No abstract

No abstract

Lung ischemia-reperfusion injury remains one of the major complications after cardiac bypass surgery and lung transplantation. Due to its dual blood supply system and the availability of oxygen from alveolar ventilation, the pathogenetic mechanisms of ischemia-reperfusion injury in the lungs are more complicated than in other organs, where loss of blood flow automatically leads to hypoxia. In this review, an extensive overview is given of the molecular and cellular mechanisms that are involved in the pathogenesis of lung ischemia-reperfusion injury and the possible therapeutic strategies to reduce or prevent it. In addition, the roles of neutrophils, alveolar macrophages, cytokines, and chemokines, as well as the alterations in the cell-death related pathways, are described in detail. pulmonary; lung transplantation; ventilated ischemia IN THE PAST, THE LUNG WAS thought to be relatively resistant to ischemia because of its dual circulation and the availability of oxygen from alveolar ventilation. However, the depletion of lung oxygenation by stopping the ventilation leads to the same degree of lung impairment as a decrease in mechanotransduction by loss of blood flow, as determined by increases in vascular pressure and permeability (11), indicating that any deficiency from oxygenation or mechanotransduction can have significant repercussions (149).Reperfusion of the ischemic lung is a double-edged sword. Reestablishing the perfusion of the ischemic lung is absolutely required to maintain the viability of the lung, but reperfusion itself can trigger a complex cascade of events, the so-called pulmonary ischemia-reperfusion injury (LIRI) (48), characterized by increased microvascular permeability (Pvasc), increased pulmonary vascular resistance (PVR), pulmonary edema, impaired oxygenation, and pulmonary hypertension. Ischemia of the lung, without loss of ventilation, results in a complex pathophysiological situation and, therefore, is not comparable with ischemia in other organs. During ventilated ischemia, for example, the adenosine triphosphate (ATP) levels remain normal while reactive oxygen species (ROS) are formed (70), illustrating aspects of complexity of the pathophysiology of ventilated and anoxic lung ischemia. Therefore, a distinction should be made between ventilated ischemia, meaning a loss of blood flow, and anoxia/reoxygenation, indicating the loss of oxygenation and/or perfusion. In this review, the terms anoxia/reoxygenation and ventilated ischemia will be used, if the specific model is known and/or the mechanism is suggested to be model specific. Ischemia alone will be used, if it applies for both mechanisms, if the specific model is not known, or the research involves other organs.Complete and prolonged lung anoxia for up to several hours is unavoidable during lung transplantation, with dire consequences. Reperfusion of the transplanted lung can lead to nonspecific alveolar damage, pulmonary edema, and hypoxemia within 72 h after lung transplantation. Even with the advancements in lung preservati...

Background-Sustained pressure overload induces pathological cardiac hypertrophy and dysfunction. Oxidative stress linked to nitric oxide synthase (NOS) uncoupling may play an important role. We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advanced hypertrophy, fibrosis, and dysfunction. Methods and Results-C57/Bl6 mice underwent transverse aortic constriction for 4 weeks, increasing cardiac mass (190%) and diastolic dimension (144%), lowering ejection fraction (Ϫ46%), and triggering NOS uncoupling and oxidative stress. Oral BH4 was then administered for 5 more weeks of pressure overload. Without reducing loading, BH4 reversed hypertrophy and fibrosis, recoupled endothelial NOS, lowered oxidant stress, and improved chamber and myocyte function, whereas untreated hearts worsened. If BH4 was started at the onset of pressure overload, it did not suppress hypertrophy over the first week when NOS activity remained preserved even in untreated transverse aortic constriction hearts. However, BH4 stopped subsequent remodeling when NOS activity was otherwise declining. A broad antioxidant, Tempol, also reduced oxidant stress yet did not recouple NOS or reverse worsened hypertrophy/fibrosis from sustained transverse aortic constriction. Microarray analysis revealed very different gene expression profiles for both treatments. BH4 did not enhance net protein kinase G activity. Finally, transgenic mice with enhanced BH4 synthesis confined to endothelial cells were unprotected against pressure overload, indicating that exogenous BH4 targeted myocytes and fibroblasts. Conclusions-NOS recoupling by exogenous BH4 ameliorates preexisting advanced cardiac hypertrophy/fibrosis and is more effective than a less targeted antioxidant approach (Tempol). These data highlight the importance of myocyte NOS uncoupling in hypertrophic heart disease and support BH4 as a potential new approach to treat this disorder.