Editing Hypoxia (medicine) (section)

==Mechanism==
Tissue hypoxia from low oxygen delivery may be due to low haemoglobin concentration (anaemic hypoxia), low cardiac output (stagnant hypoxia) or low haemoglobin saturation (hypoxic hypoxia).<ref name="Lacroix et al" /> The consequence of oxygen deprivation in tissues is a switch to anaerobic metabolism at the cellular level. As such, reduced systemic blood flow may result in increased serum lactate.<ref name="Kluckow and Seri 2012" /> Serum lactate levels have been correlated with illness severity and mortality in critically ill adults and in ventilated neonates with respiratory distress.<ref name="Kluckow and Seri 2012" />

===Physiological responses===
All vertebrates must maintain oxygen homeostasis to survive, and have evolved physiological systems to ensure adequate oxygenation of all tissues. In air breathing vertebrates this is based on lungs to acquire the oxygen, hemoglobin in red corpuscles to transport it, a vasculature to distribute, and a heart to deliver. Short term variations in the levels of oxygenation are sensed by chemoreceptor cells which respond by activating existing proteins, and over longer terms by regulation of gene transcription. Hypoxia is also involved in the pathogenesis of some common and severe pathologies.<ref name="Michiels 2004" />

The most common causes of death in an aging population include myocardial infarction, stroke and cancer. These diseases share a common feature that limitation of oxygen availability contributes to the development of the pathology. Cells and organisms are also able to respond adaptively to hypoxic conditions, in ways that help them to cope with these adverse conditions. Several systems can sense oxygen concentration and may respond with adaptations to acute and long-term hypoxia.<ref name="Michiels 2004" />
The systems activated by hypoxia usually help cells to survive and overcome the hypoxic conditions. [[Erythropoietin]], which is produced in larger quantities by the kidneys under hypoxic conditions, is an essential hormone that stimulates production of red blood cells, which are the primary transporter of blood oxygen, and glycolytic enzymes are involved in anaerobic ATP formation.<ref name="Lumb 2017" />

Hypoxia-inducible factors (HIFs) are [[transcription factors]] that respond to decreases in available oxygen in the cellular environment, or hypoxia.<ref name="Smith et al 2008" /><ref name="Wilkins et al 2016" /> The HIF signaling cascade mediates the effects of hypoxia on the cell. Hypoxia often keeps cells from [[Cellular differentiation|differentiating]]. However, hypoxia promotes the [[angiogenesis|formation of blood vessels]], and is important for the formation of a [[vascular system]] in [[embryo]]s and tumors. The hypoxia in [[wound]]s also promotes the migration of [[keratinocyte]]s and the restoration of the [[epithelium]].<ref name="Benizri et al 2008" /> It is therefore not surprising that HIF-1 modulation was identified as a promising treatment paradigm in wound healing.<ref name="Duscher et al" />

Exposure of a tissue to repeated short periods of hypoxia, between periods of normal oxygen levels, influences the tissue's later response to prolonged ischaemic exposure. Thus is  known as [[ischaemic preconditioning]], and it is known to occur in many tissues.<ref name="Lumb 2017" />

===Acute===
{{see also|Hypoxic ventilatory response#Acute hypoxic ventilatory response}}
If oxygen delivery to cells is insufficient for the demand (hypoxia), electrons will be shifted to [[pyruvic acid]] in the process of [[lactic acid fermentation]].  This temporary measure (anaerobic metabolism) allows small amounts of energy to be released.  Lactic acid build up (in tissues and blood) is a sign of inadequate mitochondrial oxygenation, which may be due to hypoxemia, poor blood flow (e.g., shock) or a combination of both.<ref name="Hobler and Carey 1973" /> If severe or prolonged it could lead to cell death.<ref name="Fulda et al 2010" />

In humans, hypoxia is detected by the peripheral chemoreceptors in the [[carotid body]] and [[aortic body]], with the carotid body chemoreceptors being the major mediators of reflex responses to hypoxia.<ref name="Arieff 2013" /> This response does not control ventilation rate at normal P<sub>O<sub>2</sub></sub>, but below normal the activity of neurons innervating these receptors increases dramatically, so much as to override the signals from central chemoreceptors in the [[hypothalamus]], increasing P<sub>O<sub>2</sub></sub> despite a falling P<sub>CO<sub>2</sub></sub>{{citation needed|date=September 2022}}

In most tissues of the body, the response to hypoxia is [[vasodilation]]. By widening the blood vessels, the tissue allows greater perfusion.

By contrast, in the [[lung]]s, the response to hypoxia is vasoconstriction. This is known as [[hypoxic pulmonary vasoconstriction]], or "HPV", and has the effect of redirecting blood away from poorly ventilated regions, which helps match perfusion to ventilation, giving a more even oxygenation of blood from different parts of the lungs.<ref name="Michiels 2004" /> In conditions of hypoxic breathing gas, such as at high altitude, HPV is generalized over the entire lung, but with sustained exposure to generalized hypoxia, HPV is suppressed.<ref name="Gao et al 2021" />
Hypoxic ventilatory response (HVR) is the increase in [[ventilation (physiology)|ventilation]] induced by hypoxia that allows the body to take in and transport lower concentrations of oxygen at higher rates.  It is initially elevated in lowlanders who travel to high altitude, but reduces significantly over time as people [[acclimatize]].<ref name="Cymerman and Rock" /><ref name="Teppema and Dahan 2010" />

===Chronic===
{{see also|Hypoxic ventilatory response#Chronic hypoxic ventilatory response|High-altitude adaptation in humans}}
When the pulmonary capillary pressure remains elevated chronically (for at least 2 weeks), the lungs become even more resistant to pulmonary edema because the lymph vessels expand greatly, increasing their capability of carrying fluid away from the interstitial spaces perhaps as much as 10-fold. Therefore, in patients with chronic [[mitral stenosis]], pulmonary capillary pressures of 40 to 45&nbsp;mm Hg have been measured without the development of lethal pulmonary edema.<ref name="Guytun and Hall" />

There are several potential physiologic mechanisms for hypoxemia, but in patients with chronic obstructive pulmonary disease ([[COPD]]), [[Ventilation/perfusion ratio|ventilation/perfusion]] (V/Q) mismatching is most common, with or without alveolar hypoventilation, as indicated by arterial carbon dioxide concentration. Hypoxemia caused by V/Q mismatching in COPD is relatively easy to correct, and relatively small flow rates of supplemental oxygen (less than 3 L/min for the majority of patients) are required for long term [[oxygen therapy]] (LTOT). Hypoxemia normally stimulates ventilation and produces dyspnea, but these and the other signs and symptoms of hypoxia are sufficiently variable in COPD to limit their value in patient assessment. Chronic alveolar hypoxia is the main factor leading to development of cor pulmonale — right ventricular hypertrophy with or without overt right ventricular failure — in patients with COPD. Pulmonary hypertension adversely affects survival in COPD, proportional to resting mean pulmonary artery pressure elevation. Although the severity of airflow obstruction as measured by forced expiratory volume tests [[FEV1]] correlates best with overall prognosis in COPD, chronic hypoxemia increases mortality and morbidity for any severity of disease. Large-scale studies of long term oxygen therapy in patients with COPD show a [[dose–response relationship]] between daily hours of supplemental oxygen use and survival. Continuous, 24-hours-per-day oxygen use in appropriately selected patients may produce a significant survival benefit.<ref name="Pierson 2000" />

===Pathological responses===
====Cerebral ischemia====
The brain has relatively high energy requirements, using about 20% of the oxygen under resting conditions, but low reserves, which make it specially vulnerable to hypoxia. In normal conditions, an increased demand for oxygen is easily compensated by an increased cerebral blood flow. but under conditions when there is insufficient oxygen available, increased blood flow may not be sufficient to compensate, and hypoxia can result in brain injury. A longer duration of cerebral hypoxia will generally result in larger areas of the brain being affected. The [[brainstem]], [[hippocampus]] and [[cerebral cortex]] seem to be the most vulnerable regions. Injury becomes irreversible if oxygenation is not soon restored. Most cell death is by [[necrosis]] but delayed [[apoptosis]] also occurs. In addition, presynaptic neurons release large amounts of glutamate which further increases Ca<sup>2+</sup> influx and causes catastrophic collapse in postsynaptic cells. Although it is the only way to save the tissue, reperfusion also produces reactive oxygen species and inflammatory cell infiltration, which induces further cell death. If the hypoxia is not too severe, cells can suppress some of their functions, such as protein synthesis and spontaneous electrical activity, in a process called ''[[Penumbra (medicine)|penumbra]]'', which is reversible if the oxygen supply is resumed soon enough.<ref name="Michiels 2004" />

====Myocardial ischemia====

Parts of the heart are exposed to ischemic hypoxia in the event of occlusion of a coronary artery. Short periods of ischaemia are reversible if reperfused within about 20 minutes, without development of necrosis, but the phenomenon known as ''stunning'' is generally evident. If hypoxia continues beyond this period, necrosis propagates through the myocardial tissue.<ref name="Michiels 2004" /> Energy metabolism in the affected area shifts from mitochondrial respiration to anaerobic glycolysis almost immediately, with concurrent reduction of effectiveness of contractions, which soon cease. Anaerobic products accumulate in the muscle cells, which develop acidosis and osmotic load leading to cellular edema. Intracellular Ca2+ increases and eventually leads to cell necrosis. Arterial flow must be restored to return to aerobic metabolism and prevent necrosis of the affected muscle cells, but this also causes further damage by [[reperfusion injury]]. Myocadial stunning has been described as "prolonged postischaemic dysfunction of viable tissue salvaged by reperfusion", which manifests as temporary contractile failure in oxygenated muscle tissue. This may be caused by a release of reactive oxygen species during the early stages of reperfusion.<ref name="Michiels 2004" />

====Tumor angiogenesis====
As tumors grow, regions of relative hypoxia develop as the oxygen supply is unevenly utilized by the tumor cells. The formation of new blood vessels is necessary for continued tumor growth, and is also an important factor in metastasis, as the route by which cancerous cells are transported to other sites.<ref name="Michiels 2004" />

{{expand section|date=December 2022}}