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.

We investigated whether low-level laser therapy (LLLT) can reduce muscular fatigue during tetanic contractions in rats. Thirty-two male Wistar rats were divided into four groups receiving either one of three different LLLT doses (0.5, 1.0, and 2.5 J/cm²) or a no-treatment control group. Electrical stimulation was used to induce six tetanic muscle contractions in the tibial anterior muscle. Contractions were stopped when the muscle force fell to 50% of the initial value for each contraction (T50%). There was no significant difference between the 2.5 J/cm² laser-irradiated group and the control group in mean T50% values. Laser-irradiated groups (0.5 and 1.0 J/cm²) had significantly longer T50% values than the control group. The relative peak force for the sixth contraction in the laser-irradiated groups were significantly higher at 92.2% (SD 12.6) for 0.5 J/cm², 83.2% (SD 20.5) for 1.0 J/cm², and 82.9% (SD 18.3) for 2.5 J/cm² than for the control group [50% (SD 15)]. Laser groups receiving 0.5 and 1.0 J/cm² showed significant increases in mean performed work compared with both the control group and their first contraction values. Muscle damage was indirectly measured by creatine kinase levels in plasma. A distinct dose-response pattern was found in which 1.0 and 2.5 J/cm² LLLT groups had significantly lower creatine kinase levels than the 0.5 J/cm² LLLT group and the control group. We conclude that LLLT doses of 0.5 and 1.0 J/cm² can prevent development of muscular fatigue in rats during repeated tetanic contractions.

Background and purpose: The inflammation‐resolving lipid mediator resolvin E1 (RvE1) effectively stops inflammation‐induced 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)‐κB 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‐κB ligand‐induced nuclear translocation of the p50 subunit of NF‐κB. OC survival and apoptosis were not altered by RvE1. Messenger RNA for both receptors of RvE1, ChemR23 and BLT₁ is expressed in OC cultures. Leukotriene B₄ (LTB₄) competed with [³H]RvE1 binding on OC cell membrane preparations, and the LTB₄ antagonist U75302 prevented RvE1 inhibition of OC growth, indicating that BLT₁ mediates RvE1 actions on OC. Primary OC synthesized the RvE1 precursor 18R‐hydroxy‐eicosapentaenoic acid and LTB₄. 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.British Journal of Pharmacology (2008) 155, 1214–1223; doi:10.1038/bjp.2008.367; published online 22 September 2008

Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4(+) T-cell activity. We propose that in renal fibrogenesis, M2 macrophages are recruited and activated in a T helper subset 2 cell (T(H)2)-prone inflammatory milieu in a MyD88-dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with diminished T(H)2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2 macrophage infiltration, namely interleukin (IL)-10(+) and CD206(+) CD11b(high) cells, at 7 d after surgery. We evaluated the role of a T(H)2 cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF-β levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals. Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal fibrosis should be accompanied by the modulation of the M1:M2 and T(H)1:T(H)2 balance, as T(H)2 and M2 cells are predictive of fibrosis toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway.

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. Both systolic blood pressure (SBP, 210±9 mm Hg; P <0.05) and vascular superoxide generation in vivo were increased in DOCA-salt (44.9±10.3% of ethidium bromide–positive nuclei; P <0.05) versus control uninephrectomized (UniNx) rats (118±3 mm Hg; 18.5±3%, respectively). In DOCA-salt rats, the ET _A antagonist BMS 182874 (40 mg/kg per day PO) lowered SBP (170±4 versus UniNx, 120±3 mm Hg) and normalized superoxide production (21.7±6 versus UniNx, 11.9±7%). Vitamin E (200 mg/kg per day PO) decreased superoxide formation in DOCA-salt rats (18.8±7%) but did not alter SBP. Oxidative stress in nonstimulated circulating polymorphonuclear cells (PMNs) or in PMNs treated with zymosan, an inducer of superoxide release, was similar in DOCA-salt and UniNx groups. Superoxide formation by PMNs was unaffected by treatment with BMS 182874. Western blot analysis showed increased nitrotyrosine-containing proteins in mesenteric vessels from DOCA-salt compared with UniNX. Treatment with either BMS 182874 or vitamin E abolished the differences in vascular nitrotyrosine-containing proteins between DOCA-salt and UniNX. Maximal relaxation to acetylcholine was decreased in DOCA-salt aortas (75.8±4.2% versus UniNx, 95.4±1.9%, P <0.05). BMS 182874 treatment increased acetylcholine-induced relaxation in DOCA-salt aortas to 93.5±4.5%. These in vivo findings indicate that increased vascular superoxide production is associated with activation of the endothelin system through ET _A receptors in DOCA-salt hypertension, in apparently blood pressure–independent fashion.

Background and Purpose: ATB‐346 is a hydrogen sulfide (H₂S)‐releasing anti‐inflammatory and analgesic drug. Animal studies demonstrated negligible gastrointestinal (GI) damage despite marked inhibition of COX activity and significant analgesic and anti‐inflammatory effects. In humans, ATB‐346 (250 mg once daily) was found to inhibit COX to the same extent as naproxen (550 mg twice daily).Experimental Approach: Two hundred forty‐four healthy volunteers completed a 2‐week, double‐blind study, taking either ATB‐346 (250 mg once daily) or naproxen (550 mg twice daily), with upper GI ulceration being examined endoscopically.Key Results: Forty‐two per cent of the subjects taking naproxen developed at least one ulcer (≥3‐mm diameter), while only 3% of the subjects taking ATB‐346 developed at least one ulcer. The two drugs produced comparable and substantial (>94%) suppression of COX activity. Subjects in the naproxen group developed more ulcers per subject than ATB‐346‐treated subjects and a greater incidence of larger ulcers (≥5‐mm diameter). The incidence of dyspepsia, abdominal pain, gastro‐oesophageal reflux, and nausea was lower with ATB‐346 than with naproxen. Subjects treated with ATB‐346 had significantly higher plasma levels of H₂S than those treated with naproxen.Conclusions and Implications: This Phase 2B study provides unequivocal evidence for a marked reduction of GI toxicity of the H₂S‐releasing analgesic/anti‐inflammatory drug, ATB‐346, as compared to the conventional dose of naproxen that produced equivalent suppression of COX.Linked Articles: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc