Project 3: Neutrophil Apoptosis in Acute Lung Injury Although considerable progress has been made in elucidating the mechanisms of neutrophil recruitment in acute lung inflammation, the factors regulating the fate of the transmigrated neutrophils in vivo are not as well understood. Neutrophils were thought to have an inherently limited life-span in tissues (i.e., constitutive programmed cell death), but recent evidence suggests that their survival in tissues can be regulated to some extent by local factors including adhesion, cytokines, and chemokines. Neutrophil persistence in the lung may be an important determinant of acute lung injury since the longer that neutrophils are present in lung tissue, the greater is the possibility that they may provoke lung injury by release of proteases and reactive oxygen intermediates. While the resolution of acute lung inflammation ultimately depends upon the clearance of neutrophils, the mechanism(s) of clearance may also affect the duration and severity of lung inflammation. Necrosis of neutrophils releases toxic products extracellularly, thereby perpetuating the inflammatory response and further damaging tissue. In contrast, apoptosis of neutrophils with their subsequent phagocytosis by resident macrophages or elicited monocyte-derived macrophages may terminate the inflammatory reaction. The underlying hypothesis of this proposal is that neutrophil apoptosis determines the severity and duration of acute lung inflammation; factors that promote neutrophil apoptosis and engulfment by macrophages will lead to more rapid resolution of lung inflammation while those that prevent apoptosis will prolong the inflammatory response and increase the probability of acute lung injury. This hypothesis will be examined in the following Specific Aims: 1) To Determine the Constitutive and Induced Anti-Apoptotic Proteins Expressed in Mature Neutrophils In vitro and In Vivo; 2) To determine the Function of Pro and Anti-Apoptotic Proteins in Neutrophil Survival in a Murine Model of Acute Lung Inflammation; 3) To Define the Adhesion Receptors Mediating Phagocytosis/Clearance of Apoptotic Neutrophils in a Murine Model of Acute Lung Inflammation; and 4) To Determine the Consequences of Accelerated or Reduced Neutrophil Apoptosis on Lung Injury in a Murine Model of Acute Lung Inflammation. It is hoped that these studies will yield new information on the molecular mechanisms involved in the resolution of acute lung inflammation and perhaps yield new approaches to the therapy of ARDS.
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