The goals are to define the physiological mechanisms by which metabolism of lung proteins is regulated, and to investigate the role of this regulation in the response of the tissue to injury. The physiological and biochemical integrity of the lung, both at the tissue and cellular levels, is determined in part by structural and enzymatic proteins. Although alterations in the levels of these components may determine developmental, physiological or pathological changes, little lung-specific information is available detailing the basic regulation of their synthesis or degradation, or regarding how these pathways may be modulated during or following lung injury. In the course of the proposed research, these issues will be addressed by investigation of factors which initiate and regulate rapid compensatory hyperplastic lung growth following partial pneumonectomy in rats. Experiments will employ intact animals, isolated perfused lungs and isolated purified type II pneumocytes in primary culture. The regulatory roles of substrate and hormone availability and other factors, such as tissue inflation and pulmonary blood flow, prior to, during and after the compensatory response will be investigated: a) to define alterations at the tissue, cellular and biochemical levels which preceed and/or accompany compensatory lung growth; b) to determine how these changes are modulated by factors which accelerate or retard the growth response; c) to define alterations in protein and DNA metabolism which account for the growth response, identify factors responsible for these changes, and localize their site of action; and d) to attribute these changes to specific cell types within the lung using quantitative morphometric techniques, cultured cell preparations and, if possible, cell-specific proteins. It is proposed that as factors which initiate and regulate compensatory growth of the lung following partial pneumonectomy are identified and their mechanisms of action are defined, significant information regarding the physiological regulation of lung growth and of protein metabolism in the tissue will emerge, as will a more complete understanding of the response of the lung to injury.
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