Mechanism of preservation of the intestinal mucosa architecture and NF-κB/PGE2 reduction by hydrogen sulfide on cholera toxin-induced diarrhea in mice

Abstract

Aims: Investigate the involvement of Hydrogen sulfide (H₂S) in inflammatory parameters and intestinal morphology caused by cholera toxin (CT) in mice.

Main methods: Mice were subjected to the procedure of inducing diarrhea by CT in the isolated intestinal loop model. The intestinal loops were inoculated with H₂S donor molecules (NaHS and GYY 4137) or saline and CT. To study the role of EP2 and EP4 prostaglandin E2 (PGE2) receptors in the H₂S antisecretory effect, PAG (DL-propargylglycine - inhibitor of cystathionine-γ-lyase (CSE)), PF-04418948 (EP2 antagonist) and ONO-AE3-208 (EP4 antagonist) were used. The intestinal loops were evaluated for intestinal secretion, relation of the depth of villi and intestinal crypts, and real-time PCR for the mRNA of the CXCL2, IL-6, NOS-2, IL-17, NF-κB1, NF-κBIA, SLC6A4 and IFN-γ genes.

Key findings: H₂S restored the villus/crypt depth ratio caused by CT. NaHS and GYY 4137 increased the expression of NF-κB1 and for the NF-κBIA gene, only GYY 4137 increased the expression of this gene. The increased expression of NF-κB inhibitors, NF-κB1 and NF-κBIA by H₂S indicates a possible decrease in NF-κB activity. The pretreatment with PAG reversed the protective effect of PF-04418948 and ONO-AE3-208, indicating that H₂S probably decreases PGE2 because in the presence of antagonists of this pathway, PAG promotes intestinal secretion.

Significance: Our results point to a protective activity of H₂S against CT for promoting a protection of villus and crypt intestine morphology and also that its mechanism occurs at least in part due to decreasing the activity of NF-κB and PGE2.

Keywords: Cholera; Hydrogen sulfide; Intestinal morphometry; NF-κB.