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Hypoxic Pulmonary Vasoconstriction: From Molecular Mechanisms to Medicine.
Dunham-Snary, KJ, Wu, D, Sykes, EA, Thakrar, A, Parlow, LRG, Mewburn, JD, Parlow, JL, Archer, SL
Chest. 2017;(1):181-192
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Abstract
Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic Po2 without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the nonventilated lung, thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PAP, and initiates PH. Exaggerated or heterogeneous HPV contributes to high-altitude pulmonary edema. Conversely, impaired HPV, whether due to disease (eg, COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudohypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen sensing are important in human health and disease.
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Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction.
Sommer, N, Strielkov, I, Pak, O, Weissmann, N
The European respiratory journal. 2016;(1):288-303
Abstract
Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulated in vivo by the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCs via direct or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV.
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[Calcium sensitivity in vascular smooth muscle cell during hypoxic pulmonary vasoconstriction].
Koubský, K
Ceskoslovenska fysiologie. 2015;(1):19-22
Abstract
Hypoxic pulmonary vasoconstriction is a means of optimising the oxygenation of blood in the lungs by redistributing the flow from poorly ventilated areas into well ventilated ones. It is caused by a direct effect of hypoxia on pulmonary vascular smooth muscle cells. For a vascular smooth muscle cell to contract, an increased intracellular concentration of calcium is needed. However, the contraction force can also be regulated independently of calcium concentration by calcium sensitivity. The sensitivity is regulated mainly by activation/deactivation of myosin light chain phosphatase. Several metabolic pathways converge on this enzyme. The increase in calcium sensitivity is an important process during hypoxic pulmonary vasoconstriction.
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Assessment of pulmonary vasculature and right heart by invasive haemodynamics and echocardiography.
Hemnes, AR, Forfia, PR, Champion, HC
International journal of clinical practice. Supplement. 2009;(162):4-19
Abstract
Understanding the haemodynamical profile of the right ventricle and pulmonary circulation is critical to not only the initial evaluation of, but also the continued management of pulmonary hypertension. Despite advances in non-invasive imaging techniques, right heart catheterisation (RHC) remains the gold standard for diagnosis of pulmonary hypertension and its various causes. Even so, integration of invasive haemodynamical data with the echo-Doppler exam provides the most comprehensive assessment of the pathophysiology of pulmonary hypertension in the individual patient. Here, we review technical aspects of basic RHC as well as specialised procedures including exercise and fluid challenge in the evaluation of pulmonary hypertension. Interpretation of data in the context of pulmonary vascular disease is discussed. Echocardiographical assessment of the right ventricular structure and function in pulmonary vascular disease are discussed along with the integration of haemodynamical and echocardiographical data in the clinical context.
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An anesthesiologist's guide to hypoxic pulmonary vasoconstriction: implications for managing single-lung anesthesia and atelectasis.
Nagendran, J, Stewart, K, Hoskinson, M, Archer, SL
Current opinion in anaesthesiology. 2006;(1):34-43
Abstract
PURPOSE OF THE REVIEW Hypoxic pulmonary vasoconstriction is the pulmonary circulation's homeostatic mechanism for matching regional perfusion to ventilation and optimizing systemic PaO2. The role of hypoxic pulmonary vasoconstriction in anesthesiology is reviewed. RECENT FINDINGS In hypoxic pulmonary vasoconstriction, airway hypoxia causes resistance pulmonary arteries to constrict, diverting blood to better-oxygenated alveoli. Hypoxic pulmonary vasoconstriction optimizes O2 uptake in atelectasis, pneumonia, asthma, and adult respiratory distress syndrome. During single-lung anesthesia, hypoxic pulmonary vasoconstriction helps maintain systemic oxygenation. When hypoxic pulmonary vasoconstriction is weak, systemic hypoxemia is exacerbated. Although not widely used, the peripheral chemoreceptor agonist almitrine enhances hypoxic pulmonary vasoconstriction and improves PaO2 during single-lung anesthesia. The mechanism of hypoxic pulmonary vasoconstriction involves a redox-based O2 sensor within pulmonary artery smooth muscle cells. Pulmonary artery smooth muscle cells mitochondria vary production of reactive O2 species in proportion to PaO2. Hypoxic withdrawal of these redox second messengers inhibits voltage-gated potassium channels, depolarizing the pulmonary artery smooth muscle cells. Depolarization activates L-type calcium channels, increasing cytosolic calcium and triggering hypoxic pulmonary vasoconstriction. SUMMARY An understanding of hypoxic pulmonary vasoconstriction is clinically relevant for anesthesiologists. Randomized clinical trials with robust endpoints are required to assess strategies for enhancing hypoxic pulmonary vasoconstriction in thoracic surgery patients.
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The mechanism(s) of hypoxic pulmonary vasoconstriction: potassium channels, redox O(2) sensors, and controversies.
Archer, S, Michelakis, E
News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society. 2002;:131-7
Abstract
Hypoxic pulmonary vasoconstriction matches perfusion to ventilation and optimizes systemic oxygenation. Alterations in PO(2) are sensed by a vascular redox O(2) sensor in the pulmonary artery smooth muscle cell, probably within the mitochondria. This creates a signal that modulates redox-sensitive K(+) channels, thereby controlling membrane potential, Ca(2+) entry, and tone.