title: Local tissue expression of the cell death ligand, fas ligand, plays a central role in the development of extrapulmonary acute lung injury.
abstract: Indirect acute lung injury (ALI) is a common manifestation in critically ill patients. Using a model of indirect ALI in mice, our laboratory has shown that local/pulmonary inhibition of extrinsic death receptor protein (Fas) leads to a decrease in lung inflammation and improved survival. However, it is unknown if local, i.e., autocrine/paracrine, inhibition of Fas ligand (FasL) affects Fas-expressing target cells itself or blockade of the actions of a more distal/endocrine source of FasL that accounts for these findings. To examine this, we used a model of indirect ALI in mice (dual insult of hemorrhagic shock followed 24 h later by cecal ligation and puncture, in which animals received FasL small interfering RNA (siRNA) intratracheally (local silencing) or intravenously (systemic/distal delivery) after hemorrhage. After intratracheal delivery of FasL siRNA, there was a significant decrease in inflammatory cytokines, myeloperoxidase activity, and caspase 3 activity in lung tissue along with protein leak as compared with controls. There was no difference found in these various outcome markers between those treated with intravenously administered FasL siRNA versus controls. The observation that local silencing of FasL, as opposed to distal/systemic silencing, ameliorates the effects of indirect ALI suggests not only that FasL produced in an autocrine/paracrine fashion in local tissues has pathological consequences within the lungs, but also that FasL might be a valuable pulmonary therapeutic target.
authors: Shock-Trauma Research Laboratories, Department of Surgery, Division of Surgical Research, Rhode Island Hospital/The Alpert School of Medicine at Brown University, Providence, RI 02903, USA. aayala@lifespan.org
authors: Rajan K
authors: RK
authors: Thakkar
authors: Chun-Shiang
authors: CS
authors: Chung
authors: Yaping
authors: Y
authors: Chen
authors: Sean F
authors: SF
authors: Monaghan
authors: Joanne
authors: J
authors: Lomas-Neira
authors: Daithi S
authors: DS
authors: Heffernan
authors: William G
authors: WG
authors: Cioffi
authors: Alfred
authors: A
authors: Ayala
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D053222:Fas Ligand Protein; D015850:Interleukin-6; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009195:Peroxidase; D053148:Caspase 3