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.

Eotaxin/CCL11 is involved in acute, but not chronic, allergic airway responses toAspergillus fumigatus

2002 ◽  
Vol 283 (1) ◽  
pp. L198-L204 ◽  
Author(s):  
Jane M. Schuh ◽  
Kate Blease ◽  
Steven L. Kunkel ◽  
Cory M. Hogaboam
Keyword(s):  
T Cell ◽  
Airway Hyperresponsiveness ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Th2 Cells ◽  
Wild Type ◽  
Cell Recruitment ◽  
Chronic Model ◽  
Airway Responses

Eotaxin/CCL11 is a major chemoattractant for eosinophils and Th2 cells. As such, it represents an attractive target in the treatment of allergic disease. The present study addresses the role of eotaxin/CCL11 during acute and chronic allergic airway responses to the fungus Aspergillus fumigatus. Mice lacking the eotaxin gene (Eo−/−) and wild-type mice (Eo+/+) were sensitized to A. fumigatus and received either an intratracheal challenge with soluble A. fumigatusantigens (acute model) or an intratracheal challenge with live A. fumigatus spores or conidia (chronic model). Airway hyperresponsiveness and eosinophil, but not T cell, recruitment were significantly decreased at 24 h after the soluble allergen in A. fumigatus-sensitized Eo−/− mice compared with similarly sensitized Eo+/+ mice. In contrast, the development of chronic allergic airway disease due to A. fumigatus conidia was not altered by the lack of eotaxin. Together, these data suggest that eotaxin initiates allergic airway disease due to A. fumigatus, but this chemokine did not appear to contribute to the maintenance of A. fumigatus-induced 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.

Glufosinate aerogenic exposure induces glutamate and IL-1 receptor dependent lung inflammation

2016 ◽  
Vol 130 (21) ◽  
pp. 1939-1954 ◽  
Author(s):  
Isabelle Maillet ◽  
Olivier Perche ◽  
Arnaud Pâris ◽  
Olivier Richard ◽  
Aurélie Gombault ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Inflammatory Cell ◽  
Pulmonary Inflammation ◽  
Airway Hyperreactivity ◽  
Dependent Lung ◽  
Cell Recruitment ◽  
Glufosinate Ammonium ◽  
Aerosol Exposure ◽  
Inflammatory Cell Recruitment ◽  
Structural Analogy

Glufosinate-ammonium (GLA), the active component of an herbicide, is known to cause neurotoxicity. GLA shares structural analogy with glutamate. It is a powerful inhibitor of glutamine synthetase (GS) and may bind to glutamate receptors. Since these potentials targets of GLA are present in lung and immune cells, we asked whether airway exposure to GLA may cause lung inflammation in mice. A single GLA exposure (1 mg/kg) induced seizures and inflammatory cell recruitment in the broncho-alveolar space, and increased myeloperoxidase (MPO), inducible NO synthase (iNOS), interstitial inflammation and disruption of alveolar septae within 6–24 h. Interleukin 1β (IL-1β) was increased and lung inflammation depended on IL-1 receptor 1 (IL-1R1). We demonstrate that glutamate receptor pathway is central, since the N-methyl-D-aspartate (NMDA) receptor inhibitor MK-801 prevented GLA-induced lung inflammation. Chronic exposure (0.2 mg/kg 3× per week for 4 weeks) caused moderate lung inflammation and enhanced airway hyperreactivity with significant increased airway resistance. In conclusion, GLA aerosol exposure causes glutamate signalling and IL-1R-dependent pulmonary inflammation with airway hyperreactivity in mice.

scholarly journals Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

2013 ◽  
Vol 304 (2) ◽  
pp. L92-L102 ◽  
Author(s):  
Yiqun Mo ◽  
Jing Chen ◽  
Connie F. Schlueter ◽  
Gary W. Hoyle
Keyword(s):  
Lung Function ◽  
Lung Injury ◽  
Airway Disease ◽  
Airway Hyperreactivity ◽  
Normal Lung ◽  
High Dose ◽  
Epithelial Repair ◽  
Keratin 5 ◽  
Normal Lung Function ◽  
Airway Fibrosis

Chlorine is a reactive gas that is considered a chemical threat agent. Humans who develop acute lung injury from chlorine inhalation typically recover normal lung function; however, a subset can experience chronic airway disease. To examine pathological changes following chlorine-induced lung injury, mice were exposed to a single high dose of chlorine, and repair of the lung was analyzed at multiple times after exposure. In FVB/NJ mice, chlorine inhalation caused pronounced fibrosis of larger airways that developed by day 7 after exposure and was associated with airway hyperreactivity. In contrast, A/J mice had little or no airway fibrosis and had normal lung function at day 7. Unexposed FVB/NJ mice had less keratin 5 staining (basal cell marker) than A/J mice in large intrapulmonary airways where epithelial repair was poor and fibrosis developed after chlorine exposure. FVB/NJ mice had large areas devoid of epithelium on day 1 after exposure leading to fibroproliferative lesions on days 4 and 7. A/J mice had airways covered by squamous keratin 5-stained cells on day 1 that transitioned to a highly proliferative reparative epithelium by day 4 followed by the reappearance of ciliated and Clara cells by day 7. The data suggest that lack of basal cells in the large intrapulmonary airways and failure to effect epithelial repair at these sites are factors contributing to the development of airway fibrosis in FVB/NJ mice. The observed differences in susceptibility to chlorine-induced airway disease provide a model in which mechanisms and treatment of airway fibrosis can be investigated.

scholarly journals Tregitopes Improve Asthma by Promoting Highly Suppressive and Antigen-Specific Tregs

2021 ◽  
Vol 12 ◽  
Author(s):  
Marieme Dembele ◽  
Shao Tao ◽  
Amir H. Massoud ◽  
S. M. Shahjahan Miah ◽  
Sandra Lelias ◽  
...  
Keyword(s):  
Adoptive Transfer ◽  
Murine Model ◽  
Airway Hyperresponsiveness ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Current Therapy ◽  
High Dose ◽  
T Regulatory Cell ◽  
Chronic Inflammatory Condition ◽  
Specific Tolerance

Tregitopes (T regulatory epitopes) are IgG-derived peptides with high affinity to major histocompatibility complex class II (MHCII), that are known to promote tolerance by activating T regulatory cell (Treg) activity. Here we characterized the effect of IgG Tregitopes in a well-established murine model of allergic asthma, demonstrating in vivo antigen-specific tolerance via adoptive transfer of Tregitope-and-allergen-activated Tregs. Asthma is a heterogeneous chronic inflammatory condition affecting the airways and impacting over 300 million individuals worldwide. Treatment is suppressive, and no current therapy addresses immune regulation in severely affected asthmatics. Although high dose intra-venous immunoglobulin (IVIg) is not commonly used in the asthma clinic setting, it has been shown to improve severe asthma in children and in adults. In our laboratory, we previously demonstrated that IVIg abrogates airway hyperresponsiveness (AHR) in a murine model of asthma and induces suppressive antigen-specific T-regulatory cells. We hypothesized that IgG-derived Tregitopes would modulate allergic airway disease by inducing highly suppressive antigen-specific Tregs capable of diminishing T effector cell responses and establishing antigen-specific tolerance. Using ovalbumin (OVA-) and ragweed-driven murine models of allergic airway disease, we characterized the immunoregulatory properties of Tregitopes and performed Treg adoptive transfer to OVA- and ragweed-allergic mice to test for allergen specificity. Treatment with Tregitopes attenuated allergen-induced airway hyperresponsiveness and lung inflammation. We demonstrated that Tregitopes induce highly suppressive allergen-specific Tregs. The tolerogenic action of IgG Tregitopes in our model is very similar to that of IVIg, so we foresee that IgG Tregitopes could potentially replace steroid-based treatment and can offer a synthetic alternative to IVIg in a range of inflammatory and allergic conditions.

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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