The many acid–base manifestations and consequences of hypoxia

Abstract

Hypoxia evokes a spectrum of acid–base changes from alkalosis to acidosis and alters many responses to hypoxia at non-genomic and genomic levels, in part via altered hypoxia-inducible factor (HIF) metabolism. Healthy people at altitude and persons hyperventilating to non-hypoxic stimuli can raise arterial pH as high as 7.7. In these circumstances, alkalosis reduces sympathetic tone, blunts hypoxic pulmonary vasoconstriction and cerebral vasodilation, and increases hemoglobin-oxygen affinity. With severe hypoxia owing to profoundly low arterial O2 content (hypoxemia) or poor perfusion (ischemia), metabolic and hypercapnic acidosis develops along with considerable lactate formation with pH falling to below 6.8. Although acidoses are considered deleterious to cell function and survival, they can be cytoprotective by various anti-inflammatory, anti-oxidant, and anti-apoptotic mechanisms. Attempts to correct acidosis under these circumstances concurrent with re-oxygenation efforts may be ill advised. This so-called ‘pH paradox’ or permissive acidosis may offer therapeutic possibilities. Rapidly growing cancers often outstrip their oxygen and nutrient delivery and metabolic waste disposal, thus limiting growth and metastatic potential. However, their excessive glycolysis and lactate formation may not necessarily represent oxygen insufficiency, but an attempt to provide sufficient amounts of small carbon intermediates to supply many synthetic pathways of cellular proliferation. In either case, there is expression and upregulation of many genes involved in acid–base homeostasis, in part by HIF-1α and HIF-2α signaling. Inhibition of these proteins or gene suppression may have important therapeutic application in cancer therapy.