NON-LYTIC EFFECTS OF PHAGOCYTES ON ISOLATED LUNG CELLS

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The overall objective of this proposal is to study the effects of stimulated phagocytes and their products as mediators of non-lytic responses of isolated lung cells. Phagocytes may play a causal role in lung injury and therefore their interaction with isolated lung cells may enhance our understanding of clinical disorders such as adult respiratory distress syndrome. Previous studies have demonstrated that increased surfactant secretion is an early indicator of damage to the alveolar Type II cell. Preliminary studies using stimulated neutrophils and their products also induce an increase in Type II cell surfactant secretion. A specific aim of this proposal is to determine the nature of the agents responsible for stimulated phagocyte induced Type II cell response, using neutrophils, monocytes, cultured monocytes and alveolar macrophages. The role of reactive oxygen species as inducers of the Type II cell responses will be determined using scavengers of reactive oxygen species, altered phagocytes and model systems. The responsible species will be identified and purified from stimulated phagocyte supernatants. Manipulations of the Type II cell glutathione cycle will be performed to assess the effects of oxidant stress on the susceptibility of Type II cells to subsequent phagocyte exposure. The nature and extent of Type II cell responses to stimulated phagocytes will be examined. Integrity of membranes, surface receptors and the ability to synthesize surfactant will be examined. The possibility that these phagocyte products cause long-term lethality will be addressed. By utilizing this model system of stimulated phagocyte-mediated responses, it is hoped that insight will be gained of the possible involvement of toxic phagocyte products such as reactive oxygen species in pulmonary disorders.