Rationale: Hyperoxia-induced acute lung injury has been used for many years as a model of oxidative stress mimicking clinical acute lung injury and the acute respiratory distress syndrome. Excess quantities of reactive oxygen species (ROS) are responsible for oxidative stress-induced lung injury. ROS are produced by mitochondrial chain transport, but also by NADPH oxidase (NOX) family members. Although NOX1 and NOX2 are expressed in the lungs, their precise function has not been determined until now. Objectives: To determine whether NOX1 and NOX2 contribute in vivo to hyperoxia-induced acute lung injury. Methods: Wild-type and NOX1-and NOX2-deficient mice, as well as primary lung epithelial and endothelial cells, were exposed to room air or 100% O 2 for 72 hours. Measurements and Main Results: Lung injury was significantly prevented in NOX1-deficient mice, but not in NOX2-deficient mice. Hyperoxia-dependent ROS production was strongly reduced in lung sections, in isolated epithelial type II cells, and lung endothelial cells from NOX1-deficient mice. Concomitantly, lung cell death in situ and in primary cells was markedly decreased in NOX1-deficient mice. In wild-type mice, hyperoxia led to phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), two mitogen-activated protein kinases involved in cell death signaling, and to caspase-3 activation. In NOX1-deficient mice, JNK phosphorylation was blunted, and ERK phosphorylation and caspase-3 activation were decreased. Conclusions: NOX1 is an important contributor to ROS production and cell death of the alveolocapillary barrier during hyperoxia and is an upstream actor in oxidative stress-induced acute lung injury involving JNK and ERK pathways in mice.
Exposure to high oxygen concentration causes direct oxidative cell damage through increased production of reactive oxygen species. In vivo oxygen-induced lung injury is well characterized in rodents and has been used as a valuable model of human respiratory distress syndrome. Hyperoxia-induced lung injury can be considered as a bimodal process resulting (1) from direct oxygen toxicity and (2) from the accumulation of inflammatory mediators within the lungs. Both apoptosis and necrosis have been described in alveolar cells (mainly epithelial and endothelial) during hyperoxia. While the in vitro response to oxygen seems to be cell type-dependent in tissue cultures, it is still unclear which are the death mechanisms and pathways implicated in vivo. Even though it is not yet possible to distinguish unequivocally between apo-ptosis, necrosis, or other intermediate form(s) of cell death, a great variety of strategies has been shown to prevent alveolar damage and to increase animal survival during hyperoxia. In this review, we summarize the different cell death pathways leading to alveolar damage during hyperoxia, with particular attention to the pivotal role of mitochondria. In addition, we discuss the different protective mechanisms potentially interfering with alveolar cell death.
COPII proteins are necessary to generate secretory vesicles at the endoplasmic reticulum. In yeast, the Sec24p protein is the only COPII component in which two close orthologues have been identified. By using gene knock-out in yeast, we found that the absence of one of these Sec24 orthologues resulted in a selective secretion defect for a subset of proteins released into the medium. Data base searches revealed the existence of an entire family of Sec24-related proteins in humans, worms, flies, and plants. We identified and cloned two new human cDNAs encoding proteins homologous to yeast Sec24p, in addition to two human cDNAs already present within the data bases. The entire Sec24 family identified to date is characterized by clusters of highly conserved residues within the 2/3 carboxyl-terminal domain of all the proteins and a divergent amino terminus domain. Human (h) Sec24 orthologues co-immunoprecipitate with hSec23Ap and migrate as a complex by size exclusion chromatography. Immunofluorescence microscopy confirmed that these proteins co-localize with hSec23p and hSec13p. Together, our data suggest that in addition to its role in the shaping up of the vesicle, the Sec23-24p complex may be implicated in cargo selection and concentration.
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