Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice

Abstract

The recently described ‘gasomediator’ hydrogen sulfide (H2S) has been involved in pain mechanisms, butits effect on pruritus, a sensory modality that similarly to pain acts as a protective mechanism, is poorlyknown and controversial. The effects of the slow-releasing (GYY4137) and spontaneous H2S donors (Na2Sand Lawesson’s reagent, LR) were evaluated in histamine and compound 48/80 (C48/80)-dependent dor-sal skin pruritus and inflammation in male BALB/c mice. Animals were intradermally (i.d.) injected withC48/80 (3 g/site) or histamine (1 mol/site) alone or co-injected with Na2S, LR or GYY4137 (within the0.3–100 nmol range). The involvement of endogenous H2S and KATPchannel-dependent mechanism werealso evaluated. Pruritus was assessed by the number of scratching bouts, whilst skin inflammation wasevaluated by the extravascular accumulation of intravenously injected125I-albumin (plasma extravasa-tion) and myeloperoxidase (MPO) activity (neutrophil recruitment). Histamine or C48/80 significantlyevoked itching behavior paralleled by plasma extravasation and increased MPO activity. Na2S and LR sig-nificantly ameliorated histamine or C48/80-induced pruritus and inflammation, although these effectswere less pronounced or absent with GYY4137. Inhibition of endogenous H2S synthesis increased bothTyrode and C48/80-induced responses in the skin, whereas the blockade of KATPchannels by gliben-clamide did not. H2S-releasing donors significantly attenuate C48/80-induced mast cell degranulationeither in vivo or in vitro. We provide first evidences that H2S donors confer protective effect againsthistamine-mediated acute pruritus and cutaneous inflammation. These effects can be mediated, at leastin part, by stabilizing mast cells, known to contain multiple mediators and to be primary initiators ofallergic processes, thus making of H2S donors a potential alternative/complementary therapy for treatinginflammatory allergic skin diseases and related pruritus.