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.

scholarly journals The Biology of Prostaglandins and Their Role as a Target for Allergic Airway Disease Therapy

2020 ◽  
Vol 21 (5) ◽  
pp. 1851 ◽  
Author(s):  
Kijeong Lee ◽  
Sang Hag Lee ◽  
Tae Hoon Kim
Keyword(s):  
Nasal Polyposis ◽  
Allergic Inflammation ◽  
Cell Types ◽  
Airway Disease ◽  
G Protein Coupled Receptors ◽  
Allergic Airway Disease ◽  
Airway Diseases ◽  
Disease Therapy ◽  
Lipid Compounds ◽  
G Protein Coupled

Prostaglandins (PGs) are a family of lipid compounds that are derived from arachidonic acid via the cyclooxygenase pathway, and consist of PGD2, PGI2, PGE2, PGF2, and thromboxane B2. PGs signal through G-protein coupled receptors, and individual PGs affect allergic inflammation through different mechanisms according to the receptors with which they are associated. In this review article, we have focused on the metabolism of the cyclooxygenase pathway, and the distinct biological effect of each PG type on various cell types involved in allergic airway diseases, including asthma, allergic rhinitis, nasal polyposis, and aspirin-exacerbated respiratory disease.

scholarly journals Cleavage of Fibrinogen by Proteinases Elicits Allergic Responses Through Toll-Like Receptor 4

Science ◽  
2013 ◽  
Vol 341 (6147) ◽  
pp. 792-796 ◽  
Author(s):  
Valentine Ongeri Millien ◽  
Wen Lu ◽  
Joanne Shaw ◽  
Xiaoyi Yuan ◽  
Garbo Mak ◽  
...  
Keyword(s):  
Allergic Disease ◽  
Allergic Inflammation ◽  
Allergic Airway Inflammation ◽  
Airway Disease ◽  
Airway Epithelial Cells ◽  
Allergic Airway Disease ◽  
Airway Epithelial ◽  
Toll Like Receptor ◽  
Defensive Strategy ◽  
Toll Like Receptor 4

Proteinases and the innate immune receptor Toll-like receptor 4 (TLR4) are essential for expression of allergic inflammation and diseases such as asthma. A mechanism that links these inflammatory mediators is essential for explaining the fundamental basis of allergic disease but has been elusive. Here, we demonstrate that TLR4 is activated by airway proteinase activity to initiate both allergic airway disease and antifungal immunity. These outcomes were induced by proteinase cleavage of the clotting protein fibrinogen, yielding fibrinogen cleavage products that acted as TLR4 ligands on airway epithelial cells and macrophages. Thus, allergic airway inflammation represents an antifungal defensive strategy that is driven by fibrinogen cleavage and TLR4 activation. These findings clarify the molecular basis of allergic disease and suggest new therapeutic strategies.

scholarly journals Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuying Zeng ◽  
Yun Zhang ◽  
Xinyan Huang ◽  
Lizhen Song ◽  
Katherine Polsky ◽  
...  
Keyword(s):  
Hypersensitivity Pneumonitis ◽  
Fungal Spores ◽  
Airway Disease ◽  
Airway Hyperreactivity ◽  
Allergic Airway Disease ◽  
High Dose ◽  
Cell Recruitment ◽  
Robust Model ◽  
Inflammatory Cell Recruitment ◽  
Diffuse Lung

Abstract Background Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger). Methods C57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 μg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined. Results In comparison to mice challenged only with A. niger, addition of LPS (1 μg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and TH2 responses while enhancing TH1 and TH17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies. Conclusions In contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP.

scholarly journals IL-10 AND IL-35 AS INFLAMMATION REGULATORS IN PATIENTS WITH ALLERGIC RHINITIS AND MILD ATOPIC ASTHMA

2022 ◽  
pp. 1-12
Keyword(s):  
Allergic Rhinitis ◽  
Healthy Subjects ◽  
Respiratory Diseases ◽  
Allergic Inflammation ◽  
Serum Levels ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Atopic Asthma ◽  
Healthy State ◽  
Immunosuppressive Cytokines

Background. Significantly less is known about the immunoregulative cytokines, especially in allergic airway disease. This study aims to present the involvement of IL-35 and IL-10 in patients with allergic rhinitis (AR) and allergic bronchial asthma (BA). Methodology. The study comprised 71 patients –AR, patients with concomitant AR and mild atopic BA, and healthy controls (HC). We examined the serum levels of IL-35 and IL-10, along with other instrumental examinations, between March and September 2021. Findings. Levels of the regulatory cytokines IL-35 and IL-10 were significantly lower in patients than in HC (87.19±11.90 vs. 96.12±1.79 pg/ml; and 30.26±17.55 vs. 111.56±65.03 pg/ml, respectively). Furthermore, threefold higher serum IL-10 levels were found in healthy subjects compared to patients (p = 0.006). No difference in the levels of interleukins was found between the studied groups. Conclusions. Our results indicate that elevated IL-35 and IL-10 may play an essential role in reducing the activity of underlying allergic inflammation in allergic respiratory diseases, although no difference in the levels of the studied cytokines was found between the different groups of patients. Therefore, we can speculate that the immunosuppressive cytokines IL-35 and IL-10 were involved in maintaining the healthy state of no inflammation.

scholarly journals Effect of Lavandula dentata extract on Ovalbumin-induced Asthma in Male Guinea Pigs

2020 ◽  
Vol 80 (1) ◽  
pp. 87-96
Author(s):  
Z. N. Almohawes ◽  
H. S. Alruhaimi
Keyword(s):  
Oxidative Stress ◽  
Total Cholesterol ◽  
Tween 80 ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Adult Males ◽  
Sod Activity ◽  
Glucose Levels ◽  
Asthma Model ◽  
Guinea Pig Model

Abstract Asthma is an inflammatory disease of the lungs, and it causes oxidative stress. Lavandula dentata is an aromatic herb with anti-oxidative and anti-inflammatory activities. This study examined the activity of L. dentata extract on a guinea pig model of asthma. Adult males were divided into five groups: First group was control, second was asthma model induced by OVA, third was treated with L. dentata extract orally (300 mg/kg) for 21 days; the fourth was an asthma model with L. dentata extract (300 mg/kg) and fifth was treated with Tween 80 for 21 days. OVA treatment increased IgE, triglycerides, total cholesterol, glucose levels in serum, WBC count in blood and MDA in lungs. Also, OVA reduced SOD activity, GSH content in lungs, and GGT activity in serum (p<0.05). L. dentata extract treatment in asthma model reduced elevated IgE, triglycerides, total cholesterol, glucose levels in serum, and MDA in lungs (p<0.05), while it increased GSH content in lungs (p<0.05). These results suggest the possibility that L . dentata extract can exert suppressive effects on asthma, and may provide evidence that it is a useful agent for the treatment of allergic airway disease, it also limits oxidative stress induced by OVA. L. dentata extract appears to have hypolipidemic and hypoglycemic activities.

scholarly journals Regulatory T cells and IL-10 in allergic inflammation

2005 ◽  
Vol 202 (11) ◽  
pp. 1459-1463 ◽  
Author(s):  
Catherine M. Hawrylowicz
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Allergic Inflammation ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Active Disease

Recent studies suggest that human regulatory T (T reg) cells protect against the development of allergic and asthmatic disease and that their function is impaired during active disease. Two new studies contribute to our understanding of the role that T reg cells play in the control of allergic airway disease in mice. However, these studies also highlight several outstanding questions in the field.

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.

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