Inhalation of smoke produces serious lung injury and increases the morbidity and mortality of patients with cutaneous burns. The current study is designed to define the mechanisms responsible for the inhalation injury, to define the mechanisms by which cutaneous burns exacerbate the inhalation injury, and to develop therapeutic procedures for attenuating that injury. Our preliminary data indicate that smoke inhalation results in a significant pulmonary sequestration of leukocytes, sloughing of mucosal lining of the airways, increased vascular permeability in the lung, a depressed pulmonary gas exchange, and in the extreme cases, death. We postulate that with smoke inhalation the lung is stimulated to release agents which are chemotactic for polymorphonuclear leukocytes (PMN). After sequestration in the lungs, the phagocytizing PMN's extrude large quantities of proteases and oxygen metabolites which damage lung tissues. The cellular injury results in increased vascular permeability, pulmonary edema, ventilation-perfusion imbalance and impaired gas exchange. We will study the effects of smoke inhalation on hemodynamics, lung vascular permeability, pulmonary gas exchange and pulmonary histomorphology in the chronically instrumented sheep lung lymph fistula model. During the initial phase of the study, we will define the changes in vascular integrity, gas exchange and morphology following smoke inhalation. Concomitantly, we will quantitate the chemotactic effect of smoke inhalation, the resulting pulmonary sequestration of PMN and the release of proteases by the PMN. The second phase studies will define the role of extruded neutrophil proteases and oxygen metabolites in disrupting the structure and function of the lung. Injured, non-phagocytic cells may release agents (prostaglandins or histamine) which may exacerbate the ventilation-perfusion imbalance and thus parallel studies have been designed to define the role of these agents. After identification of the agents responsible for the smoke inhalation injury, it will be possible to modulate the action of those agents by perfusion of specific blockers or antiproteases. Therefore, the third phase studies will establish therapeutic techniques which attenuate lung injury. Clinically, smoke inhalation injury is greatly exacerbated by cutaneous burns. Therefore, the fourth phase of the study is designed to define the mechanisms by which cutaneous burns can increase the inhalation injury. Together, these studies will help establish the appropriate therapy for patients suffering smoke inhalation injury.