Apoptosis and inflammatory cell in the pathogenesis of acute lung injury

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Apoptosis mediated by Fas/Fas ligand (FasL) interaction has been implicated in human disease processes, including pulmonary disorders. However, the role of the Fas/FasL system and other apoptotic factors in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) is poorly defined. We have previously reported upregulation of pro-apoptosis molecules associated with cytotoxic lymphocytes (CTLs) such as Fas, FasL, perforin, and granzymes in bronchoalveolar lavage cells from patients in the acute phase of septic ARDS. This observation strongly suggested a role of apoptosis in the pathogenesis of the acute lung injury. Thus, we first studied the expressions of pro-apoptosis molecules in an experimental murine lung injury model of intratracheally instilled LPS. Expressions of the pro-apoptosis molecules and their mRNAs were dose-dependently upregulated, with maximal expression in the early phase in the LPS instilled lung and most apparent 24 hours after LPS-instillation. In … More tratracheal administration of P2 antibody, which is an anti-Fas blocking antibody, attenuated the lung injury after LPS-instillation without attenuating mRNA expressions of pro-apoptosis molecules and neutrophil accumulation in the lung. Secondly, cellular expression of the Fas/FasL system was assessed by semi-quantitative immunofluorescence microscopy in lung tissue obtained at autopsy from a different set of patients. Both Fas and FasL were immunolocalized to a greater extent in the patients who died with ALI or ARDS than in the patients who died without pulmonary disease. Both proteins were co-expressed by epithelial cells that lined the alveolar walls, as well as by inflammatory cells and sloughed epithelial cells that were located in the air spaces. Semi-quantitative immunohistochemistry showed that markers of apoptosis (TUNEL, caspase 3,Bax and p53) were more prevalent in alveolar wall cells from the patients who died with ALI or ARDS compared to the patients who died without pulmonary disease. These results again indicate that Fas/FasL system could be important in the pathogenesis of LPS induced ALI, and proper regulation of FasL/Fas system might be important for potential ARDS treatment. Less