Rationale: Indirect acute lung injury is associated with high morbidity and mortality. No specific therapies have been developed, because the underlying pathophysiological processes remain elusive. Objective: To investigate the contribution of Fas induced apoptotic and non-apoptotic/inflammatory signaling to the pathology of indirect acute lung injury. Methods: Mouse model of indirect acute lung injury, induced by the successive exposure to hemorrhagic shock and cecal ligation and puncture. Quantification of active Caspase-3 and FLICE-inhibitoryprotein (FLIP) short by western blotting and immunohistochemistry, cytokines/chemokines via cytometric-bead-array or ELISA. M30-immunostaining to evaluate epithelial cell apoptosis. Lung injury assessment via myeloperoxidase activity, bronchoalveolar lavage protein and lung histology. Measurements and Main Results: Twelve hours following the insult lung MCP-1, KC, MIP-2, IL-6, TNF- and Caspase-3 were increased and FLICE-inhibitory-protein-short was decreased. Fas and Fas-ligand deficient mice showed a marked protection in lung inflammation and apoptosis and decreased acute lung injury. This was associated with a 10 day survival benefit. Similarly, four 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 lead to a production of chemokines which was extracellular-signal-regulated kinase (ERK) dependent. Conclusions: Activation of apoptotic and non apoptotic/inflammatory Fas signaling is an early important pathophysiological event in the development of indirect acute lung injury following hemorrhagic shock and sepsis, in which, lung epithelial cells appear to play a central role.