To finally assess the therapeutic capacity of such a siRNA approach, experiments were designed to modulate PMN immigration based on the neutrophil hypothesis using in vivo siRNA constructs against the murine chemokines KC and MIP-2 during the development of indirect septic ALI. To this end, suitable siRNA constructs were instilled into the lungs of animals 2 h following HEM and prior to CLP. ALI was assessed 24 h after the induction of sepsis. Silencing of MIP-2 markedly reduced tissue and plasma IL-6 concentrations, tissue MIP-2, as well as lung PMN influx, interstitial edema, alveolar congestion, and disruption of lung tissue architecture (164) . In contrast, KC-siRNA treatment, while reducing plasma KC, tissue KC, and tissue IL-6, produced neither a significant reduction in plasma IL-6 nor lung PMN influx nor lung damage (164) . Alternatively, based on the epithelial cell hypothesis, siRNA sequences against Fas and caspase-8 were intratracheally instilled during septic ALI. Interestingly, while these sequences markedly diminished lung Fas and caspase-8 expression in a gene specific fashion, when lung apoptosis was assessed, pulmonary tissue caspase-3 activity was reduced only in response to Fas but not caspase-8 silencing. As silencing here, as commonly observed, did not result in a total depletion of the target protein, but rather in a diminished expression, it is possible that sufficient active caspase-8 was still present to mediate the apoptotic effects either through direct activation of caspase-3 or indirectly through cleavage of the proapoptotic protein Bid (152, 175) . Our data also indicated that silencing of Fas on lung epithelial cells was associated with a reduction in lung inflammation, PMN influx, and a diminished extent of lung injury (118) , thus emphasizing the relevance of epithelial cell integrity during indirect septic ALI.