The inflammatory response is involved in many diverse disease processes including those which affect the lung. Much is known regarding the role of the neutrophil in this process, but little investigation has centered on the monocyte. Monocytes are suggested to temporarily lag behind the neutrophil in their influx into areas of acute inflammation. Our general hypothesis is that neutrophils attract monocytes into acute inflammatory lesions due to their proteolytic generation of monocyte-specific connective tissue derived chemoattractants. Monocyte adherence to endothelium, an initial step in cellular emigration, in the presence and absence of monocyte-specific (fibronectin fragments) and nonspecific (C5a des arg), stimuli will be examined. A quantitative microtiter adherence assay in vitro and a well established rabbit model of acute lung injury in vivo will be utilized. I will study the peripheral blood kinetics and pulmonary transit time of monocytes in normal and rabbits with pulmonary inflammation. Indium radiolabelling of monocytes and sequential gamma camera scintigram techniques will be used. These results will be compared to studies done in the same manner in neutropenic and neutrophil replenished neutropenic rabbits in order to ascertain the role of neutrophils in monocyte influx into an area of acute lung injury. I will further investigate neutrophil protease degradation of connective tissue as a mechanism responsible for generation of monocyte-specific chemoattractants, specifically the 120K fragment of fibronectin, which may induce monocyte influx into inflammatory sites. Purified neutrophil elastase and elastase inhibitor will be used in these experiments. After acute monocyte inflammatory mechanisms have been defined, future experiments will investigate the the progression of the inflammatory reaction to the chronic state. These studies will lead to a better understanding of the role of the monocyte and its relation to the neutrophil in the acute inflammatory response. My ultimate goal is to define the basic mechanisms of monocyte involvement in the acute inflammatory setting when tissue damage is in progress. If basic mechanisms are known, therapeutic modalities to be used clinically in acute lung injury can more judiciously be investigated. The institution at which I will carry out this proposal has a firm background in cellular biology and immunology research. Numerous consultants are readily available for consultation and guidance on this project.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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National Jewish Health
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Doherty, D E; Downey, G P; Schwab 3rd, B et al. (1994) Lipolysaccharide-induced monocyte retention in the lung. Role of monocyte stiffness, actin assembly, and CD18-dependent adherence. J Immunol 153:241-55
Hirose, N; Lynch, D A; Cherniack, R M et al. (1993) Correlation between high resolution computed tomography and tissue morphometry of the lung in bleomycin-induced pulmonary fibrosis in the rabbit. Am Rev Respir Dis 147:730-8
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Doherty, D E; Downey, G P; Worthen, G S et al. (1988) Monocyte retention and migration in pulmonary inflammation. Requirement for neutrophils. Lab Invest 59:200-13