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

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

研究成果: ジャーナルへの寄稿記事

70 引用 (Scopus)

抄録

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% O2 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% O2. 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.

元の言語英語
ページ(範囲)1039-1048
ページ数10
ジャーナルJournal of Clinical Investigation
115
発行部数4
DOI
出版物ステータス出版済み - 4 2005

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Interleukin-11
Cytoprotection
Acute Lung Injury
Hyperoxia
Cytokines
Proteins
Necrosis
Poisons
Apoptosis
Oxidants
Vascular Endothelial Growth Factor A
Cell Death
Premature Mortality
In Situ Nick-End Labeling
Lung Injury
Epithelial Cells
Oxygen
Gene Expression

All Science Journal Classification (ASJC) codes

  • Medicine(all)

これを引用

Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury. / He, Chuan Hua; Waxman, Aaron B.; Lee, Chun Geun; Link, Holger; Rabach, Morgan E.; Ma, Bing; Chen, Qingsheng; Zhu, Zhou; Zhong, Mei; Nakayama, Keiko; Nakayama, Keiichi I.; Homer, Robert; Elias, Jack A.

:: Journal of Clinical Investigation, 巻 115, 番号 4, 04.2005, p. 1039-1048.

研究成果: ジャーナルへの寄稿記事

He, CH, Waxman, AB, Lee, CG, Link, H, Rabach, ME, Ma, B, Chen, Q, Zhu, Z, Zhong, M, Nakayama, K, Nakayama, KI, Homer, R & Elias, JA 2005, 'Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury', Journal of Clinical Investigation, 巻. 115, 番号 4, pp. 1039-1048. https://doi.org/10.1172/JCI23004
He, Chuan Hua ; Waxman, Aaron B. ; Lee, Chun Geun ; Link, Holger ; Rabach, Morgan E. ; Ma, Bing ; Chen, Qingsheng ; Zhu, Zhou ; Zhong, Mei ; Nakayama, Keiko ; Nakayama, Keiichi I. ; Homer, Robert ; Elias, Jack A. / Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury. :: Journal of Clinical Investigation. 2005 ; 巻 115, 番号 4. pp. 1039-1048.
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title = "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{\%} O2 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{\%} O2. 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.",
author = "He, {Chuan Hua} and Waxman, {Aaron B.} and Lee, {Chun Geun} and Holger Link and Rabach, {Morgan E.} and Bing Ma and Qingsheng Chen and Zhou Zhu and Mei Zhong and Keiko Nakayama and Nakayama, {Keiichi I.} and Robert Homer and Elias, {Jack A.}",
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T1 - Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury

AU - He, Chuan Hua

AU - Waxman, Aaron B.

AU - Lee, Chun Geun

AU - Link, Holger

AU - Rabach, Morgan E.

AU - Ma, Bing

AU - Chen, Qingsheng

AU - Zhu, Zhou

AU - Zhong, Mei

AU - Nakayama, Keiko

AU - Nakayama, Keiichi I.

AU - Homer, Robert

AU - Elias, Jack A.

PY - 2005/4

Y1 - 2005/4

N2 - 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% O2 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% O2. 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.

AB - 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% O2 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% O2. 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.

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