Injury to the pulmonary surfactant is considered a key element in the development of Adult Respiratory Distress Syndrome-type injury. Based on existing evidence in the literature and our own preliminary data, we concluded that contrary to previous belief, injury to the pulmonary surfactant system in vivo in a variety of pathological conditions, cannot be attributed solely to reactive oxygen species. Instead, we hypothesize that peroxynitrite (ONOO), produced by the chemical reaction of nitric oxide (-NO) with endogenous superoxide (O2-), play a key and central role in the initiation and propagation of alveolar epithelial injury during -NO inhalation. We have thus designed a series of integrated physiological biochemical, biophysical and cell biology studies to define the fundamental mechanisms by which NO-derived species injure the mammalian alveolar epithelium and the pulmonary surfactant system both in vivo and in vitro. This goal will be tested by fulfilling the following Specific Aims: (1). Quantify the relative extent to which O2-, -NO, ONOO-, add secondary products derived from activated alveolar macrophages chemical generators of these reactive species, or exposure to gaseous -NO, inhibit the surface active properties of surfactant and surfactant replacement mixtures; (2) examine the contribution of these reactive species in surfactant lipid and apoprotein (SP-A, SP-B and SP-C) injury and determine the extent to which this injury alters apoprotein and surfactant function; (3) define mechanisms of O2-,-NO and ONOO--mediated inhibition of alveolar type II (ATII) cell surfactant secretion and (4) assess the development and progression of injury to pulmonary surfactant and alveolar epithelium in vivo during exposure of rabbits to inhaled -NO and hyperoxia. Completion of these Specific Aims will reveal fundamental knowledge about novel mechanisms mediating oxidant and -NO injury to the alveolar epithelium and pulmonary surfactant. Fresh insight in the potential toxicity of the recently described signal transducing and therapeutic agent, -NO will provide the rational basis for devising strategies for limiting its toxicity, thus enhancing its clinical use as a vasodilatory agent.
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