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

AIMS

Investigate the involvement of Hydrogen sulfide (HS) 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 HS donor molecules (NaHS and GYY 4137) or saline and CT. To study the role of EP2 and EP4 prostaglandin E2 (PGE2) receptors in the HS 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

HS 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 HS 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 HS 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 HS 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.