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Trauma-hemorrhagic shock-induced pulmonary epithelial and endothelial cell injury utilizes different programmed cell death signaling pathways.

Abstract
Intestinal ischemia after trauma-hemorrhagic shock (T/HS) results in gut barrier dysfunction and the production/release of biologically active and tissue injurious factors in the mesenteric lymph, which, in turn, causes acute lung injury and a systemic inflammatory state. Since T/HS-induced lung injury is associated with pulmonary endothelial and epithelial cell programmed cell death (PCD) and was abrogated by mesenteric lymph duct ligation, we sought to investigate the cellular pathways involved. Compared with trauma-sham shock (T/SS) rats, a significant increase in caspase-3 and M30 expression was detected in the pulmonary epithelial cells undergoing PCD, whereas apoptosis-inducing factor (AIF), but not caspase-3, was detected in endothelial cells undergoing PCD. This AIF-mediated pulmonary endothelial PCD response was validated in an in situ femoral vein assay where endothelial cells were found to express AIF but not caspase-3. To complement these studies, human umbilical vein endothelial cell (HUVEC), human lung microvascular endothelial cell (HLMEC), and human alveolar type II epithelial cell (A549) lines were used as in vitro models. T/HS lymph induced the nuclear translocation of AIF in HUVEC and HLMEC, and caspase inhibition in these cells did not afford any cytoprotection. For proof of principle, AIF silencing in HUVEC reversed the cytotoxic effects of T/HS on cell viability and DNA fragmentation. In A549 cells, T/HS lymph activated caspase-3-mediated apoptosis, which was partially abrogated by N-benzyloxycarbonyl-Val-Ala-Asp (zVAD). Additionally, T/HS lymph did not cause the nuclear translocation of AIF in A549 cells. Collectively, T/HS-induced pulmonary endothelial PCD occurs via an AIF-dependent caspase-independent pathway, whereas epithelial cells undergo apoptosis by a caspase-dependent pathway.
AuthorsDimtrios Barlos, Edwin A Deitch, Anthony C Watkins, Frank J Caputo, Qi Lu, Billy Abungu, Iriana Colorado, Da-Zhong Xu, Rena Feinman
JournalAmerican journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 296 Issue 3 Pg. L404-17 (Mar 2009) ISSN: 1040-0605 [Print] United States
PMID19118093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • AIFM1 protein, human
  • Apoptosis Inducing Factor
  • RNA, Small Interfering
  • Caspases
Topics
  • Acute Lung Injury (pathology, physiopathology)
  • Animals
  • Apoptosis (physiology)
  • Apoptosis Inducing Factor (antagonists & inhibitors, genetics, physiology)
  • Caspases (physiology)
  • Cells, Cultured
  • Endothelial Cells (pathology)
  • Epithelial Cells (pathology)
  • Humans
  • Lung (pathology, physiopathology)
  • Lymph (physiology)
  • Male
  • RNA Interference
  • RNA, Small Interfering (genetics)
  • Rats
  • Rats, Sprague-Dawley
  • Shock, Hemorrhagic (pathology, physiopathology)
  • Signal Transduction

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