Hydrogen sulfide, another simple gas with complex biology.

BACTERIAL INFECTIONS HAVE been one of the major scourges of humankind throughout history. Sepsis is recognized as a global health problem with an increasing incidence (5). The rate of hospitalization for sepsis more than doubled between 2000 and 2008 in the US (16). No monotherapy has been successful in improving mortality, including the recent failure of recombinant activated protein C to show efficacy in clinical trials (21). Although early antibiotic intervention is critical, the rise of antibiotic-resistant bacteria underscores the importance of understanding this syndrome. In addition to infection, the immune system is thought to be hyperactivated early on and the cardiovascular system appears to be altered, causing ischemia and underperfusion. The impairment of these systems may lead to multiple organ failure that is the hallmark feature of sepsis. In this issue of American Journal of Physiology Gastrointestinal and Liver Physiology Norris et al. (36) set out to examine the potential dysregulation of blood flow to the liver and the role of hydrogen sulfide (H2S) in a rodent endotoxemia model. Interestingly, sepsis-associated liver injury is a predictive sign of poor prognosis (23). Since the liver is crucial for metabolic and immunological homeostasis (39), any functional impairment to the liver is likely to have wide ramifications for the course of disease. Although the original discovery that the host produces a gas, nitric oxide (NO), that could generate toxic derivatives, was met with some skepticism, the identification of multiple enzyme systems that mediate this event has paved the road of acceptance for the discovery of other gaseous substances including carbon monoxide (CO) and most recently H2S, both of which are known environmental pollutants. However, it is now recognized that H2S is a blood flow regulator in addition to being an endogenous modulator of inflammation, as well as a modulator of neuronal activity (22), blood pressure regulator (55), and an inducer of insulin secretion (56). Many of these effects are reported to involve H2S directly increasing KATP channel currents (56, 61). The main enzymes responsible for its biosynthesis are cystathionine-lyase (CSE) and cystathionine-synthetase, although others have been implicated (28, 42). Clearly, much like the complexity of nitric oxide biology, H2S also has multiple biological actions. The role of H2S in the regulation of hepatic perfusion was first investigated by Fiorucci et al. (12). They were able to demonstrate that CSE is expressed in hepatocytes and hepatic stellate cells (HSCs) also known as Ito cells, but importantly not in the sinusoidal endothelial cells (SECs). Portal infusion of an H2S donor, NaHS, antagonized increased hepatic resistance induced by norepinephrine infusion in a KATP channeldependent manner. From this work, it seemed reasonable to conclude that endogenous H2S would function as a vasodilator, preserving blood flow. This raised the question why the inhibition of endogenous H2S via propargylglycine (PAG) decreased hepatic dysfunction in endotoxemia (59). Previous work by Norris et al. (37) indicated that H2S might have differential effects on presinusoidal and sinusoidal sites within the liver. In this issue, Norris et al. (36) expand on their previous work and study the effect of endogenous H2S on the hepatic microcirculation under basal conditions and in a model of endotoxemia using very sophisticated intravital microscopy. They demonstrate that portal infusion of the H2S donor Na2S elicits a small but significant decrease in sinusoidal diameter and an increase in diameter variability. During endotoxemia it is well known that the liver microvasculature becomes very sensitive to vasoconstrictors including endothelin. Inhibition of endogenous H2S in endotoxemic rats via PAG decreased the LPSinduced microcirculatory hypersensitivity to endothelin-1 (ET1), leading to an attenuated ET-1-induced increase in portal pressure and an abrogation of sinusoidal constriction. This had significant physiological consequences since blockade with PAG improved tissue oxygen delivery measured by a very stylish technique: NADH autofluorescence. The regulation of hepatic microvascular blood flow is very complex because the liver consists of both a venous and arterial source of blood leading to the liver. Multiple vasoregulators and an intricate interplay of HSCs, Kupffer cells (KCs), and SECs contribute to hepatic blood flow regulation. In the classic paradigm ET-1, NO, and CO are kept in a balanced state to maintain a normal sinusoidal perfusion under basal conditions. Endothelial ET-1 binds to the ETA receptor, which is primarily expressed by HSCs (17). These cells surround the sinusoids and are thought to contract, thus reducing blood flow. Binding to ETB1 receptors expressed by SECs leads to the activation of endothelial nitric oxide synthase (eNOS) and ensuing relaxation. Basal CO levels are maintained by the constitutively expressed parenchymal heme oxygenase-2 (HO-2). NO and CO both interact with the soluble guanylyl cyclase, leading to an increase in intracellular cGMP. NO has been shown to limit the release of ET-1 and to increase the expression of endothelial HO-1 (41). This balance is disturbed in the state of inflammation. Six hours after LPS injection there is a marked increase in the hepatic mRNA level of inducible nitric oxide synthase (iNOS), ET-1, the ETA receptor, the ETB receptor, and HO-1 (45). A shift from vasodilating ETA to vasoconstricting ETB2 receptors has been proposed (1). Additionally, endotoxin suppresses ET-1-mediated eNOS activation through Cav-1. It is thought that low-level NO produced by eNOS protects the liver microcirculation in sepsis, whereas the strong Address for reprint requests and other correspondence: P. Kubes, Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Dept. of Physiology and Pharmacology, Univ. of Calgary, HRIC 4A26A, 3280 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1 (e-mail: [email protected]). Am J Physiol Gastrointest Liver Physiol 304: G1066–G1069, 2013; doi:10.1152/ajpgi.00125.2013. Editorial Focus