Neutrophils have been implicated as the major cellular mediator in many forms of acute lung injury including the adult respiratory distress syndrome (ARDS) by virtue of their ability to become sequestered in the pulmonary vasculature and cause subsequent damage to the endothelium through the release of reactive oxygen species and proteases. However, events that control neutrophil-mediated inflammation are poorly understood and even less is known about the ability of acute phase proteins to regulate inflammatory processes resulting in acute lung injury. The objective of the proposed research is to test the HYPOTHESIS that the acute phase proteins, C-reactive protein (CRP) and ceruloplasmin, regulate neutrophil-mediated acute lung injury that results in permeability edema. The experimental approach focuses upon an examination of control mechanisms by these acute phase proteins of neutrophil-mediated injury to cultured endothelial cells and in isolated perfused rabbit lungs as well as in transgenic mice expressing rabbit reactive protein.
The specific aims are: 1). to examine the ability of CRP and ceruloplasmin to reduce or prevent neutrophil-mediated acute lung injury in isolated perfused rabbit lungs and in transgenic mice; 2. to examine mechanisms of inhibition of neutrophil-mediated acute lung injury by these acute phase proteins; 3. to determine the mechanisms of inhibition of neutrophil activation and function by CRP and ceruloplasmin in vitro; and 4. to examine effects of CRP and ceruloplasmin on neutrophil-mediated endothelial injury and altered endothelial cell function in vitro. Mechanisms of regulation by each acute phase protein will be determined by measurement of their effect on selective but distinct steps involved in neutrophil activation and function. The effect of purified rabbit acute phase proteins and rabbit neutrophils on alterations of endothelial cell integrity will also be studied using cultured rabbit endothelial cells. Finally, through a series of structure-function studies, specific regions of CRP and ceruloplasmin involved in modulation of neutrophil-mediated injury to endothelial cells that can result in acute lung injury will be identified. Results of these studies should provide useful new information on the role of these acute phase proteins in the pathogenesis and resolution of acute lung injury and should also provide new possibilities for prophylactic and therapeutic measures for ARDS.
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