Asthma prevalence and mortality have increased steadily over the last decade. These facts highlight the need for a better understanding of the cellular and molecular mechanisms that contribute to the pathogenesis of asthma. While the pathophysiologic manifestations of this disease have traditionally been thought to be reversible, there is now evidence that in some asthmatics structural changes to the airway occur that can lead to persistent obstruction and bronchial hyperactivity. These structural changes, referred to as airway remodeling, include an increase in airway smooth muscle mass, mucous gland hyperplasia, and disruption of airway epithelium and subepithelial fibrosis. Furthermore, published data support that increased smooth muscle mass is likely the major determinant of airflow limitation in asthmatics with chronic obstruction. As a result, it is critical to understand the molecular mechanisms of airway smooth muscle growth that underlie these chronic changes in asthmatic airways. Both in vitro and in vivo studies suggest that the growth factor PDGF and the cytokine IL-11 are important contributors to airway smooth muscle cell proliferation. These mitogens signal via unique receptors that either have inherent tyrosine kinase activity or that lead to activation of the mitogen-activated protein kinase and phosphoinositol-3-kinase pathways. We and others have shown that these proximal pathways also converge to activate the Janus kinases (Jak) and signal transducers and activators of transcription (STAT; Jak-STAT pathway). This proposal seeks to test the hypothesis, using both in vitro and in vivo models, that activation of the Jak-STAT pathway plays a central role in airway smooth muscle mitogenesis and airway remodeling.
Our specific aims are to: 1) To characterize PDGF- and IL-11-mediated activation of the Jak-STAT pathway in HASMC, 2) To determine the mechanisms of STAT-induced proliferation in HASMC and 3) To examine the role of the Jak-STAT pathway in ASM proliferation in two different animal models of airway remodeling. It is anticipated that these studies will contribute to our understanding of the mechanisms of chronic airway inflammation and subsequent remodeling seen in asthma, and may provide novel therapeutic strategies for this common and debilitating pulmonary disorder.
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