THE PATHOGENESIS OF ARDS

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Although the pathogenesis for ARDS has been extensively studied, the cellular and molecular events that lead to the development of the acute lung injury in humans have not yet been determine We propose to study patients at risk for developing ARDS and with ARDS to try to define better the mechanism of the acute lung injury. Based on available data from ARDS patients and in vitro and in vivo data from models of acute lung injury, we hypothesize that the development of ARDS is dependent on the neutrophil and results from the synergism between a leukocyte priming agent and a leukocyte stimulating agent. We specifically propose that either endotoxin or tumor necrosis factor may directly stimulate neutrophil sequestration and prime neutrophils for subsequent stimulation by complement fragments. Stimulated neutrophils release 02 metabolities and proteases, both of which can cause cell injury directly. 02 metabolites can also indirectly enhance injury by activating complement, stimulating neutrophils and, locally, inactivating antiproteinases. Xanthine oxidase may be released either from stimulated or injured endothelial cells and generated more 02 metabolites. This process could be modulated by existing and stimulated antioxidant scavengers. Variations in cellular responsiveness to endotoxin could enhance or quench this cascade. The specific questions which will be addressed include: a. Are complement fragments, endotoxin and tumor necrosis factor important in the development of ARDS? b. Are the variations in neutrophil responsibility to endotoxin important in the development of ARDS? c. Do alterations in blood oxidant - anti-oxidant balance occur specifically in the development of ARDS? d. Are alterations in blood protease and antiprotease activity important in the development of ARDS? e. Does the analysis of the above factors provide sufficient insight into the mechanism of lung injury to provide a rationale for the use of a specific intervention therapy during the time a patient is at risk for the development of ARDS in an attempt to prevent the development of the syndrome?