CORM-3 alleviates the intestinal injury in a rodent model of hemorrhage shock and resuscitation: roles of GFAP-positive glia.

Hemorrhagic shock and resuscitation (HSR) can induce severe intestinal damages, thereby leading to sepsis and long-term complications including dysbacteriosis and pulmonary injury. The NOD-like receptor protein 3 (NLRP3) inflammasome facilitates inflammation-associated cell recruitment in the gastrointestinal tract, and participates in many inflammatory bowel diseases. Previous studies have shown that exogenous carbon monoxide (CO) exerts neuroprotective effects against pyroptosis after HSR. We aimed to investigate whether carbon monoxide-releasing molecules-3 (CORM-3), an exogenous CO compound, could attenuate HSR-induced intestinal injury and the potential underlying mechanism.Rats were subjected to a HSR model by bleeding and re-infusion. Following resuscitation, 4 mg/kg of CORM-3 was administered intravenously into femoral vein. At 24 h and 7 d after HSR modeling, the pathological changes in intestinal tissues were evaluated by H&E staining. The intestinal pyroptosis, glial fibrillary acidic protein (GFAP)-positive glial pyroptosis, DAO (diamine oxidase) content, intestine tight junction proteins including zonula occludens-1 (ZO-1) and claudin-1 were further detected by immunofluorescence, western blot and chemical assays at 7 d after HSR. CORM-3 administration led to significantly mitigated HSR-induced intestinal injury, aggravation of intestinal pyroptosis indicated by cleaved caspase-1, IL-1ß and IL-18, upregulation of GFAP-positive glial pyroptosis, decreased intensity of ZO-1 and claudin-1 in the jejunum, and increased of DAO in the serum. Nigericin, an agonist of NLRP3, significantly reversed the protective effects of CORM-3. CORM-3 alleviates the intestinal barrier dysfunction in a rodent model of HSR, and the potential mechanism may be associated with inhibition of NLRP3-associated pyroptosis. CORM-3 administration could be a promising therapeutic strategy for intestinal injury after hemorrhagic shock.

CORM-3 exerts a neuroprotective effect in a rodent model of traumatic brain injury via the bidirectional gut-brain interactions.

OBJECTIVE: Traumatic brain injury (TBI) induced the gastrointestinal inflammation that is associated with TBI-related morbidity and mortality. Carbon monoxide-releasing molecule (CORM)-3 is a water-soluble exogenous carbon monoxide that exerts protective effects against inflammation-induced pyroptosis. We investigated the gastrointestinal inflammation in a rodent model of traumatic brain injury (TBI) with subsequent hemorrhagic shock and resuscitation (HSR), as well as effects of CORM-3 using an intestinal injection on both gut and brain. METHODS: Following exposure to TBI plus HSR, rats were administrated with CORM-3 (8 mg/kg) through an intestinal injection after resuscitation immediately. The pathological changes and pyroptosis in the gut were measured at 24 h and 30 day post-trauma. We also assessed the intestinal and cortical CO content, as well as IL-1ß and IL-18 levels in the serum within 48 h after trauma. We then explored pathological changes in the ventromedial prefrontal cortex (vmPFC) and neurological behavior deficits on 30 day post-trauma. RESULTS: After TBI + HSR exposure, CORM-3-treated rats presented significantly decreased pyroptosis, more CO content in the jejunum, and lower IL-1ß, IL-18 levels in the serum at 24 h after trauma. Moreover, the rats treated with CORM-3 exerted ameliorated jejunal and vmPFC injury, enhanced learning/memory ability and exploratory activity, improved anxiety-like behaviors than the TBI + HSR-treated rats on 30 day post-trauma. CONCLUSION: These experimental data demonstrated and bidirectional gut-brain interactions after TBI, anti-inflammatory effects of CORM-3, which may improve late outcomes after brain injury.