to oral or inhaled corticosteroid therapy. Due to feasibility issues associated with sputum cell profiling in daily clinical practice, peripheral blood eosinophil counts and fractional exhaled nitric oxide levels have been evaluated as surrogate biomarkers for assessing the extent of airway eosinophilia in COPD patients, both in stable disease and acute exacerbations. The diagnostic value of these markers is not equivalent and depends heavily on the patient’s condition at the time of sample collection. Additionally, the sensitivity and specificity of these tests may be influenced by the patient’s maintenance treatment. Overall, eosinophilic COPD may represent a distinct disease phenotype that needs to be further investigated in terms of prognosis and treatment outcomes.
40
Boberg, Emma, Kristina Johansson, Carina Malmhäll, Julie Weidner, and Madeleine Rådinger. "House Dust Mite Induces Bone Marrow IL-33-Responsive ILC2s and TH Cells." International Journal of Molecular Sciences 21, no. 11 (May 26, 2020): 3751. http://dx.doi.org/10.3390/ijms21113751.
Full textAbstract:
Type 2 innate lymphoid cells (ILC2s) and their adaptive counterpart type 2 T helper (TH2) cells respond to interleukin-33 (IL-33) by producing IL-5, which is a crucial cytokine for eosinophil development in the bone marrow. The aim of this study was to determine if bone marrow ILC2s, TH cells, and eosinophils are locally regulated by IL-33 in terms of number and activation upon exposure to the common aeroallergen house dust mite (HDM). Mice that were sensitized and challenged with HDM by intranasal exposures induced eosinophil development in the bone marrow with an initial increase of IL5Rα+ eosinophil progenitors, following elevated numbers of mature eosinophils and the induction of airway eosinophilia. Bone marrow ILC2s, TH2, and eosinophils all responded to HDM challenge by increased IL-33 receptor (ST2) expression. However, only ILC2s, but not TH cells, revealed increased ST2 expression at the onset of eosinophil development, which significantly correlated with the number of eosinophil progenitors. In summary, our findings suggest that airway allergen challenges with HDM activates IL-33-responsive ILC2s, TH cells, and eosinophils locally in the bone marrow. Targeting the IL-33/ST2 axis in allergic diseases including asthma may be beneficial by decreasing eosinophil production in the bone marrow.
41
Hancox, Robert J., Ian D. Pavord, and Malcolm R. Sears. "Associations between blood eosinophils and decline in lung function among adults with and without asthma." European Respiratory Journal 51, no. 4 (March 21, 2018): 1702536. http://dx.doi.org/10.1183/13993003.02536-2017.
Full textAbstract:
Eosinophilic inflammation and airway remodelling are characteristic features of asthma, but the association between them is unclear. We assessed associations between blood eosinophils and lung function decline in a population-based cohort of young adults.We used linear mixed models to analyse associations between blood eosinophils and spirometry at 21, 26, 32 and 38 years adjusting for sex, smoking, asthma and spirometry at age 18 years. We further analysed associations between mean eosinophil counts and changes in spirometry from ages 21 to 38 years.Higher eosinophils were associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratios and lower FEV1 % predicted values for both pre- and post-bronchodilator spirometry (all p-values ≤0.048). Although eosinophil counts were higher in participants with asthma, the associations between eosinophils and spirometry were similar among participants without asthma or wheeze. Participants with mean eosinophil counts >0.4×109 cells·L−1 between 21 and 38 years had greater declines in FEV1/FVC ratios (difference 1.8%, 95% CI 0.7–2.9%; p=0.001) and FEV1 values (difference 3.4% pred, 95% CI 1.5–5.4% pred); p=0.001) than those with lower counts.Blood eosinophils are associated with airflow obstruction and enhanced decline in lung function, independently of asthma and smoking. Eosinophilia is a risk factor for airflow obstruction even in those without symptoms.
42
Mitchell, Charlotte, Karin Provost, Naiqian Niu, Robert Homer, and Lauren Cohn. "Airway epithelium response to IFN-γ regulates allergic airway inflammation (91.7)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 91.7. http://dx.doi.org/10.4049/jimmunol.184.supp.91.7.
Full textAbstract:
Abstract IFN-γ produced by Th1 cells inhibits Th2-induced allergic airway disease by decreasing airway eosinophilia, mucus production and chitinase activity. To define pathways by which IFN-γ inhibits allergic airway inflammation, we generated bone marrow chimeras with IFN-γ receptor (IFN-γR) deficient mice, transferred OVA-specific Th1, Th2 or Th1+Th2 cells and exposed mice to inhaled OVA. In mice receiving Th1+Th2 cells, IFN-γR was required on both hematopoietic and non-hematopoietic cells for maximal inhibition of mucus and chitinase activity, while IFN-γR expression on hematopoietic cells was sufficient for inhibition of airway eosinophilia. We hypothesized that airway epithelial cells are essential non-hematopoietic cells required to mediate the inhibitory effects of IFN-γ during airway inflammation. We generated epi-IFN-γR mice that express IFN-γR only on airway epithelial cells. Epi-IFN-γR mice that received Th1+Th2 cells showed near total inhibition of mucus, suggesting that IFN-γ directly inhibits mucus in epithelial cells. In epi-IFN-γR mice that received Th1+Th2 cells there was partial inhibition of chitinase activity, likely due to direct effects of IFN-γ on the epithelium. In epi-IFN-γR mice, airway eosinophilia was moderately inhibited through effects on eosinophil development in the bone marrow. These studies show the importance of airway epithelial cells in the regulation of allergic airway disease and highlight the epithelium as a target for therapy in airway disease.
43
Pretolani, M., C. Ruffié, J. R. Lapa e Silva, D. Joseph, R. R. Lobb, and B. B. Vargaftig. "Antibody to very late activation antigen 4 prevents antigen-induced bronchial hyperreactivity and cellular infiltration in the guinea pig airways." Journal of Experimental Medicine 180, no. 3 (September 1, 1994): 795–805. http://dx.doi.org/10.1084/jem.180.3.795.
Full textAbstract:
This report examines the effect of an anti-VLA-4 monoclonal antibody (mAb) HP1/2 on antigen-induced bronchial hyperreactivity to methacholine, and on eosinophil and T lymphocyte infiltration in the airways of guinea pigs sensitized and challenged by aerosolized ovalbumin and used 24 h thereafter. The intravenous administration of 2.5 mg/kg of HP1/2, but not of its isotype-matched mAb 1E6, 1 h before and 4 h after antigen inhalation, markedly inhibited the increased bronchopulmonary responses to intravenous methacholine, as well as airway eosinophilia in bronchoalveolar lavage (BAL) fluid and in bronchial tissue. HP1/2 also suppressed the antigen-induced infiltration of the bronchial wall by CD4+ and CD8+ T lymphocytes, identified by immunohistochemical technique using specific mAbs that recognize antigenic epitopes of guinea pig T cells. Treatment with HP1/2 also resulted in a significant increase in the number of blood eosinophils, suggesting that inhibition by anti-VLA-4 mAb of eosinophil recruitment to the alveolar compartment may partially account for their accumulation in the circulation. These findings indicate that eosinophil and lymphocyte adhesion and subsequent infiltration into the guinea pig airways that follow antigen challenge are mediated by VLA-4. Furthermore, concomitant inhibition of antigen-induced bronchial hyperreactivity and of cellular infiltration by anti-VLA-4 mAb suggests a relationship between airway inflammation and modifications in the bronchopulmonary function.
44
Esnault, Stephane, Elizabeth A. Kelly, Sean H. Johnson, Larissa P. DeLain, Madeline J. Haedt, Andrea L. Noll, Nathan Sandbo, and Nizar N. Jarjour. "Matrix Metalloproteinase-9-Dependent Release of IL-1βby Human Eosinophils." Mediators of Inflammation 2019 (February 17, 2019): 1–11. http://dx.doi.org/10.1155/2019/7479107.
Full textAbstract:
Asthma is often associated with airway eosinophilia, and therapies targeting eosinophils are now available to treat severe eosinophilic asthma. Eosinophilic asthma is often due to a type-2 immune response and production of IL-5, which leads to eosinophilopiesis and recruitment of mature eosinophils in the airways. A concomitant type-2 and type-17 response has been reported in some individuals. IL-17 may be enhanced by IL-1βproduction and can lead to neutrophilic inflammation. In fact, both eosinophilic and neutrophilic (mixed granulocytic) inflammation are simultaneously present in a large population of patients with asthma. In monocyte/macrophage cell populations, release of mature IL-1βoccurs via toll-like receptor ligand-induced activation of the inflammasome. Within the inflammasome, a cascade of events leads to the activation of caspase-1, which cleaves pro-IL-1βprotein into a mature, releasable, and active form. We have demonstrated that eosinophils can release IL-1βin a Toll-like receptor ligand-independent fashion. The objective of this study was to determine the mechanisms underlying the production and maturation of IL-1βin cytokine-activated eosinophils. Using eosinophils from circulating blood and from bronchoalveolar lavage fluid after an airway allergen challenge, the present study demonstrates that cytokine-activated eosinophils express and release a bioactive form of IL-1βwith an apparent size less than the typical 17 kDa mature form produced by macrophages. Using a zymography approach and pharmacological inhibitors, we identified matrix metalloproteinase-9 (MMP-9) as a protease that cleaves pro-IL-1βinto a ~15 kDa form and allows the release of IL-1βfrom cytokine-activated eosinophils. Therefore, we conclude that activated eosinophils produce MMP-9, which causes the release of IL-1βin an inflammasome/caspase-1-independent manner. The production of IL-1βby eosinophils may be a link between the eosinophilic/type-2 immune response and the neutrophilic/type-17 immune response that is often associated with a more severe and treatment-refractory type of asthma.
45
Xavier-Elsas, P., C. L. C. A. Silva, L. Pinto, T. Queto, B. M. Vieira, M. G. Aranha, B. De Luca, et al. "Modulation of the Effects of Lung Immune Response on Bone Marrow by Oral Antigen Exposure." BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/474132.
Full textAbstract:
Allergic airway inflammation is attenuated by oral tolerization (oral exposure to allergen, followed by conventional sensitization and challenge with homologous antigen), which decreases airway allergen challenge-induced eosinophilic infiltration of the lungs and bone marrow eosinophilia. We examined its effects on bone marrow eosinophil and neutrophil production. Mice of wild type (BP-2, BALB/c, and C57BL/6) and mutant strains (lacking iNOS or CD95L) were given ovalbumin (OVA) or water (vehicle) orally and subsequently sensitized and challenged with OVA (OVA/OVA/OVA and H2O/OVA/OVA groups, resp.). Anti-OVA IgG and IgE, bone marrow eosinophil and neutrophil numbers, and eosinophil and neutrophil production ex vivo were evaluated. T lymphocytes from OVA/OVA/OVA or control H2O/OVA/OVA donors were transferred into naïve syngeneic recipients, which were subsequently sensitized/challenged with OVA. Alternatively, T lymphocytes were cocultured with bone marrow eosinophil precursors from histocompatible sensitized/challenged mice. OVA/OVA/OVA mice of the BP-2 and BALB/c strains showed, relative to H2O/OVA/OVA controls, significantly decreased bone marrow eosinophil counts and ex vivo eosinopoiesis/neutropoiesis. Full effectiveness in vivo required sequential oral/subcutaneous/intranasal exposures to the same allergen. Transfer of splenic T lymphocytes from OVA/OVA/OVA donors to naive recipients prevented bone marrow eosinophilia and eosinopoiesis in response to recipient sensitization/challenge and supressed eosinopoiesis upon coculture with syngeneic bone marrow precursors from sensitized/challenged donors.
46
Li, Li, Yiyang Xia, Andrea Nguyen, Yew Hon Lai, Lili Feng, Tim R. Mosmann, and David Lo. "Effects of Th2 Cytokines on Chemokine Expression in the Lung: IL-13 Potently Induces Eotaxin Expression by Airway Epithelial Cells." Journal of Immunology 162, no. 5 (March 1, 1999): 2477–87. http://dx.doi.org/10.4049/jimmunol.162.5.2477.
Full textAbstract:
Abstract Airway inflammation associated with asthma is characterized by massive infiltration of eosinophils, mediated in part by specific chemoattractant factors produced in the lung. Allergen-specific Th2 cells appear to play a central role in asthma; for example, adoptively transferred Th2 cells induced lung eosinophilia associated with induction of specific chemokines. Interestingly, Th2 supernatant alone administered intranasally to naive mice induced eotaxin, RANTES, monocyte-chemotactic protein-1, and KC expression along with lung eosinophilia. We tested the major cytokines individually and found that IL-4 and IL-5 induced higher levels of macrophage-inflammatory protein-1α and KC; IL-4 also increased the production of monocyte-chemotactic protein-1; IL-13 and IL-4 induced eotaxin. IL-13 was by far the most potent inducer of eotaxin; indeed, a neutralizing anti-IL-13 Ab removed most of the eotaxin-inducing activity from Th2 supernatants, although it did not entirely block the recruitment of eosinophils. While TNF-α did not stimulate eotaxin production by itself, it markedly augmented eotaxin induction by IL-13. IL-13 was able to induce eotaxin in the lung of JAK3-deficient mice, suggesting that JAK3 is not required for IL-13 signaling in airway epithelial cells; however, eosinophilia was not induced in this situation, suggesting that JAK3 transduces other IL-13-mediated mechanisms critical for eosinophil recruitment. Our study suggests that IL-13 is an important mediator in the pathogenesis of asthma and therefore a potential target for asthma therapy.
47
Muralidharan, Abenaya, Md Bashir Uddin, Christopher Bauer, Wenzhe Wu, Xiaoyong Bao, and Keer Sun. "IFN-γ Attenuates Eosinophilic Inflammation but Is Not Essential for Protection against RSV-Enhanced Asthmatic Comorbidity in Adult Mice." Viruses 14, no. 1 (January 14, 2022): 147. http://dx.doi.org/10.3390/v14010147.
Full textAbstract:
The susceptibility to respiratory syncytial virus (RSV) infection in early life has been associated with a deficient T-helper cell type 1 (Th1) response. Conversely, healthy adults generally do not exhibit severe illness from RSV infection. In the current study, we investigated whether Th1 cytokine IFN-γ is essential for protection against RSV and RSV-associated comorbidities in adult mice. We found that, distinct from influenza virus, prior RSV infection does not induce significant IFN-γ production and susceptibility to secondary Streptococcus pneumoniae infection in adult wild-type (WT) mice. In ovalbumin (OVA)-induced asthmatic mice, RSV super-infection increases airway neutrophil recruitment and inflammatory lung damage but has no significant effect on OVA-induced eosinophilia. Compared with WT controls, RSV infection of asthmatic Ifng−/− mice results in increased airway eosinophil accumulation. However, a comparable increase in eosinophilia was detected in house dust mite (HDM)-induced asthmatic Ifng−/− mice in the absence of RSV infection. Furthermore, neither WT nor Ifng−/− mice exhibit apparent eosinophil infiltration during RSV infection alone. Together, these findings indicate that, despite its critical role in limiting eosinophilic inflammation during asthma, IFN-γ is not essential for protection against RSV-induced exacerbation of asthmatic inflammation in adult mice.
48
Squebola-Cola, Dalize M., Glaucia C. Mello, Lorenzo Pissinatti, André A. Schenka, Gabriel F. Anhê, Ivani A. DeSouza, Antonio Condino-Neto, and Edson Antunes. "Airway exposure to staphylococcal enterotoxin A potentiates allergen-induced bone marrow eosinophilia and trafficking to peripheral blood and airways." American Journal of Physiology-Lung Cellular and Molecular Physiology 304, no. 10 (May 15, 2013): L639—L645. http://dx.doi.org/10.1152/ajplung.00025.2013.
Full textAbstract:
Bone marrow (BM) eosinopoiesis is a common feature during allergen exposure in atopic individuals. Airway exposure to staphylococcal superantigens aggravates allergic airway disease and increases the output of BM eosinophils. However, the exact mechanisms regulating eosinophil mobilization and trafficking to the peripheral circulation and airways remain to be elucidated. Therefore, this study aimed to investigate the mechanisms determining the BM eosinopoiesis in allergic mice under exposure to staphylococcal enterotoxin A (SEA). Ovalbumin (OVA)-sensitized male BALB/C mice were intranasally exposed to SEA (1 μg), and at 4, 12, 24, and 48 h later animals were challenged with OVA (10 μg, twice a day). Measurement of IL-5, eotaxin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels, flow cytometry for CCR3+, VLA4+, and CCR3+VLA4+, as well as adhesion assays to VCAM-1 were performed in BM. Prior airway exposure to SEA time dependently increased the BM eosinophil number in OVA-challenged mice. Eosinophils gradually disappear from peripheral blood, being recruited over time to the airways, where they achieve a maximal infiltration at 24 h. SEA exposure increased the levels of IL-5 and eotaxin (but not GM-CSF) in BM of OVA-challenged mice. Marked increases in CCR3+and CCR3+VLA4+expressions in BM eosinophils of OVA-challenged mice were observed, an effect largely reduced by prior exposure to SEA. Adhesion of BM eosinophils to VCAM-1 was increased in OVA-challenged mice, but prior SEA exposure abrogated this enhanced cell adhesion. Accumulation of BM eosinophils by airway SEA exposure takes place through IL-5- and CCR3-dependent mechanisms, along with downregulation of CCR3/VL4 and impaired cell adhesion to VCAM-1.
49
Shinagawa, Kazuhiko, Victoria A. Ploplis, and Francis J. Castellino. "A severe deficiency of coagulation factor VIIa results in attenuation of the asthmatic response in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 5 (May 2009): L763—L770. http://dx.doi.org/10.1152/ajplung.90638.2008.
Full textAbstract:
Eosinophil counts in the bronchoalveolar lavage fluid of wild-type (WT) mice increased after ovalbumin (OVA) challenge, a response that was diminished in comparably challenged low-expressing coagulation factor VII (FVIItTA/tTA) mice. Levels of T helper type 2 (Th2) cytokines, IL-4, IL-5, and IL-13, and eosinophil-attracting chemokines, eotaxin and RANTES, were also lower in the OVA-challenged FVIItTA/tTAmice. Eosinophils purified from low-FVII mice underwent apoptosis at a faster rate compared with WT eosinophils, and eosinophil migration in response to eotaxin was reduced in eosinophils obtained from FVIItTA/tTAmice. Airway hyperresponsiveness and mucous layer thickness were reduced in OVA-treated FVIItTA/tTAmice, and addition of exogenous coagulation factor X (FX) enhanced mucin production in human epithelial NCI-H292 cells. Correspondingly, incubation of FX with NCI-H292 cells resulted in activated (a) FX production, suggesting that the components required for FX activation were present on NCI-H292 cells. These results demonstrate that FVIIa functions in the asthmatic response to an allergen by stimulating lung eosinophilia, airway hyperresponsiveness, and mucin production, this latter effect through its ability to activate FX in conjunction with tissue factor.
50
Adamko, Darryl J., Bethany L. Yost, Gerald J. Gleich, Allison D. Fryer, and David B. Jacoby. "Ovalbumin Sensitization Changes the Inflammatory Response to Subsequent Parainfluenza Infection." Journal of Experimental Medicine 190, no. 10 (November 15, 1999): 1465–78. http://dx.doi.org/10.1084/jem.190.10.1465.
Full textAbstract:
Asthma exacerbations, many of which are virus induced, are associated with airway eosinophilia. This may reflect altered inflammatory response to viruses in atopic individuals. Inhibitory M2 muscarinic receptors (M2Rs) on the airway parasympathetic nerves limit acetylcholine release. Both viral infection and inhalational antigen challenge cause M2R dysfunction, leading to airway hyperresponsiveness. In antigen-challenged, but not virus-infected guinea pigs, M2R dysfunction is due to blockade of the receptors by the endogenous antagonist eosinophil major basic protein (MBP). We hypothesized that sensitization to a nonviral antigen before viral infection alters the inflammatory response to viral infection, so that M2R dysfunction and hyperreactivity are eosinophil mediated. Guinea pigs were sensitized to ovalbumin intraperitoneally, and 3 wk later were infected with parainfluenza. In sensitized, but not in nonsensitized animals, virus-induced hyperresponsiveness and M2R dysfunction were blocked by depletion of eosinophils with antibody to interleukin (IL)-5 or treatment with antibody to MBP. An additional and unexpected finding was that sensitization to ovalbumin caused a marked (80%) reduction in the viral content of the lungs. This was reversed by the antibody to IL-5, implicating a role for eosinophils in viral immunity.