• Mario Perl, Chun-Shiang Chung, Ulrike Perl, Joanne Lomas-Neira, Monique de Paepe, William G Cioffi, and Alfred Ayala.
• Shock-Trauma Research Laboratory, Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University, 593 Eddy Street, Aldrich 239, Providence, RI 02903, USA.
• Am. J. Respir. Crit. Care Med. 2007 Sep 15;176(6):591-601.

RationaleIndirect acute lung injury (ALI) is associated with high morbidity and mortality. No specific therapies have been developed, because the underlying pathophysiological processes remain elusive.ObjectivesTo investigate the contribution of Fas-induced apoptotic and nonapoptotic/inflammatory signaling to the pathology of indirect ALI.MethodsA mouse model of indirect ALI, induced by successive exposure to hemorrhagic shock and cecal ligation and puncture, was used. Quantification of active caspase-3 and the short splice variant of FLICE-inhibitory protein, (FLIP)short, was performed by Western blotting and immunohistochemistry, and cytokines/chemokines were assessed by cytometric bead array or ELISA. M30 immunostaining was done to evaluate epithelial cell apoptosis. Lung injury was assessed on the basis of myeloperoxidase activity, bronchoalveolar lavage protein, and lung histology.Measurements And Main ResultsTwelve hours after insult, lung monocyte chemoattractant protein-1, keratinocyte-derived chemokine, macrophage inflammatory protein-2, IL-6, tumor necrosis factor-alpha, and caspase-3 were increased and FLIP(short) was decreased. Fas- and Fas ligand-deficient mice showed marked protection from lung inflammation and apoptosis and decreased ALI. This was associated with a 10-day survival benefit. Similarly, 4 hours after pulmonary instillation of Fas-activating antibody in vivo, lung chemokines were markedly elevated in background mice and, interestingly, to a similar degree in macrophage-deficient animals. Fas activation on lung epithelial cells in vitro led to chemokine production that was dependent on extracellular signal-regulated kinase.ConclusionsActivation of apoptotic and nonapoptotic/inflammatory Fas signaling is an early important pathophysiological event in the development of indirect ALI after hemorrhagic shock and sepsis, in which lung epithelial cells appear to play a central role.

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