The objective of the proposed research is to investigate the species-dependent role of the pulmonary vasculature in removal from the circulation of blood-borne particulate material and in initiation of pulmonary inflammation. Pulmonary endocytic uptake of inert particles, bacteria, and endotoxin will be determined in sheep, pigs and rats. Bacteremia and endotoxemia are associated with clinical development of pulmonary inflammation and edema in both human and veterinary patients. It is hypothesized that the degree of pulmonary clearance of these agents from the blood and the cellular response to localization in the lung may play an important role in this syndrome. The objective will be approached through the following specific aims: 1) to determine the endocytic capacity of the pulmonary capillaries in three different species, 2) to characterize a unique population of intravascular pulmonary macrophages, previously shown to localize particles in the lungs of ruminants, and 3) to determine the pathophysiologic role of pulmonary endotoxin uptake in cellular and biochemical events of the inflammatory response, and subsequently, in the effect of that response on normal pulmonary defense mechanisms. Species comparison of relative organ uptake and site of cellular localization will be done using radioisotope quantitation, magnetometry, and morphologic markers. The pulmonary uptake of endotoxin will be correlated with the degree of granulocytic margination and infiltration. The contribution of intravascular pulmonary macrophages to pulmonary leukostasis during endotoxemia will be assessed using macrophage isolation and in vitro assays. The effect of acute pulmonary inflammation on alveolar macrophage function will be addressed using an in vivo phagocytic assay in sheep with endotoxin-induced acute pulmonary inflammation. The candidate has a unique combination of training in cell biology, respiratory biology and large animal veterinary medicine that contribute to interest and capability for this research area. The facilities available for isotope and magnetometry study and alveolar macrophage evaluation, combined with the expertise, open collaboration, and productivity of the sponsoring research group provide a stimulating environment in which to carry out the research.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Research Manpower Review Committee (MR)
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Harvard University
Schools of Public Health
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Rogers, R A; Tasat, D R; Warner, A E et al. (1994) Quantitative recovery of pulmonary intravascular macrophages from sheep lungs. J Leukoc Biol 56:692-701
DeCamp, M M; Warner, A E; Molina, R M et al. (1992) Hepatic versus pulmonary uptake of particles injected into the portal circulation in sheep. Endotoxin escapes hepatic clearance causing pulmonary inflammation. Am Rev Respir Dis 146:224-31
Georgi, A; Mottola-Hartshorn, C; Warner, A et al. (1990) Detection of individual fluorescently labeled reovirions in living cells. Proc Natl Acad Sci U S A 87:6579-83
Warner, A E; DeCamp Jr, M M; Molina, R M et al. (1988) Pulmonary removal of circulating endotoxin results in acute lung injury in sheep. Lab Invest 59:219-30
Warner, A E; Molina, R M; Brain, J D (1987) Uptake of bloodborne bacteria by pulmonary intravascular macrophages and consequent inflammatory responses in sheep. Am Rev Respir Dis 136:683-90