APOPTOSIS IN ACUTE LUNG INJURY

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Accumulation and activation of inflammatory cells in the lung characterize the acute respiratory distress syndrome (ARDS). However, the precise mechanism for lung epithelial and endothelial cell damage remains unknown. Based on evidence that rapid apoptosis caused by CD8^+ cytolytic T cells can induce pathological cell death, we hypothesized that this mechanism may also participate in the acute lung injury. To determizae the possible contribution of apoptosis in the pathogenesis of acute lung injury (ALI), we investigated Fas antigen (Fas), Fas ligand (FasL), perforin, granzyme A, and granzyme B expressions in septic ARDS patients, and in a murine model of ALI after intratracheal instillation of Escherichia coli lipopolysaccharide (LPS) into the left lung. Quantitative PCR analysis revealed that the mRNAs for several apoptosis molecules were highly upregulated in the acute phase of ARDS following sepsis. The level of soluble FasL in the BALF increased only in the acute ARDS patients. W … More hile, in a murine LPS model, expressions of the pro-apoptosis molecules' mRNA were dose-dependently upregulated, with maximal expression in the early phase in the instilled lung and most apparent one day after LPS-instillation. Negligible mRNA expression of pro-apoptosis molecules was observed in non-instilled lungs. The terminal deoxynucleotidyl-transferase mediated dUTP biotin nick end labeling (TUNEL) demonstrated positive signals in neutrophils and macrophages as well as in alveolar wall cells of the instilled lung one day after the LPS-instillation. Immunohistochemistry demonstrated that Fas was upregulated in alveolar and inflammatory cells and FasL-positive inflammatory cells migrated into the air spaces in the LPS-instilled lung. Intratracheal administration of P2 antibody, which is an anti-Fas blocking antibody, attenuated the lung injury after 30 μg LPS-instillation without attenuating mRNA expressions of pro-apoptosis molecules and neutrophil accumulation in the lung. These results indicate that Fas/FasL system could be important in the pathogenesis of ALI, and proper regulation of FasL/Fas system might be important for potential ARDS treatment. Less