Chronic asthma is associated with airway smooth muscle (ASM) cell hyperplasia which contributes to the increased hyper-reactivity and decreased airflow typical of this condition. The type of mitogens regulating ASM cell proliferation is not clearly understood. Preliminary observations in our lab strongly suggest a role for the Insulin-like Growth Factor Binding Protein (IGFBP) protease, Matrix Metalloproteinase- 1, in ASM cell growth. IGFBP proteases are one of the many components of IGF axis. We propose to systematically evaluate the presence of IGFs, their receptors (IGF-R), IGFBPs, and IGFBP proteases in human ASM (hASM) cells and evaluate the action of these factors on hASM proliferation and programmed cell death (Apoptosis). We hypothesize that specific mediators such as inflammation associated cytokines, which affect the mitogenesis of ASM cells, act via modulation of the IGF axis which, in turn, directly controls ASM cellular growth. We hope to document that selective manipulation of the cellular environment with the cytokines associated with asthma will alter the IGF axis status and thereby lead to hASM hyperplasia. We hope to demonstrate that IGFBPs and their proteases are important regulators of hASM cell growth and proliferation and intervention at the level of the IGF axis will prevent the pro-mitogenic effects of inflammation in the asthmatic airways, and may slow down ASM hyperplasia. We believe that these studies may help us understand the dis-regulated growth of ASM in asthma and allow us to optimize our therapeutic approaches to this disease.
