Hydrogen Sulfide and Sulfite: Novel Mediators in the Pathophysiology of Shock and Inflammation

Gaseous transmitters, such as nitric oxide (NO) and carbon monoxide (CO), play important roles both in physiology and in disease. In recent years, another naturally occurring gas, hydrogen sulfide (H2S), has been found to be of importance (1). Cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) are key enzymes of the transsulfuration pathway, which interconverts L-methionine and L-cysteine but can also use L-cysteine as an alternative substrate to form H2S. Both enzymes are expressed in a range of mammalian cells and tissues. Although other enzymes can catalyze the production of H2S, CBS seems to be the main H2S-forming enzyme in the central nervous system, whereas CSE is the main enzyme forming H2S in the cardiovascular system (1). The role of H2S in inflammation is only recently beginning to emerge. We and others have recently reported that an inhibitor of H2S-synthesizing enzyme CSE, DL-propargylglycine (PAG), reduces the organ injury caused by acute severe endotoxemia in the rat or mouse (2, 3). The protection afforded by PAG was associated with a reduction in leukocyte recruitment. The inhibition of H2S synthesis by PAG has also been demonstrated to be beneficial in other models of inflammation, such as cerulein-induced pancreatitis (4) and carrageenan-induced hindpaw edema (5). Thus, it has been proposed that endogenous H2S has proinflammatory properties and, hence, plays a pivotal role in the pathophysiology of conditions associated with local or systemic inflammation. Sulfite is a major air pollutant and also enters the body in foods and beverages, as sulfiting agents are widely used as preservatives for their antimicrobial properties. In addition, sulfite is endogenously generated as a consequence of normal metabolism of sulfur-containing amino acids (6). It is rapidly detoxified by oxidation to sulfate by the action of a mitochondrial enzyme, sulfite oxidase (6), and is ultimately excreted into the urine. A rare congenital deficiency of sulfite oxidase in humans leads to mental retardation, neurologic symptoms, and early death (7). The mechanism of sulfite toxicity remains unclear, but it has been suggested that formation of protein-modifying sulfite radicals through interaction with ONOO− may be involved (8). Our understanding of the role(s) of sulfite in physiology and pathophysiology is very limited. Sulfite has been proposed to act as an endogenous mediator in host defense and/or inflammation, as it activates human neutrophils in vitro, leading to increased production of interleukin (IL)-12 and IL-8 (9, 10), decreased production of IL-1ra (9), increased production of oxygen radicals (11-13), and increased Mac-1-dependent adhesion of neutrophils (14). In addition, endotoxemia is associated with increased serum concentrations of sulfite in rats (15). Furthermore, it was reported in this journal in 2004 that the serum sulfite concentrations measured in patients in the acute phase of pneumonia are significantly higher than those measured during their recovery phase or in control subjects (16). In this issue of Shock (17), Mitsuhashi and colleagues provide evidence that activated neutrophils convert H2S nonenzymatically to sulfite in vitro. This phenomenon occurred in the presence of oxidative stress, as the sulfite production from NaHS was markedly suppressed by the NADPH oxidase inhibitor diphenyleneiodonium (DPI). A water-soluble radical initiator 2,2′-azobis-(amidinopropane) dihydrochloride (AAPH) increased the formation of sulfite in the NaHS-containing media, whereas ascorbic acid markedly suppressed this increase. To evaluate whether these findings had in vivo relevance, the authors measured the serum levels of H2S and sulfite in rats after injection of 1 mg/kg of LPS. LPS significantly increased the serum levels of H2S and sulfite, but the increase in sulfite was suppressed in animals subjected to simultaneous injections of LPS and ascorbic acid, suggesting that oxidative stress-dependent conversion of H2S to sulfite might indeed occur in vivo. These are interesting findings, as the activation of neutrophils is one of the key events in the pathogenesis of endotoxemia and indeed, more generally, of the inflammatory response. Therefore, these findings raise the question whether the proinflammatory effects previously thought to have been elicited by H2S can in fact be, at least partially, brought about by sulfite. Previous in vivo studies have measured the expression of CSE (and CBS) and the production of H2S in target organs and found these parameters to be increased after various stimuli triggering the inflammatory response such as LPS administration (2, 3), hemorrhage and resuscitation (18), carrageenan injection (5), and cerulein injections (4). The plasma levels of H2S have also been increased in hemorrhagic shock (18) and acute pancreatitis in the rat (4) and in septic patients (3). However, as none of these studies measured the plasma levels of sulfite, the relative contributions of H2S and sulfite to the pathophysiology of the above-mentioned conditions cannot be evaluated. In conclusion, H2S and sulfite are interesting novel proinflammatory mediators of inflammation. Their (relative) contributions to the pathophysiology of the inflammatory response and the exact mechanisms of action warrant further investigation and should, as suggested by Dr. Mitsuhashi and colleagues (17), indeed stimulate exciting new research projects aimed at gaining a better understanding of the roles of these new mediators in health and disease.