Urocortin: a few inflammatory remarks.

Urocortin is a molecule with a bright future, that is, if it can maintain its reputation as a powerful cardioprotective agent lacking any detrimental effects (1). In this paper, however, urocortin stands accused of aiding and abetting lipopolysaccharides (LPS) in activating the inflammatory response. Should the case be sustained, it could have serious consequences for urocortin’s future as a therapeutic agent. At this juncture the evidence that urocortin is involved in inflammation is circumstantial and remains controversial. In the associated report, Cureton et al. (2) looked for clues specifically relating to one aspect of the inflammatory response, that of microvascular permeability, and they obtained evidence of wrongdoing, but is it enough to hang the accused? Or does there remain reasonable doubt? First, let us take a closer look underneath urocortin’s mask. As with many proteins, urocortin has retained the name originally given to it on the basis of its homology, in this case to fish urotensin I and CRH. However, despite its sequence homology to CRH, it is now clear that urocortin no longer plays a role in regulating thermogenesis, anxiety, and energy homeostasis via receptors in the brain (3). Instead, it is believed to have a more significant role in the periphery, in which its administration can have powerful effects on cardiovascular function, gastrointestinal activity, reproductive function, and immune function (3). In the cardiovascular system, urocortin causes vasodilation as well as protects the heart against ischemia and reperfusion injury (4, 5) by reducing oxidative stress and mitochondrial damage (6). Urocortin also has other beneficial effects on the heart, including the ability to greatly improve cardiac function, even in patients with heart failure, which has led to much interest in its therapeutic potential (7, 8). However, the potential side effects of long-term treatment with urocortin are not known. Urocortin was recently shown to inhibit angiogenesis in tumors (9), which raises concern because such an inhibitory action would not be favorable in heart disease. So it would seem that, barring some minor transgressions, urocortin’s record is clean. Let us turn our attention now to the crime scene, in which urocortin is accused of having potentiated inflammation. The acute inflammatory response is a homeostatic selfdefense mechanism. It entails a veritable barrage of defensive measures including an army of host macrophages, lymphocytes, and other cells that are activated and release inflammatory cytokines, which, among other things, cause rapid vasodilation and an increase in the size of the gaps between endothelial cells. This has two important effects: it allows extravasation of leukocytes into the interstitium and causes exudation of plasma fluid, which contains reparative and protective proteins such as fibrin and immunoglobulins. However, if these processes are pushed too far, it can result in a pathological leakage of fluid and cells out of the microvasculature causing edema, contributing to the pathology of the life-threatening, and difficult-to-treat, condition of sepsis. Injection of bacterial LPS can be used as a model for studying sepsis. LPS strongly activates the innate immune system via the tolllike receptor-4 pathway (10) and leads to an increase in vascular leak. Cureton et al. demonstrated that urocortin causes a significant increase in vascular leak by about 2-fold, which is, in fact, similar to the effect of LPS on its own. However, in the presence of LPS, urocortin’s effect is greatly enhanced, increasing vascular permeability about 7-fold. Here is our first clue implicating urocortin in inflammation and suggesting that it acts with an accomplice. To understand the implications of this observation, it is useful to know how permeability is measured. Microvascular leak or permeability is a measure of the rate that water can move across the microvessel wall. This