scholarly journals Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma

2006 ◽  
Vol 203 (5) ◽  
pp. 1173-1184 ◽  
Author(s):  
Jiankun Tong ◽  
Hozefa S. Bandulwala ◽  
Bryan S. Clay ◽  
Robert A. Anders ◽  
Rebecca A. Shilling ◽  
...  
Keyword(s):  
T Cells ◽  
Airway Inflammation ◽  
Inflammatory Cells ◽  
Airway Disease ◽  
Airway Hyperreactivity ◽  
Allergic Airway Disease ◽  
Mucus Production ◽  
Human T Cells ◽  
Highly Sensitive

Persistent airway inflammation, mucus production, and airway hyperreactivity are the major contributors to the frequency and severity of asthma. Why lung inflammation persists in asthmatics remains unclear. It has been proposed that Fas-mediated apoptosis of inflammatory cells is a fundamental mechanism involved in the resolution of eosinophilic airway inflammation. Because infiltrating eosinophils are highly sensitive to Fas-mediated apoptosis, it has been presumed that direct ligation of Fas on eosinophils is involved. Here, we utilize adoptive transfers of T cells to demonstrate that the delayed resolution of eosinophilia in Fas-deficient mice is a downstream effect of Fas deficiency on T cells, not eosinophils. Interestingly, the mice that received Fas-deficient T cells, but not the controls, developed a persistent phase of inflammation that failed to resolve even 6 wk after the last challenge. This persistent phase correlated with decreased interferon (IFN)γ production by Fas-deficient T cells and could be reproduced with adoptive transfer of IFNγ-deficient T cells. These data demonstrate that Fas deficiency on T cells is sufficient for the development of long-term allergic airway disease in mice and implies that deregulation of death receptors such as Fas on human T cells could be an important factor in the development and/or chronic nature of asthma.

scholarly journals Regulatory T cells mediated immunomodulation during asthma: a therapeutic standpoint

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Mohammad Afzal Khan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Airway Inflammation ◽  
Therapeutic Potential ◽  
Airway Remodeling ◽  
Clinical Manifestations ◽  
Inflammatory Cells ◽  
Airway Disease ◽  
Vital Role ◽  
Allergic Airway Disease

AbstractAsthma is an inflammatory disease of the lung airway network, which is initiated and perpetuated by allergen-specific CD4+ T cells, IgE antibodies, and a massive release of Th2 cytokines. The most common clinical manifestations of asthma progression include airway inflammation, pathological airway tissue and microvascular remodeling, which leads to airway hyperresponsiveness (AHR), and reversible airway obstruction. In addition to inflammatory cells, a tiny population of Regulatory T cells (Tregs) control immune homeostasis, suppress allergic responses, and participate in the resolution of inflammation-associated tissue injuries. Preclinical and clinical studies have demonstrated a tremendous therapeutic potential of Tregs in allergic airway disease, which plays a crucial role in immunosuppression, and rejuvenation of inflamed airways. These findings supported to harness the immunotherapeutic potential of Tregs to suppress airway inflammation and airway microvascular reestablishment during the progression of the asthma disease. This review addresses the therapeutic impact of Tregs and how Treg mediated immunomodulation plays a vital role in subduing the development of airway inflammation, and associated airway remodeling during the onset of disease.

scholarly journals Airway responsiveness in CD38-deficient mice in allergic airway disease: studies with bone marrow chimeras

2015 ◽  
Vol 308 (5) ◽  
pp. L485-L493 ◽  
Author(s):  
Alonso G. P. Guedes ◽  
Joseph A. Jude ◽  
Jaime Paulin ◽  
Laura Rivero-Nava ◽  
Hirohito Kita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Airway Inflammation ◽  
Surface Protein ◽  
Inflammatory Cells ◽  
Airway Disease ◽  
Airway Responsiveness ◽  
Allergic Airway Disease ◽  
Lower Airway ◽  
Protein Antigens ◽  
Bone Marrow Chimeras

CD38 is a cell-surface protein involved in calcium signaling and contractility of airway smooth muscle. It has a role in normal airway responsiveness and in airway hyperresponsiveness (AHR) developed following airway exposure to IL-13 and TNF-α but appears not to be critical to airway inflammation in response to the cytokines. CD38 is also involved in T cell-mediated immune response to protein antigens. In this study, we assessed the contribution of CD38 to AHR and inflammation to two distinct allergens, ovalbumin and the epidemiologically relevant environmental fungus Alternaria. We also generated bone marrow chimeras to assess whether Cd38+/+inflammatory cells would restore AHR in the CD38-deficient ( Cd38−/−) hosts following ovalbumin challenge. Results show that wild-type (WT) mice develop greater AHR to inhaled methacholine than Cd38−/−mice following challenge with either allergen, with comparable airway inflammation. Reciprocal bone marrow transfers did not change the native airway phenotypic differences between WT and Cd38−/−mice, indicating that the lower airway reactivity of Cd38−/−mice stems from Cd38−/−lung parenchymal cells. Following bone marrow transfer from either source and ovalbumin challenge, the phenotype of Cd38−/−hosts was partially reversed, whereas the airway phenotype of the WT hosts was preserved. Airway inflammation was similar in Cd38−/−and WT chimeras. These results indicate that loss of CD38 on hematopoietic cells is not sufficient to prevent AHR and that the magnitude of airway inflammation is not the predominant underlying determinant of AHR in mice.

scholarly journals Mcl-1 protects eosinophils from apoptosis and exacerbates allergic airway inflammation

Thorax ◽  
2020 ◽  
Vol 75 (7) ◽  
pp. 600-605
Author(s):  
Jennifer M Felton ◽  
David A Dorward ◽  
Jennifer A Cartwright ◽  
Philippe MD Potey ◽  
Calum T Robb ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Kinase Inhibitor ◽  
Allergic Airway Inflammation ◽  
Allergic Diseases ◽  
Airway Disease ◽  
Lavage Fluid ◽  
Allergic Airway Disease ◽  
Cyclin Dependent Kinase ◽  
Mucus Production ◽  
Effector Cells

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.

scholarly journals Inhibition of MAPK and STAT3-SOCS3 by Sakuranetin Attenuated Chronic Allergic Airway Inflammation in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Fernanda P. R. Santana ◽  
Rafael C. da Silva ◽  
Simone dos S. Grecco ◽  
Aruanã J. M. C. R. Pinheiro ◽  
Luciana C. Caperuto ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Intracellular Signaling ◽  
Lung Inflammation ◽  
Serum Antibody ◽  
Allergic Airway Disease ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Mucus Production ◽  
Th17 Cytokines

Asthma allergic disease is caused by airway chronic inflammation. Some intracellular signaling pathways, such as MAPK and STAT3-SOCS3, are involved in the control of airway inflammation in asthma. The flavonoid sakuranetin demonstrated an anti-inflammatory effect in different asthma models. Our aim was to clarify how sakuranetin treatment affects MAPK and STAT3-SOCS3 pathways in a murine experimental asthma model. Mice were submitted to an asthma ovalbumin-induction protocol and were treated with vehicle, sakuranetin, or dexamethasone. We assayed the inflammatory profile, mucus production, and serum antibody, STAT3-SOCS3, and MAPK levels in the lungs. Morphological alterations were also evaluated in the liver. LPS-stimulated RAW 264.7 cells were used to evaluate the effects of sakuranetin on nitric oxide (NO) and cytokine production. In vivo, sakuranetin treatment reduced serum IgE levels, lung inflammation (eosinophils, neutrophils, and Th2/Th17 cytokines), and respiratory epithelial mucus production in ovalbumin-sensitized animals. Considering possible mechanisms, sakuranetin inhibits the activation of ERK1/2, JNK, p38, and STAT3 in the lungs. No alterations were found in the liver for treated animals. Sakuranetin did not modify in vitro cell viability in RAW 264.7 and reduced NO release and gene expression of IL-1β and IL-6 induced by LPS in these cells. In conclusion, our data showed that the inhibitory effects of sakuranetin on eosinophilic lung inflammation can be due to the inhibition of Th2 and Th17 cytokines and the inhibition of MAPK and STAT3 pathways, reinforcing the idea that sakuranetin can be considered a relevant candidate for the treatment of inflammatory allergic airway disease.

scholarly journals Disulfide disruption reverses mucus dysfunction in allergic airway disease

2019 ◽  
Author(s):  
Leslie E. Morgan ◽  
Siddharth K. Shenoy ◽  
Dorota Raclawska ◽  
Nkechinyere A. Emezienna ◽  
Vanessa L. Richardson ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Allergic Inflammation ◽  
Airway Disease ◽  
Airway Hyperreactivity ◽  
Allergic Airway Disease ◽  
Mucus Hypersecretion ◽  
Asthma Model ◽  
Targeted Treatments ◽  
Fungal Allergen ◽  
Respiratory Conditions

Airway mucus is essential for healthy lung defense1, but excessive mucus in asthma obstructs airflow, leading to severe and potentially fatal outcomes2–5. Current asthma therapies reduce allergic inflammation and relax airway smooth muscle, but treatments are often inadequate due to their minimal effects on mucus obstruction6,7. The lack of efficacious mucus-targeted treatments stems from a poor understanding of healthy mucus function and pathological mucus dysfunction at a molecular level. The chief macromolecules in mucus, polymeric mucins, are massive glycoproteins whose sizes and biophysical properties are dictated in part by covalent disulfide bonds that link mucin molecules into assemblies of 10 or more subunits8. Once secreted, mucin glycopolymers can aggregate to form plugs that block airflow. Here we show that reducing mucin disulfide bonds depolymerizes mucus in human asthma and reverses pathological effects of mucus hypersecretion in a mouse allergic asthma model. In mice challenged with a fungal allergen, inhaled mucolytic treatment acutely loosened mucus mesh, enhanced mucociliary clearance (MCC), and abolished airway hyperreactivity (AHR) to the bronchoprovocative agent methacholine. AHR reversal was directly related to reduced mucus plugging. Furthermore, protection in mucolytic treated mice was identical to prevention observed in mice lacking Muc5ac, the polymeric mucin required for allergic AHR in murine models9. These findings establish grounds for developing novel fast-acting agents to treat mucus hypersecretion in asthma10,11. Efficacious mucolytic therapies could be used to directly improve airflow, help resolve inflammation, and enhance the effects of inhaled treatments for asthma and other respiratory conditions11,12.

Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes

2007 ◽  
Vol 293 (3) ◽  
pp. L730-L739 ◽  
Author(s):  
Jill R. Johnson ◽  
Filip K. Swirski ◽  
Beata U. Gajewska ◽  
Ryan E. Wiley ◽  
Ramzi Fattouh ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inflammatory Responses ◽  
Airway Remodeling ◽  
Bronchial Hyperresponsiveness ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Th Cell ◽  
And Function ◽  
Deficient Mice ◽  
Chronic Airway

Asthma is a chronic airway inflammatory disease that encompasses three cardinal processes: T helper (Th) cell type 2 (Th2)-polarized inflammation, bronchial hyperreactivity, and airway wall remodeling. However, the link between the immune-inflammatory phenotype and the structural-functional phenotype remains to be fully defined. The objective of these studies was to evaluate the relationship between the immunologic nature of chronic airway inflammation and the development of abnormal airway structure and function in a mouse model of chronic asthma. Using IL-4-competent and IL-4-deficient mice, we created divergent immune-inflammatory responses to chronic aeroallergen challenge. Immune-inflammatory, structural, and physiological parameters of chronic allergic airway disease were evaluated in both strains of mice. Although both strains developed airway inflammation, the profiles of the immune-inflammatory responses were markedly different: IL-4-competent mice elicited a Th2-polarized response and IL-4-deficient mice developed a Th1-polarized response. Importantly, this chronic Th1-polarized immune response was not associated with airway remodeling or bronchial hyperresponsiveness. Transient reconstitution of IL-4 in IL-4-deficient mice via an airway gene transfer approach led to partial Th2 repolarization and increased bronchial hyperresponsiveness, along with full reconstitution of airway remodeling. These data show that distinct structural-functional phenotypes associated with chronic airway inflammation are strictly dependent on the nature of the immune-inflammatory response.

scholarly journals Dilodendron bipinnatum Radlk. ameliorates airway inflammation through multiple targets in a murine model of ovalbumin-induced allergic airway disease

2018 ◽  
Vol 226 ◽  
pp. 17-25 ◽  
Author(s):  
Ruberlei Godinho de Oliveira ◽  
Fábio Miyajima ◽  
Geovane Roberto de Campos Castilho ◽  
Amílcar Sabino Damazo ◽  
Antonio Macho ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Murine Model ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Multiple Targets

scholarly journals The effect of short-term and long-term application of fisetin on experimentally induced airway hyperreactivity

2017 ◽  
Vol 64 (1) ◽  
pp. 7-9
Author(s):  
I. Kazimierová ◽  
L. Pappová ◽  
M. Šútovská ◽  
S. Fraňová
Keyword(s):  
Airway Inflammation ◽  
Airway Resistance ◽  
Chronic Administration ◽  
Airway Hyperreactivity ◽  
Whole Body ◽  
Short Term ◽  
Specific Airway Resistance ◽  
Term Administration

AbstractBackground:Fisetin, a derivate from the flavonol group may possess a variety of pharmacological effects. The aim of the presented study was to evaluate the bronchodilatory effect of fisetin after the acute or the chronic administration to guinea pigs with allergic airway inflammation.Methods:Experimental animals were sensitized and challenged by ovalbumin. Fisetin was administered in dose 5mg/kg/p.o., either once after the end of 21-days sensitization or daily during the 21-days sensitization. By using the whole-body plethysmograph, we monitored the specific airway resistance, a parameter of airway hyperreactivityin vivo. The changes of the specific airway resistance were evaluated after the short-term inhalation of the bronchoconstriction mediator-histamine (10−6mol.1−1).Results:Our results showed that the short-term as well as the long-term administration of fisetin caused decrease of the specific airway resistance values. The bronchodilatory effect of fisetin was comparable to the long-acting beta2sympathomimetic – salmeterol after the long-term administration. The measurements of the bronchodilatory activity after single administration have revealed more prolonged effect of fisetin comparing to the short-acting beta2sympathomimetic – salbutamol, as this remained even after the 5 hours, when salbutamol was already ineffective.Conclusion:In conclusion, flavonol – fisetin has shown bronchodilatory potential. In the light of this fact, fisetin may represent potential substance that can be effective in both prevention as well as control of airway inflammation symptoms.

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