Epithelial cell death is an important contributor to oxidant-mediated acute lung injury.

RATIONALE: Acute lung injury and the acute respiratory distress syndrome are characterized by increased lung oxidant stress and apoptotic cell death. The contribution of epithelial cell apoptosis to the development of lung injury is unknown. OBJECTIVES: To determine whether oxidant-mediated activation of the intrinsic or extrinsic apoptotic pathway contributes to the development of acute lung injury. METHODS: Exposure of tissue-specific or global knockout mice or cells lacking critical components of the apoptotic pathway to hyperoxia, a well-established mouse model of oxidant-induced lung injury, for measurement of cell death, lung injury, and survival. MEASUREMENTS AND MAIN RESULTS: We found that the overexpression of SOD2 prevents hyperoxia-induced BAX activation and cell death in primary alveolar epithelial cells and prolongs the survival of mice exposed to hyperoxia. The conditional loss of BAX and BAK in the lung epithelium prevented hyperoxia-induced cell death in alveolar epithelial cells, ameliorated hyperoxia-induced lung injury, and prolonged survival in mice. By contrast, Cyclophilin D-deficient mice were not protected from hyperoxia, indicating that opening of the mitochondrial permeability transition pore is dispensable for hyperoxia-induced lung injury. Mice globally deficient in the BH3-only proteins BIM, BID, PUMA, or NOXA, which are proximal upstream regulators of BAX and BAK, were not protected against hyperoxia-induced lung injury suggesting redundancy of these proteins in the activation of BAX or BAK. CONCLUSIONS: Mitochondrial oxidant generation initiates BAX- or BAK-dependent alveolar epithelial cell death, which contributes to hyperoxia-induced lung injury.

Lung cancer in chronic obstructive pulmonary disease: enhancing surgical options and outcomes.

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for both the development of primary lung cancer, as well as poor outcome after lung cancer diagnosis and treatment. Because of existing impairments in lung function, patients with COPD often do not meet traditional criteria for tolerance of definitive surgical lung cancer therapy. Emerging information regarding the physiology of lung resection in COPD indicates that postoperative decrements in lung function may be less than anticipated by traditional prediction tools. In patients with COPD, more inclusive consideration for surgical resection with curative intent may be appropriate as limited surgical resections or nonsurgical therapeutic options provide inferior survival. Furthermore, optimizing perioperative COPD medical care according to clinical practice guidelines including smoking cessation can potentially minimize morbidity and improve functional status in this often severely impaired patient population.

Airborne particulate matter inhibits alveolar fluid reabsorption in mice via oxidant generation.

Ambient particulate matter is increasingly recognized as a significant contributor to human cardiopulmonary morbidity and mortality in the United States and worldwide. We sought to determine whether exposure to ambient particulate matter would alter alveolar fluid clearance in mice. Mice were exposed to a range of doses of a well-characterized particulate matter collected from the ambient air in Düsseldorf, Germany through a single intratracheal instillation, and alveolar fluid clearance and measurements of lung injury were made. Exposure to even very low doses of particulate matter (10 microg) resulted in a significant reduction in alveolar fluid clearance that was maximal 24 h after the exposure, with complete resolution after 7 d. This was paralleled by a decrease in lung Na,K-ATPase activity. To investigate the mechanism of this effect, we measured plasma membrane Na,K-ATPase abundance in A549 cells and Na,K-ATPase activity in primary rat alveolar type II cells after exposure to particulate matter in the presence or absence of the combined superoxide dismutase and catalase mimetic EUK-134 (5 microM). Membrane but not total protein abundance of the Na,K-ATPase was decreased after exposure to particulate matter, as was Na,K-ATPase activity. This decrease was prevented by the combined superoxide dismutase/catalase mimetic EUK-134. The intratracheal instillation of particulate matter results in alveolar epithelial injury and decreased alveolar fluid clearance, conceivably due to downregulation of the Na,K-ATPase.