The effect of serine protease inhibitors on airway inflammation in a chronic allergen-induced asthma mouse model.

Chih-Che Lin,Shung-Te Kao,Li-Jen Lin,Chung-Jen Chiang,Joseph Lin,Yun-Peng Chao,Shulhn-Der Wang

doi:10.1155/2014/879326

Abstract

Serine protease inhibitors reportedly attenuated airway inflammation and had antioxidant in multiorgan. However, the effects of the serine protease inhibitors nafamostat mesilate (FUT), gabexate mesilate (FOY), and ulinastatin (UTI) on a long-term challenged mouse model of chronic asthma are unclear. BALB/c mice (6 mice/group) were intratracheally inoculated with five doses of Dermatophagoides pteronyssinus (Der p; 50 μL, 1 mg/mL) at one-week intervals. Therapeutic doses of FUT (0.0625 mg/kg), FOY (20 mg/kg), or UTI (10,000 U/kg) were, respectively, injected intraperitoneally into these mice. Control mice received sterile PBS. At 3 days after the last challenge, mice were sacrificed to assess airway hyperresponsiveness (AHR), remodeling, and inflammation; lung histological features; and cytokine expression profiles. Compared with untreated controls, mice treated with FUT, FOY, and UTI had decreased AHR and goblet cell hyperplasia, decreased eosinophil and neutrophil infiltration, decreased Der p-induced IL-4 levels in serum and IL-5, IL-6, IL-13, and IL-17 levels in bronchoalveolar lavage fluid, and inhibited nuclear factor (NF)-κB activity in lung tissues. The serine protease inhibitors FUT, FOY, and UTI have potential therapeutic benefits for treating asthma by downregulating Th2 cytokines and Th17 cell function and inhibiting NF-κB activation in lung tissue.

Highlights

Asthma is a common chronic inflammatory disease of the airways and is characterized by intermittent attacks of breathlessness, airway hyperreactivity, wheezing, and cough in response to allergen exposure
In a previous report using an acute murine asthma model, we demonstrated that FUT and FOY inhibited antigeninduced airway eosinophilia, IgE production, and IL-4 and TNF-α levels and augmented IL-12 levels, a critical Th1 cytokine, in bronchoalveolar lavage fluid (BALF); UTI had no effect [12]
We used repetitive Dermatophagoides pteronyssinus (Der p) challenges to test the effects of three protease inhibitors (FUT, FOY, and UT1) on allergen-induced chronic airway inflammation in a mouse model

Summary

Introduction

Asthma is a common chronic inflammatory disease of the airways and is characterized by intermittent attacks of breathlessness, airway hyperreactivity, wheezing, and cough in response to allergen exposure. The chronic inflammation in asthma is characterized by eosinophilic recruitment, airway hyperresponsiveness (AHR), goblet cell hyperplasia/metaplasia, epithelial hypertrophy/hyperplasia, mucus hypersecretion, collagen deposition, smooth muscle cell hypertrophy/hyperplasia, and subepithelial fibrosis [1, 2]. CD4+ T cells, including Th1, Th2, Th17, and Treg cells, are active during different phases of bronchial asthma, and the expression of their various cellular products play different roles in lung inflammation [4]. Both extracellular endogenous proteases and exogenous proteases play major roles in asthma pathophysiology.

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