OXYGEN TOXICITY AND PULMONARY VASCULAR INJURY

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We have recently identified new effects of oxygen toxicity on pulmonary blood vessels (i) during hyperoxia (acute, adaptive and subacute), and additional injury; (ii) weaning to air and (iii) recovery in air. We will study experimentally in the rat these blood vessel injuries in the normal lung and in the lung with progressive fibrosis. Morphometric techniques, with light and electron microscopy, will establish the temporal course and severity of pulmonary artery damage in preacinar and intraacinar segments, including obliteration of vessels and wall restructuring of patent ones. These findings will be correlated with the development, severity and persistence of pulmonary hypertension established by the use of indwelling catheters. We will test the following hypotheses: that hyperoxia-induced structural changes and pulmonary hypertension correlate closely, that the restructured pulmonary vascular bed senses a reduced but still hyperoxic tension as hypoxia and constricts, and that gradual weaning alters sensitivity to this; that the response of the restructured bed to a vasoconstrictor will increase and to a vasodilator decrease; that in the fibrotic lung pulmonary vascular injury by hyperoxia occurs faster and at a lower tension while regression will be slower and less complete because of persistent adventitial fibrosis in patent vessels and greater lumen obliteration. A cellular adaptation to hyperoxic injury is the development of muscle in non-muscular regions of the vessel wall, contributing to hypertension by narrowing patent segments and perhaps modifying vasoactivity. We will explore the hypothesis that 'precursor smooth muscle cells' within the intima of non-muscular regions of distal artery segments develop into new medial muscle cells by change in phenotype. To establish this we will examine by autoradiography the proliferative response of cells of the pulmonary artery wall to hyperoxic injury and by immunocytochemical techniques the synthesis of smooth muscle myosin. We will corrrelate the pattern and timing of mitosis and myosin synthesis with subcellular features of the precursor cells (microfilaments, dense bodies and cell position in relation to basement membrane and internal elastic lamina) and relate this to increase in number of mature medial smooth muscle cells.