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...
The homodimeric flavohemeprotein endothelial nitric oxide synthase (eNOS) oxidizes l-arginine to l-citrulline and nitric oxide (NO), which acutely vasodilates blood vessels and inhibits platelet aggregation. Chronically, eNOS has a major role in the regulation of blood pressure and prevention of atherosclerosis by decreasing leukocyte adhesion and smooth muscle proliferation. However, a disturbed vascular redox balance results in eNOS damage and uncoupling of oxygen activation from l-arginine conversion. Uncoupled eNOS monomerizes and generates reactive oxygen species (ROS) rather than NO. Indeed, eNOS uncoupling has been suggested as one of the main pathomechanisms in a broad range of cardiovascular and pulmonary disorders such as atherosclerosis, ventricular remodeling, and pulmonary hypertension. Therefore, modulating uncoupled eNOS, in particular eNOS-dependent ROS generation, is an attractive therapeutic approach to preventing and/or treating cardiopulmonary disorders, including protective effects during cardiothoracic surgery. This review provides a comprehensive overview of the pathogenetic role of uncoupled eNOS in both cardiovascular and pulmonary disorders. In addition, the related therapeutic possibilities such as supplementation with the eNOS substrate l-arginine, volatile NO, and direct NO donors as well as eNOS modulators such as the eNOS cofactor tetrahydrobiopterin and folic acid are discussed in detail.
IN THIS ISSUE OF the American Journal of Kang et al. (2) demonstrated that antihypertensive treatments, e.g., triple therapy with reserpine ϩ hydrochlorothiazide ϩ hydralazine or oral tetrahydrobiopterin (BH 4 ), increase vascular BH 4 levels and the ratio of BH 4 to 7,8-dihydrobiopterin (BH 2 ), restore nitric oxide (NO)/cGMP signaling, and restore endothelial NO synthase (NOS3) phosphorylation at Ser1177 in small mesenteric arteries from angiotensin II-infused rats. Decreased levels of BH 4 have been demonstrated both in the vasculature (1) and the myocardium (3), respectively, by using a model of salt-sensitive low renininduced hypertension and aortic banding-induced hypertension. So far, the data showing that antihypertensive treatment itself can restore BH 4 and NO levels were missing.The data of Kang et al. (2) are both challenging and intriguing because they further unravel the antihypertensive effects of these drugs and demonstrate that these antihypertensive therapies lower blood pressure through a BH 4 -dependent mechanism, restoring NO/cGMP signaling and NOS3 phosphorylation in small arteries. However, no data are provided regarding the effects of these therapies on the BH 4 levels and the NOS3-uncoupling status in large arteries or in the myocardium. Further mechanistic insight is needed to improve this somewhat premature finding and to investigate whether these data can be extrapolated to ventricular remodeling, an important consequence of hypertension, associated with decreased BH 4 levels in the myocardium (3).In addition, the combination of reserpine, hydrochlorothiazide, and hydralazine is not reflective of the current standards of care with respect to the treatment of hypertension in patients. How much of the decrease in hypertension is due to each drug is one major question that needs answering. In addition, the mechanism of hydralazine is not completely clear, and there is evidence that it directly increases cGMP activity (4).Furthermore, Kang et al. (2) demonstrate that triple therapy (but not oral BH 4 therapy) significantly increases guanosine triphosphate cyclohydrolase (GTPCH)-I activity in small arteries without a change in GTPCH-I expression. Although it is known that shear stress can affect GTPCH-I expression and activity (5), previous studies have not examined this correlation in models of systemic hypertension. Therefore, this study further explores the pathogenesis of hypertension and provides new therapeutic strategies to tackle hypertension. DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).
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