Significance: Hydrogen sulfide is emerging as an important mediator of many aspects of inflammation, and perhaps most importantly as a factor promoting the resolution of inflammation and repair of injury. Recent Advances: In the gastrointestinal tract, H 2 S has been shown to promote healing of ulcers and the resolution of mucosal inflammation. On the other hand, suppression of endogenous H 2 S synthesis impairs mucosal defense and leads to increased granulocyte infiltration. H 2 S has been exploited in the design of more effective and safe anti-inflammatory drugs. Critical Issues: Enteric bacteria can be a significant source of H 2 S, which could affect mucosal integrity; indeed, luminal H 2 S can serve as an alternative to oxygen as a metabolic substrate for mitochondrial respiration in epithelial cells. Enterocytes and colonocytes thereby represent a ''metabolic barrier'' to the diffusion of bacteria-derived H 2 S into the subepithelial space. A compromise of this barrier could result in modulation of mucosal function and integrity by bacterial H 2 S. Future Directions: Improvements in methods for measurement of H 2 S and development of more selective inhibitors are crucial for gaining a better understanding of the pathophysiological importance of this mediator. Results from animal studies suggest that H 2 S-releasing agents are promising therapeutic agents for many indications, but these compounds need to be assessed in a clinical setting. Antioxid. Redox Signal. 17, 58-67.

Background and purpose: The inflammation-resolving lipid mediator resolvin E1 (RvE1) effectively stops inflammationinduced bone loss in vivo in experimental periodontitis. It was of interest to determine whether RvE1 has direct actions on osteoclast (OC) development and bone resorption. Experimental approach: Primary OC cultures derived from mouse bone marrow were treated with RvE1 and analysed for OC differentiation, cell survival and bone substrate resorption. Receptor binding was measured using radiolabelled RvE1. Nuclear factor (NF)-kB activation and Akt phosphorylation were determined with western blotting. Lipid mediator production was assessed with liquid chromatography tandem mass spectrometry. Key results: OC growth and resorption pit formation were markedly decreased in the presence of RvE1. OC differentiation was inhibited by RvE1 as demonstrated by decreased number of multinuclear OC, a delay in the time course of OC development and attenuation of receptor activator of NF-kB ligand-induced nuclear translocation of the p50 subunit of NF-kB. OC survival and apoptosis were not altered by RvE1. Messenger RNA for both receptors of RvE1, ChemR23 and BLT 1 is expressed in OC cultures. Leukotriene B 4 (LTB 4 ) competed with [ 3 H]RvE1 binding on OC cell membrane preparations, and the LTB 4 antagonist U75302 prevented RvE1 inhibition of OC growth, indicating that BLT 1 mediates RvE1 actions on OC. Primary OC synthesized the RvE1 precursor 18R-hydroxy-eicosapentaenoic acid and LTB 4 . Co-incubation of OC with peripheral blood neutrophils resulted in transcellular RvE1 biosynthesis. Conclusions and implications: These results indicate that RvE1 inhibits OC growth and bone resorption by interfering with OC differentiation. The bone-sparing actions of RvE1 are in addition to inflammation resolution, a direct action in bone remodelling.

Abstract-Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ET A receptors in DOCA-salt rats would decrease oxidative stress. Key Words: endothelin Ⅲ receptors, endothelin Ⅲ deoxycorticosterone Ⅲ hypertension, arterial Ⅲ oxidative stress R eactive oxygen species (ROS), such as superoxide anion (⅐O 2 Ϫ ), hydrogen peroxide, and peroxynitrite (ONOO Ϫ ), are generated as intermediates in reduction-oxidation reactions. The major source of ROS in the vasculature is the nonmitochondrial NADPH oxidase. Under physiological conditions, ROS production is inactivated by an elaborate cellular and extracellular antioxidant defense system, of which glutathione peroxidase is a major component. In pathological conditions, increased generation of ROS and/or depletion of the antioxidant capacity results in increased bioavailability of ROS, referred to as oxidative stress. 1 There is increasing evidence that oxidative stress plays a pathological role in hypertension. 2 Several recent studies have provided compelling evidence for increased ROS generation in the vascular tissues of hypertensive rats. Enhanced ⅐O 2 Ϫ production has been demonstrated in mesenteric arterioles of SHR in vivo. 3 Likewise, increased ⅐O 2 Ϫ generation has been reported in cultured aortic endothelial cells from SHR compared with WKY. 4 Oxidative stress has been implicated in a variety of other hypertensive models including Angiotensin II (Ang II)-induced hypertension, 5,6 Dahl salt-sensitive hypertension, 7 and in human essential hypertension. 8 By promoting NO inactivation, lipid peroxidation, DNA damage, and protein modification, oxidative stress plays a key role in endothelial dysfunction and end-organ damage. Furthermore, ROS activate many redox-sensitive, growth-related intracellular signaling pathways in vascular smooth muscle and endothelial cells, which is particularly important in altered proliferation and hypertrophy, contributing to vascular remodeling, a characteristic feature of hypertensive disease. 9,10 Cytokines, growth factors, and vasoactive agents such as Ang II regulate the activity and expression of enzymes involved in ROS production. 1 In Ang II-dependent models of hypertension, vascular production of ⅐O 2 Ϫ is increased through activation of vascular NADPH oxidase. 5,6 Indeed,