Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury.
Hyperoxic acute lung injury (HALI) is characterized by a cell death response with features of apoptosis and necrosis that is inhibited by IL-11 and other interventions. We hypothesized that Bfl-1/A1, an antiapoptotic Bcl-2 protein, is a critical regulator of HALI and a mediator of IL-11-induced cytoprotection. To test this, we characterized the expression of A1 and the oxygen susceptibility of WT and IL-11 Tg(+) mice with normal and null A1 loci. In WT mice, 100% O(2) caused TUNEL(+) cell death, induction and activation of intrinsic and mitochondrial-death pathways, and alveolar protein leak. Bcl-2 and Bcl-xl were also induced as an apparent protective response. A1 was induced in hyperoxia, and in A1-null mice, the toxic effects of hyperoxia were exaggerated, Bcl-2 and Bcl-xl were not induced, and premature death was seen. In contrast, IL-11 stimulated A1, diminished the toxic effects of hyperoxia, stimulated Bcl-2 and Bcl-xl, and enhanced murine survival in 100% O(2). In A1-null mice, IL-11-induced protection, survival advantage, and Bcl-2 and Bcl-xl induction were significantly decreased. VEGF also conferred protection via an A1-dependent mechanism. In vitro hyperoxia also stimulated A1, and A1 overexpression inhibited oxidant-induced epithelial cell apoptosis and necrosis. A1 is an important regulator of oxidant-induced lung injury, apoptosis, necrosis, and Bcl-2 and Bcl-xl gene expression and a critical mediator of IL-11- and VEGF-induced cytoprotection.
He
Chuan Hua
CH
Department of Internal Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
Waxman
Aaron B
AB
Lee
Chun Geun
CG
Link
Holger
H
Rabach
Morgan E
ME
Ma
Bing
B
Chen
Qingsheng
Q
Zhu
Zhou
Z
Zhong
Mei
M
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
Homer
Robert
R
Elias
Jack A
JA
D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D020287:In Situ Nick-End Labeling; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology* / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017370:Interleukin-11; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D020169:Caspases; D010100:Oxygen