Open AccessLocal Tissue Expression of the Cell Death Ligand, Fas Ligand, Plays a Central Role in the Development of Extrapulmonary Acute Lung Injury
Author(s) -
Rajan K. Thakkar,
ChunShiang Chung,
Ya Ping Chen,
Sean F. Monaghan,
Joanne Lomas-Neira,
Daithi S. Heffernan,
William G. Cioffi,
Alfred Ayala
Publication year - 2011
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/shk.0b013e31821c236d
Subject(s) - fas ligand , autocrine signalling , paracrine signalling , medicine , gene silencing , lung , immunology , tumor necrosis factor alpha , inflammation , apoptosis , cancer research , receptor , biology , programmed cell death , biochemistry , gene
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.