Published ahead of print on June 28, 2007, doi:10.1164/rccm.200611-1743OC Am. J. Respir. Crit. Care Med., Volume 176, Number 6, September 2007, 591-601 A more recent version of this article appeared on September 15, 2007
Submitted on November 30, 2006 Fas Induced Pulmonary Apoptosis and Inflammation During Indirect Acute Lung InjuryMario Perl1,1 Shock-Trauma Research Laboratories in the Division of Surgical Research, Rhode Island Hospital and Brown University, School of Medicine, Providence, RI, USA, 2 Department of Pathology, Women and Infants Hospital, Brown University, School of Medicine, Providence, RI, USA, 3 Department of Surgery, Rhode Island Hospital and Brown University, School of Medicine, Providence, RI, USA * To whom correspondence should be addressed. E-mail: aayala{at}lifespan.org.
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- Key words: apoptosis, acute lung injury, hemorrhagic shock, sepsis, inflammation, epithelial cells
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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.
