Hydrogen sulfide (H2S) is thought to act through several pathways, some of which are illustrated above, to reduce inflammation and protect tissues from injury (such as ulceration in the gastrointestinal tract). H2S can suppress leukocyte adherence to the vascular endothelium, leukocyte extravasation and consequent formation of oedema. It can substitute for oxygen in driving mitochondrial respiration, thereby attenuating oxidative-stress-related tissue injury. The ability of H2S to inhibit the activity of phosphodiesterases (PDEs) can contribute to its ability to relax vascular smooth muscle, resulting in enhanced blood flow. Resolution of inflammation can be enhanced by H2S through actions such as the promotion of neutrophil apoptosis, and driving macrophage differentiation towards the M2 (anti-inflammatory) phenotype. H2S can modulate the activity of a number of transcription factors: it inhibits nuclear factor-κB (NF-κB), leading to a reduced production of pro-inflammatory cytokines, and sulfhydrates Kelch-like ECH-associated protein 1 (KEAP1), which then releases active nuclear factor erythroid 2-related factor 2 (NRF2), resulting in increased expression of antioxidant-response elements (AREs). Increased production of H2S occurs around sites of damage, such as around ulcers in the gastrointestinal tract, and can accelerate the healing of such damage via the stimulation of angiogenesis. Anti-nociceptive effects of H2S have also been demonstrated. Adapted from Ref. 193, American Physiological Society.