Hypoxia and inflammation are two sides of the same coin

Abstract

Hypoxia and inflammation share an interdependent relationship (1). Many recent publications implicate hypoxia-elicited inflammation, or inflammation during hypoxic conditions in the outcomes of a wide array of human diseases (2). On the one hand, inflammatory disease states are frequently characterized by tissue hypoxia, or stabilization of hypoxia-dependent transcription factors, such as hypoxia-inducible factor (HIF) (3). For example, intestinal inflammation, such as occurs during inflammatory bowel disease, is characterized by the occurrence of severe hypoxia of the mucosal surface, and concomitant stabilization of HIF (4, 5). Stabilization of HIF1A during intestinal inflammation is caused by alterations in metabolic supply and demand ratios, particularly for oxygen, leading to “inflammatory hypoxia” (6). Similarly, lung inflammation, such as occurs during acute lung injury, is associated with metabolic alterations leading to the stabilization of HIF1A (7). On the other hand, disease conditions that are primarily caused by a lack of oxygen are characterized by secondary inflammatory changes. For example, ischemia and reperfusion injury is characterized by inflammatory responses that lead to subsequent organ dysfunction (8). The functional role of hypoxia-signaling and stabilization of HIFs during acute inflammatory or hypoxic disease states has been the focus of many recent studies. Surprisingly, many of these studies show that pharmacologic stabilization of HIF functions in an adaptive manner by increasing ischemia tolerance (9) and controlling excessive inflammation (10). Many of the studies have linked the anti-inflammatory effects of hypoxia-signaling to a transcriptional program that is under the control of HIF, where pharmacologic activators of HIFs provide tissue protection (11, 12). However, a recent study by Scholz et al. … [↵][1]1To whom correspondence should be addressed. E-mail: Holger.Eltzschig{at}UCDenver.edu. [1]: #xref-corresp-1-1