Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses
Open Access
- 24 January 2013
- journal article
- Published by Springer Science and Business Media LLC in Respiratory Research
- Vol. 14 (1), 8
- https://doi.org/10.1186/1465-9921-14-8
Abstract
Background Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. Methods BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. Results Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. Conclusion These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil- and eosinophil-dominant phases of the response to secondary allergen challenge.Keywords
This publication has 50 references indexed in Scilit:
- Neutrophil Serine Proteinases Activate Human Nonepithelial Cells to Produce Inflammatory Cytokines Through Protease-Activated Receptor 2The Journal of Immunology, 2003
- Expression of and functional responses to protease-activated receptors on human eosinophilsJournal of Leukocyte Biology, 2003
- The role of T lymphocytes in the pathogenesis of asthmaJournal of Allergy and Clinical Immunology, 2003
- Protease-Activated Receptor 2 Mediates Eosinophil Infiltration and Hyperreactivity in Allergic Inflammation of the AirwayThe Journal of Immunology, 2002
- Expression and Function of Proteinase-activated Receptor 2 in Human Bronchial Smooth MuscleAmerican Journal of Respiratory and Critical Care Medicine, 2001
- Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1The Journal of Experimental Medicine, 2001
- Protease-activated Receptor-2 (PAR2) in the AirwaysPulmonary Pharmacology & Therapeutics, 2001
- Proteinase-activated receptors.2001
- Pulmonary T cells and eosinophils: Coconspirators or independent triggers of allergic respiratory pathology?Journal of Allergy and Clinical Immunology, 2001
- Role of neutrophil elastase in hypersecretion in asthmaEuropean Respiratory Journal, 1999