Trauma victims frequently have a concomitant pulmonary component as a result of inhalation of toxic materials, acid aspiration, or chest contusion. We have modeled the combination of systemic trauma with pulmonary damage in chronically instrumented sheep. Systemic trauma is modeled by a standardized 40% 3 degree burn. Insufflating the animals with smoke from burning cotton material induces lung injury. The experimental preparation models a serious clinical situation seen in victims of fire accidents, a form of trauma associated with a high of morbidity and mortality. We propose using this ovine model to investigate the pathophysiological mechanisms responsible for pulmonary injury associated with systemic trauma. Previous reports of acute lung damage have strongly implicated the polymorphonuclear neutrophil as the vector of injury. In many situations, deposition of neutrophils in the pulmonary microcirculation is dependent on a series of specific families of adherence molecules. The selectin family of compounds mediates the primary step in this adherence process and activation and may trigger the cascade of events leading to pulmonary pathology. This proposal evaluates the role of the selectin molecules in the development of the pulmonary pathophysiology. We hypothesize that selectin mediated contact with the pulmonary microvasculature will lead to neutrophil adherence, activation, release of oxygen free radicals, tissue damage, and pulmonary malfunction.
The specific aims below will test this hypothesis. The studies are performed in sheep that have been surgically prepared for chronic study. The animals are given a 40% full thickness burn and insufflated with smoke. 1. Determine if L-selectin expression on leukocytes is reduced and P is expressed and E selectin is up regulated on pulmonary vascular endothelium with burns and the combination of burn and smoke. We also propose that these changes in selectins are associated with the deposition of neutrophils, their activation and production of tissue injury. 2. Determine if antibodies to the selectins will effect the cardiopulmonary sequelae seen with burns in combination with smoke insufflation. 3. Determine if compounds that block the function of selectins will reduce the pathophysiologic consequences associated with thermal injury in combination with smoke inhalation. In these studies the blood and tissue levels of neutrophils and selectins will be determined and correlated with indexes of tissue injury and edema formation as well as the oxygen content of the arterial blood. These studies will reveal valuable information relative to etiology and sequence of lung injury seen with trauma as well as possible therapeutic steps that can be taken to reduce the damage.
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