Abstract
This study evaluated the protective effects of inhibiting caspase-1 activity or gastric acid secretion on acute gastric injury in mice. AC-YVAD-CMK, omeprazole, or vehicle were administered to mice before cold-restraint stress- or ethanol-induced gastric injury. Survival rates and histological evidence of gastric injury of mice pretreated with AC-YVAD-CMK or omeprazole, and exposed to cold-restraint stress, improved significantly relative to the vehicle group. The increased levels of tumour necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-18 following cold-stress injury were decreased by AC-YVAD-CMK, but not omeprazole, pretreatment. The increased expression of CD68 in gastric tissues was inhibited significantly by AC-YVAD-CMK pretreatment. Inhibiting caspase-1 activity in the NLRP3 inflammasome decreased gastric cell apoptosis, and the expression of Bax and cleaved caspase-3. AC-YVAD-CMK pretreatment significantly inhibited cold-restraint stress-induced increases in the expression of phosphorylated IκB-alpha and P38. General anatomy and histological results showed the protective effect of AC-YVAD-CMK on ethanol-induced acute gastric injury. Overall, our results showed that the caspase-1 inhibitor AC-YVAD-CMK protected against acute gastric injury in mice by affecting the NLRP3 inflammasome and attenuating inflammatory processes and apoptosis. This was similar to the mechanism associated with NF-κB and P38 mitogen-activated protein kinase signalling pathways.
Highlights
Inflammasomes are multi-protein oligomers of the innate immune system
We found that pretreatment with AC-YVAD-CMK attenuated mouse acute gastric injury
The results of the real-time polymerase chain reaction (RT-PCR) analysis showed that there was no inhibitory effect of AC-YVAD-CMK pretreatment on the expression of a caspase recruitment domain (ASC) mRNA compared with the injury-alone group (P > 0.05, Fig. 1B)
Summary
Inflammasomes are multi-protein oligomers of the innate immune system. Inflammasomes play an important role in the pathogenesis of various diseases including Helicobacter pylori gastritis, gout, diabetes mellitus, and dengue haemorrhagic fever[6,7,8]. The NLRP3 inflammasome recognizes certain microbial and danger components and serves as a platform for activating caspase-1 and maturation of the pro-inflammatory cytokine, IL-1β. Dinarello et al indicated that proper regulation of the inflammasome could affect the balance between the production of anti- and pro-inflammatory cytokines[11]. Rozza et al considered that cytokines such as tumour necrosis factor (TNF)-α , interleukin (IL)-6, and IL-10 played important roles in the regulation of acute gastric ulcers[12,13]. Caspase-1 is a key enzyme of the NLRP3 inflammasome, which is a critical pro-inflammatory mediator that modulates host responses to various stress conditions[14]. We found that pretreatment with AC-YVAD-CMK attenuated mouse acute gastric injury. This protection involved silencing NLRP3 inflammasome activities and alleviating inflammatory responses and apoptosis. The underlying mechanism was associated with the NF-κ B and P38 mitogen-activated protein kinase (MAPK) signalling pathways
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