Hyperoxia causes cell injury and death associated with reactive oxygen species formation and inflammatory responses. Recent studies show that hyperoxia-induced cell death involves apoptosis, necrosis, or mixed phenotypes depending on cell type, although the underlying mechanisms remain unclear. Using murine lung endothelial cells, we found that hyperoxia caused cell death by apoptosis involving both extrinsic (Fasdependent) and intrinsic (mitochondria-dependent) pathways. Hyperoxia-dependent activation of the extrinsic apoptosis pathway and formation of the death-inducing signaling complex required NADPH oxidase-dependent reactive oxygen species production, because this process was attenuated by chemical inhibition, as well as by genetic deletion of the p47 phox subunit, of the oxidase. Overexpression of heme oxygenase-1 prevented hyperoxia-induced cell death and cytochrome c release. Likewise, carbon monoxide, at low concentrations, markedly inhibited hyperoxiainduced endothelial cell death by inhibiting cytochrome c release and caspase-9/3 activation. Carbon monoxide, by attenuating hyperoxia-induced reactive oxygen species production, inhibited extrinsic apoptosis signaling initiated by death-inducing signal complex trafficking from the Golgi apparatus to the plasma membrane and downstream activation of caspase-8. We also found that carbon monoxide inhibited the hyperoxia-induced activation of Bcl-2-related proteins involved in both intrinsic and extrinsic apoptotic signaling. Carbon monoxide inhibited the activation of Bid and the expression and mitochondrial translocation of Bax, whereas promoted Bcl-X L /Bax interaction and increased Bad phosphorylation. We also show that carbon monoxide promoted an interaction of heme oxygenase-1 with Bax. These results define novel mechanisms underlying the antiapoptotic effects of carbon monoxide during hyperoxic stress.The clinical treatment of respiratory failure often requires supplemental oxygen therapy. Prolonged exposure to an elevated oxygen tension (hyperoxia) in animal models causes acute and chronic lung injury that resembles acute respiratory distress syndrome. In rodent models, hyperoxia triggers an extensive inflammatory response in the lung that degrades the alveolar-capillary barrier, leading to impaired gas exchange and pulmonary edema (1, 2). Lung tissue damage results from the direct action of increased intracellular reactive oxygen species (ROS) 2 or as a secondary consequence of inflammatory responses of the host (3, 4). The source(s) of intracellular ROS during oxygen exposure remain unclear but may involve increased mitochondrial generation and/or activation of NADPH oxidases (5, 6). The pathological changes in hyperoxiainjured lungs coincide with the injury or death of pulmonary capillary endothelial cells and alveolar epithelial cells (2, 4 -7). Epithelial cells maintain the integrity of the alveolar-capillary barrier and defend against oxidative injury. Compromised epithelial cell function may permit fluid and macromolecules to leak into the air...

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In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.

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