Endothelial STAT3 is essential for the protective effects of HO-1 in oxidant-induced lung injury.
Administering high levels of inspired oxygen, or hyperoxia, is commonly used as a life-sustaining measure in critically ill patients. Unfortunately, the oxidant stress generated by prolonged hyperoxia can lead to respiratory failure, multiorgan failure, and death. Although the endothelial cell is known to be a target for hyperoxia-induced injury, its precise role is unclear. Heme oxygenase-1 (HO-1) and "signal transducer and activator of transcription 3" (STAT3) have been found to confer protection against endothelial cell injury. We sought to elucidate the specific roles of HO-1 and STAT3 in hyperoxic lung and endothelial cell injury. Mice or murine lung endothelial cells (MLEC) administered HO-1 siRNA exhibited marked injury and death compared with nonspecific siRNA. Overexpression of either HO-1 or STAT3 confers protection. However, HO-1 and its reaction product carbon monoxide (CO) lose their protective effects in the presence of STAT3 siRNA in MLEC or in endothelial-specific, STAT3-deficient mice. STAT3 overexpression is able to partially rescue HO-1-deficient MLEC from hyperoxia-induced cell death. Our results demonstrate 1) the importance of the endothelium in lethal hyperoxic injury, 2) HO-1 and CO require endothelial STAT3 for their protective effects, and 3) STAT3 confers endothelial cell protection via both HO-1-dependent and independent mechanisms.
Zhang
Xuchen
X
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, P.O. Box 208057, New Haven, CT 06520-8057, USA.
Shan
Peiying
P
Jiang
Ge
G
Zhang
Samuel S-M
SS
Otterbein
Leo E
LE
Fu
Xin-Yuan
XY
Lee
Patty J
PJ
D000818:Animals; D002248:Carbon Monoxide; D042783:Endothelial Cells / Q000473:pathology*; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018496:Hyperoxia / Q000473:pathology*; D008168:Lung / Q000473:pathology*; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000009:adverse effects*; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D010100:Oxygen