Targeting Hypoxia-induced Inflammation

Abstract

In the current issue of Anesthesiology, a paper by Kim et al. from the research laboratory of Dr. H. Thomas Lee investigates strategies to dampen ischemia-driven inflammation of the kidneys and subsequent multi-organ failure utilizing experimental models of acute kidney injury (AKI).1 In fact, one of the leading causes of morbidity and mortality in surgical patients is perioperative organ failure, such as occurs in the context of acute kidney injury, liver failure, intestinal or myocardial ischemia, stroke or acute lung injury. A common feature of these perioperative diseases is the presence of hypoxia-induced inflammation.2,3 The relationship between hypoxia and inflammation under these conditions is inter-dependent. For example, exposure to ambient hypoxia - as seen during high-altitude mountaineering - is associated with edema of the lungs or the brain, and systemic inflammatory responses in humans.4,5 Similarly, acute exposure of mice to ambient hypoxia (e.g. 8% of oxygen over 4–8h) leads to increased inflammatory cytokine levels and pulmonary edema.6 Moreover, prolonged donor organ exposure to ischemia during organ transplantation is known to enhance graft inflammation and early graft failure.7,8 For example, the endotoxin-receptor TLR4 is expressed in the donor kidney during kidney transplantation, and TLR4 expression levels increase with prolonged ischemia time. Donor kidneys with a loss-of-function mutation of the TLR4 receptor show attenuated kidney inflammation, and an increased rate of immediate graft function.7 Together, these studies indicate that hypoxia represents an inflammatory stimulus (Figure 1) and suggest that targeting hypoxia-elicited inflammation could represent an important therapeutic approach in perioperative medicine.