The goal of this proposal is to establish an animal model for steroid-resistant neutrophilic asthma, that replicates patient symptoms to understand the underlying cellular and molecular pathology. Asthma is a chronic inflammatory disease characterized by recruitment of inflammatory cells, bronchial hyperreactivity, mucus production, and airway remodeling and narrowing. According to Centers for Disease Control and Prevention, 8.3% of the US population (children and adults) suffers from asthma with varying degree of severity. It has commonly been considered that airway inflammation is caused by the Th2 immune response, or eosinophilia, which is a hallmark of bronchial asthma pathogenesis. However, multiple clinical reports show that as high as 50% patients with symptomatic asthma have elevated sputum neutrophil counts. This non- eosinophilic asthma is often refractory to corticosteroids, the mainstay of asthma treatment, and is strongly associated with the presence of Th17 cytokines in the bronchial tissues and sputum. The clinical pattern of neutrophilic asthma is different from eosinophilic asthma with evidence of abnormal upper airway responses. Currently, the molecular pathology underlying neutrophilic asthma is very poorly understood, mainly due to the lack of appropriate animal models. Due to its alarmingly high prevalence, there is an urgent need to understand the pathophysiology of neutrophilic asthma, to inform targeted therapy. T cells from diverse individuals show different propensity to differentiate into distinct effector lineages, which underscores their susceptibility to allergic and inflammatory diseases. Genome-wide association studies on human subjects provide valuable information about intrinsic factors governing T cell responses, but these results are highly influenced by various environmental factors including weather and diet. To minimize influence of environmental factors, we examined cytokine expressions in T cells isolated from a hybrid mouse diversity panel consisting of 107 common inbred and recombinant-inbred strains fed with the same diet and housed under specific pathogen-free conditions. These efforts have resulted in identification of mouse strains that all show strong Th2 responses, but have varying degree of Th17 responses. Based on our findings, our specific goals are to 1) develop a new animal model of neutrophilic asthma using the mouse strain with T cells that shows high propensity to both Th2 and Th17 differentiation and 2) determine the cellular and molecular mechanism underlying propensity to neutrophilic asthma in these mice.
STATEMENT Many asthma patients show neutrophilic airway inflammation, which is directly related with severity of the disease and poor responses to current corticosteroid-based therapy. This study using a well-controlled mouse genetic system will help to develop a simple neutrophilic asthma model to test the potential of therapeutics and reveal one of the mechanisms underlying genetic variations in T cell propensity to the pathogenicity of asthma. Outcomes of this study can potentially lead to improved diagnosis and treatment options based on genetic predisposition of individuals.
