title: 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.
authors.affiliation: Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School,Newark, New Jersey 07103, USA.
authors.forename: Dimtrios
authors.initials: D
authors.lastname: Barlos
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Watkins
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Caputo
authors.forename: Qi
authors.initials: Q
authors.lastname: Lu
authors.forename: Billy
authors.initials: B
authors.lastname: Abungu
authors.forename: Iriana
authors.initials: I
authors.lastname: Colorado
authors.forename: Da-Zhong
authors.initials: DZ
authors.lastname: Xu
authors.forename: Rena
authors.initials: R
authors.lastname: Feinman
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D008168:Lung / Q000473:pathology* / Q000503:physiopathology; D008196:Lymph / Q000502:physiology; D008297:Male; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000473:pathology* / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D034741:RNA, Small Interfering; D020169:Caspases