THE PATHOGENESIS OF ADULT RESPIRATORY DISTRESS SYNDROME

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The overall hypothesis of this project is that neutrophil sequestration, emigration and secretion are critical events in the development of ARDS. In our original proposal we suggested that agents such as LPS or TNF could stimulate neutrophil sequestration and, additionally, prime the cells for subsequent stimulation to secrete elastase and O2- Our work to date suggests that the outlined events do occur during the development of ARDS but no not clearly discriminate those critically ill patients at risk who do and do not develop the syndrome. In this proposal, we have expanded our hypothesis to include the following sequence: LPS and other sequelae of conditions that predispose to ARDS induce the release of IL-8 and LTB4, and lead to neutrophil sequestration, emigration and secretion of )2 and elastase. We further hypothesize that the presence of cytokines and LPS modifies the underlying functional heterogeneity of neutrophils present in normal subjects and results in the appearance of neutrophil subpopulations more likely to be sequestered that further enhance lung injury. We will address this scheme in patients at risk for, and with, ARDS, recognizing that similar pathogenic mechanisms may be common to both groups. Neutrophil retention in the lungs of patients with ARDS will be compared using autologous 111 In -labelled neutrophils before and after administration of the IL-1r antagonist, IL-1ra, the 5-lipoxygenase inhibitor Zileuton, and liposome PGE1 which may directly modulate neutrophil function. Neutrophils from normals and patients will be separated into more functionally homogenous groups based on flow cytometric, visco-elastic and volumetric criteria. LTB4 synthesis in vivo, and estimates of synthesis made in patients. The effect of Zileuton, IL-1ra and lip-PGE1 on LTB4 metabolism will be determined in correct with their effect on neutrophil functional heterogeneity. The potential for oxidants contributing to both neutrophil sequestration and lung injury will be addressed using the infusion of MnSOD.