ATP-independent Membrane Depolarization with Ischemia in the Oxygen-ventilated Isolated Rat Lung

Al-Mehdi, Abu B.; Zhao, Guochang; Fisher, Aron B.

doi:10.1165/ajrcmb.18.5.2834

Cited by 64 publications

(65 citation statements)

References 25 publications

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“…Shear stress has been implicated in pathophysiological processes in the vascular wall such as atherosclerosis, reperfusion, and EC wound healing (1)(2)(3)(4)(5)(6)(7)(8). Because both Cdc42 and Rho are sensitive to the applied shear stress, it is likely that these two small GTPases are involved in the EC signaling and gene expression in the lesion-prone areas of the arterial tree.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles for the small GTPases Cdc42 and Rho in endothelial responses to shear stress

Song¹,

Chen²,

Azuma³

et al. 1999

J. Clin. Invest.

177

132

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Endothelial cells (ECs) in blood vessels are exposed to fluid shear stress, the tangential component of the hemodynamic forces acting on the vessel wall. Shear stress has been implicated in pathophysiological processes in the vascular wall such as atherosclerosis, reperfusion, and EC wound healing (1-8). The role of shear stress in atherogenesis is manifested by the finding that the atherosclerotic lesions in the arterial tree are preferentially located in the disturbed flow region. In vitro experiments using ECs cultured in flow channels have shown that the structure and function of ECs are modulated by shear stress (reviewed in ref. 9). The early responses of ECs to applied shear stress in vitro may represent in vivo responses of ECs to the temporal and spatial changes of shear stress resulting from disturbed flow. It has been shown that shear stress modulates the expression of genes encoding growth factors, adhesion molecules, coagulation molecules, chemoattractants, proto-oncogenes, and vasoactive substances (reviewed in ref. 10). For example, the platelet-derived growth factors, intercellular adhesion molecule-1, monocyte chemotactic protein-1 (MCP-1), and c-fos genes are all transiently upregulated by shear stress (11)(12)(13)(14). Several laboratories, including ours, have attempted to define the upstream signaling pathways leading to the expression of these shear-inducible genes. It has been shown that shear stress induces a rapid and transient activation of Ras small GTPase, which in turn regulates the mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs) and c-Jun NH 2 -terminal kinases (JNKs) (15, 16). In the downstream, target genes such as the MCP-1 gene are transiently upregulated through the transcription factor activating protein-1 (AP-1) acting on the 12-O-tetradecanoyl-13-phorbolacetate-responsive element (TRE) (17). Long-term exposure of ECs to shear stress causes the elongation of ECs along the direction of flow, with rearranged microfilaments and focal adhesion sites, attenuated cortical Factin, and enhanced central stress fibers (18-21). These structural features are similar to those seen in vivo in ECs in the straight part of the arterial tree (22), an area that is relatively resistant to atherosclerosis. Recent studies indicate that the shear stress modulation of endothelial shape and F-actin network depends on tyrosine kinase activities, intracellular calcium, and an intact microtubule network but that it is independent of protein kinase C, intermediate filaments, and shear-and stretch-activated mechanosensitive channels (23).Ras-related Rho family GTPases (e.g., Cdc42, Rac, and Rho) have distinct functions in regulating the actinbased cytoskeletal structure (reviewed in refs. 24 and 25): Cdc42 regulates filopodia formation (26, 27); Rac regulates membrane ruffling (28); and Rho increases cell contractility, focal adhesions, and actin stress fibers (29). It was also shown that Rho stimulated the tyrosine phosphorylation of focal adhesion kinas...

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Section: Discussionmentioning

confidence: 99%

Distinct roles for the small GTPases Cdc42 and Rho in endothelial responses to shear stress

Song¹,

Chen²,

Azuma³

et al. 1999

J. Clin. Invest.

177

132

View full text Add to dashboard Cite

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“…2) iNOS-dependent superoxide production: During IR, iNOS has been activated by endothelial cell membrane depolarization due to the absence of shear stress during ischemia (6,7) up to 2 h after lung reperfusion (146). The high concentration of NO inhibits cytochrome oxidase, resulting in increased ROS production (94), and reacts with ROS to form peroxynitrite and other reactive nitrogen species (15).…”

Section: Mechanisms Of Lung Injury During Irmentioning

confidence: 99%

Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process

Hengst

Gielis

Lin

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

324

280

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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...

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“…Thus perfusion may be a maneuver to prevent ischemia-reperfusion signaling (31). In rat lungs, signaling was not activated until the perfusion rate decreased below a threshold level, i.e., a drop in shear by Ͼ90% of physiological flow was required for onset of ischemia signaling (8). However, the shear threshold for ischemic signaling in human lungs has not been definitively established.…”

Section: L675mentioning

confidence: 99%

Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation

Chatterjee

Nieman

Christie

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chatterjee S, Nieman GF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307: L668 -L680, 2014. First published September 19, 2014 doi:10.1152/ajplung.00198.2014.-Cessation of blood flow represents a physical event that is sensed by the pulmonary endothelium leading to a signaling cascade that has been termed "mechanotransduction." This paradigm has clinical relevance for conditions such as pulmonary embolism, lung bypass surgery, and organ procurement and storage during lung transplantation. On the basis of our findings with stop of flow, we postulate that normal blood flow is "sensed" by the endothelium by virtue of its location at the interface of the blood and vessel wall and that this signal is necessary to maintain the endothelial cell membrane potential. Stop of flow is sensed by a "mechanosome" consisting of PECAM-VEGF receptor-VE cadherin that is located in the endothelial cell caveolae. Activation of the mechanosome results in endothelial cell membrane depolarization that in turn leads to activation of NADPH oxidase (NOX2) to generate reactive oxygen species (ROS). Endothelial depolarization additionally results in opening of T-type voltage-gated Ca 2ϩ channels, increased intracellular Ca 2ϩ, and activation of nitric oxide (NO) synthase with resultant generation of NO. Increased NO causes vasodilatation whereas ROS provide a signal for neovascularization; however, with lung transplantation overproduction of ROS and NO can cause oxidative injury and/or activation of proteins that drive inflammation and cell death. Understanding the key events in the mechanosignaling cascade has important lessons for the design of strategies or interventions that may reduce injury during storage of donor lungs with the goal to increase the availability of lungs suitable for donation and thus improving access to lung transplantation. lung ischemia; ischemia-reperfusion; lung transplantation; mechanotransduction; reactive oxygen species; K ATP channel; NADPH oxidase; lung perfusion and storage; EVLP THE RELATED TERMS mechanosensing, mechanosignaling, and mechanotransduction refer to the sensing of physical forces by cells and their translation into a biochemical response, analogous to the processes termed chemotransduction. Among the various physical forces to which cells in vivo are constantly exposed, mechanical stimuli associated with blood flow are particularly important. Indeed, fluid shear stress and distending pressure that act on the vessel wall play a major role in vascular homeostasis. The vascular endothelium, by virtue of its location, serves as an interface between the blood and tissue for hemodynamic changes. Recent work demonstrates that the endothelium senses and integrates hemodynamic stimuli including shear to effect maintenance of vascular function and possibly modulate the onset of vascular disease. The currently accepted paradigm is that "sensing" of a change (either increa...

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ATP-independent Membrane Depolarization with Ischemia in the Oxygen-ventilated Isolated Rat Lung

Cited by 64 publications

References 25 publications

Distinct roles for the small GTPases Cdc42 and Rho in endothelial responses to shear stress

Distinct roles for the small GTPases Cdc42 and Rho in endothelial responses to shear stress

Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process

Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation

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