Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury.

Abstract

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.

• Authors: Chuan Hua He, Aaron B Waxman, Chun Geun Lee, Holger Link, Morgan E Rabach, Bing Ma, Qingsheng Chen, Zhou Zhu, Mei Zhong, Keiko Nakayama, Keiichi I Nakayama, Robert Homer, Jack A Elias
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 4 Pg. 1039-48 (Apr 2005) ISSN: 0021-9738 [Print] United States
• PMID: 15841185 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Interleukin-11
• Proto-Oncogene Proteins c-bcl-2
• Vascular Endothelial Growth Factor A
• Caspases
• Oxygen

Topics

• Animals
• Caspases (metabolism)
• Cell Death (physiology)
• Cells, Cultured
• In Situ Nick-End Labeling
• Interleukin-11 (genetics, metabolism)
• Lung (cytology, immunology, pathology)
• Lung Diseases (immunology, pathology)
• Lung Injury
• Mice
• Mice, Transgenic
• Oxygen (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Survival Rate
• Vascular Endothelial Growth Factor A (metabolism)