This proposal from the Department, University of Colorado seeks five year funding for a new program to investigate three pulmonary hypertensive disorders of newborns- hyaline membrane disease from premature birth, congenital diaphragmatic hernia, and persistent pulmonary hypertension of the newborn (PPHN). Collectively, these syndromes occur about 1:500 live births despite intensive, invasive and costly treatment. Morbidity and mortality remain high, up to 50% with severe disease. This program seeks to investigate the causes of high resistance to lung blood flow in these syndromes which include: inadequate blood vessel formation, obstruction from thickened arterial walls, and excessive constriction of the lung arteries. Thus, the key questions to be addressed by the basic research are: 1) how do pulmonary blood vessels form, (2) what factors contribute to vascular wall cell replication and matrix formation and thus vascular thickening, (3) what mechanisms cause high vascular tone in the fetus and sudden relief of that tone at the moment of birth, and (4) how do noxious stimuli damage vessels and their functions both before and after birth? To answer these questions the investigators will examine normal and abnormal pulmonary vascular development in fetuses and newborns in several species. Further, the investigators propose to extend to pulmonary hypertensive infants with hyaline membrane disease and congenital diaphragmatic hernia the clinical management which has been successful in PPHN, and which combines high frequency oscillatory ventilation and small amounts of inhaled nitric oxide with good hospital care. Also, based on animal experiments and encouraging preliminary clinical usage, the investigators will attempt to augment nitric oxide s benefit by administering phosphodiesterase inhibitors to prolong nitric oxides vasodilating effect in all three patient groups. The proposal seeks to improve the well being in new born children through an integrated program of basic research with experiments in whole animals, whole organs, cell cultures using state-of-the-art biochemical and genetic molecular research methods combined with innovative clinical care.
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