We propose to study the regulation of normal fetal lung growth, and of post-injury regenerative lung growth, in vivo and in vitro, with respect to the expression and effects of protein growth factors. Extensive evidence suggest that in both fetal and postnatal life, there is a strong association between the mechanical forces to which the lung is subjected and the rate of pulmonary cellular mitosis. Based on this evidence and on extensive preliminary work from this laboratory, we propose to these two related hypotheses: 1. That acinar development is mediated by the release of autocrine and parcrine growth factors by lung cells, in response to """"""""stretch"""""""" incurred during normal breathing activity, with resultant cellular oncogene responses. 2. That this process is arrested during acute generalized lung injury, and that subsequent repair and regeneration represents an amplification or reactivation of the normal process. These hypothese will be tested in four specific aims: 1. To define growth factor, growth factor receptor and proto-oncogene ontogeny in the fetal and neonatal rat lung. Northern blot and slot blot analyses of growth factors, their receptors, and related proto-oncogenes will be compared with measures of cell proliferation. 2. To determine the influence of """"""""stretch"""""""" on growth factor, receptor and proto-oncogene expression of fetal lung cells in vitro. Based upon the results from aim 1, we will study these endpoints in lung cells cultured singly and in a three dimensional multi-cell system. Both systems will be studied under static conditions and after exposure to stretch. 3. To define the effect of acute lung injury with oxygen followed by recovery on growth factor, growth factor receptor and proto-oncogene expression in the neonatal rat lung. 4. To define how acute injury with oxygen, followed by recovery, modifies the influence of """"""""stretch"""""""" on growth factor, growth factor receptor and proto-oncogene expression of fetal lung cells in vitro.
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