Bronchopulmonary dysplasia (BPD) is a major public health problem, but it remains a poorly understood pathological phenomenon. Possible involvement of growth factors and cytokines in early lung development and in athe pathogenesis of BPD has been suggested, but has not been thoroughly studied. The insulin like growth factors (IGFs) have been demonstrated to be critical regulators of cellular growth in other systems and are likely to play a key role in the lung. The IGF axis is comprised of a complex network of molecular involved in cellular proliferation and differentiation. This axis includes the two IGF ligands, two receptor with differing cellular effects, and a family of six IGF binding proteins (IGFBPs) which modulate IGF availability to IGF receptors (IGF-R) and also have independent effects on cell function and growth. The IGFBPs, in turn, are regulated by a group of IGFBP proteases which cleave the IGFBPs into lower affinity fragments. Our hypotheses are that the developing human fetal lung constitutes an environment in which IGFs, IGF-R, IGFBPs, and IGFBP proteases are locally expressed and play an important role in proliferation, differentiation and maturation. In addition, we believe that specific mediators which affect the mitogenesis of lung cells act via modulation of the IGF axis which, i n turn, directly controls cellular growth. Furthermore, we predict that as a result of oxygen toxicity, inflammation, and altered cytokine balance, the IGF axis in the lungs of infants with BPD is altered, leading to abnormal proliferation and dis- organization of lung tissues. We hope to show that perinatal and postnatal intervention with TRH and steroids will prevent the IGF-related effects of inflammation in the premature lung. In preliminary experiments, using various protein and mRNA detection techniques, as well as histo- morphological localization approaches, we have been able to demonstrate a clear ontogeny of IGFs and IGFBPs in the lung. Furthermore, examination of lung specimens from patients with BPD demonstrated dramatic changes in the expression of IGF axis components, including IGFs, IGF-R, and IGFBPs.
Our specific aims for this application are: 1) to fully characterize and define the presence and the role of the IGF axis ina the developing lung and in cultured lung cell; 2) to investigate the mechanisms by which certain mediators (such as oxygen radicals, interleukins, TGFbeta and steroids), regulate lung cell proliferation via IGF axis modulation (such as altering the IGFBP/protease balance) in lung issues and cells; 3) to compare the presence of IGF-related molecules, in normal fetal and newborn lungs and in lungs from individuals with BPD, as well as in BAL fluids from these individuals, and to detect abnormalities which could be related to the disease process; and 4) to study, in a lung organ culture model, the effects of IGFs and related molecules on the regulation of proliferation and gene expression. We expect to define the role of the iGF system in the physiology of lung development and in the pathogenesis of BPD. We believe that these studies will help us understand the dis-regulated growth of stromal cells in the lungs of patients with BPD and allow us to improve our therapeutic approaches to this disease.
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