Asthma is a major public health problem but remains a poorly understood pathological phenomenon. Hyperplasia of the bronchial stoma, particularly of the airway smooth muscle (ASM), is a feature of chronic asthma which contributes to the increased hyper-reactivity and decreased airflow typical of this condition. Growth factors are likely to be involved in the pathogenesis of the ASM hyperplasia in asthma. The insulin-like growth factors (IGF) axis is comprised of a complex network of molecules involved in cellular proliferation and differentiation. We hypothesized that the human airway smooth muscle constitutes an environment in which IGFs, IGF binding proteins (IGFBPs), and IGFBP proteases are locally expressed and play an important role in the regulation of mitogenesis. In addition, we believe that specific mediators which affect the growth and death of ASM cells act via modulation of the IGF axis which, in turn, directly controls proliferation. Furthermore, we predict that as a result of inflammation and altered cytokine balance, the IGF axis in the asthmatic airway is perturbed, leading to abnormal proliferation of ASM cells. In preliminary studies we have shown that IGFs stimulate ASM proliferation, and IGFBPs inhibit ASM growth. Furthermore, we have shown that inflammatory mediators, including leukotriene D4, TGF-beta1 and others which regulate ASM proliferation and apoptosis, act by inducing IGFBPs or the activity of IGFBP proteases such as MMP-1. Thus, such cytokines affect the of control free IGFs which directly induce mitogenesis.
Our specific aims for this application are: 1) To fully characterize and define the IGF axis in human airway smooth muscle cells, and to determine the role of IGFBPs and their proteases in regulating ASM cell growth and apoptosis. 2) To investigate the mechanisms by which certain inflammatory cytokines (such as leukotrienes, TGF-beta1, and interleukins) affect ASM cell proliferation via IGF axis modulation. 3) To identify the presence of IGF-related molecules in normal human airway tissues and to detect abnormalities in their expression in airways from asthmatic individuals. We hope to demonstrate a clear role for the IGF system in the patho- physiology of asthma. We believe that these studies may help us understand the dis-regulated growth of asthmatic airway smooth muscle and allow us to optimize our therapeutic approaches to this disease.
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