Inhibition of eCIRP Attenuates Inflammation and Gut Injury After Radiation Combined Injury with Sepsis

Background: Radiation-induced sepsis resulting from intestinal inflammation and injury is a severe complication of high-dose radiation exposure. High-dose radiation compromises the integrity of the intestinal lining, causing bacterial translocation, systemic inflammation, and sepsis. Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, plays a pivotal role in the pathogenesis of inflammatory diseases and contributes to organ injury. C23, a small molecular peptide antagonist of eCIRP, has demonstrated anti-inflammatory and organ-protective effects during organ-injury indications. However, its role in radiation-induced inflammation and injury is not known. The objective of this study is to evaluate whether C23 mitigates inflammation and injury, leading to improved survival in a murine model of partial-body irradiation (PBI) combined with sepsis. Methods: Mice were exposed to 10 Gy PBI, and at 48 h, they were subjected to cecal ligation and puncture (CLP), a well-established model of sepsis. C23 (8 mg/kg body weight [BW]) or vehicle (saline) was administered subcutaneously at 24 h and 48 h after PBI. Blood and intestinal tissue samples were collected 20 h after CLP (i.e., 68 h post-PBI) for various analyses. In another set of mice after PBI–sepsis, intestinal permeability was also assessed. In an additional cohort of mice subjected to the same experimental procedure, 10-day survival was monitored. Results: Our findings demonstrate that administration of C23 attenuated systemic inflammatory responses, intestinal permeability, intestinal injury, and apoptosis; increased crypt cell proliferation and improved survival after PBI–sepsis. Conclusions: These results reveal a novel protective role of the eCIRP antagonist, C23, in mitigating PBI–sepsis-induced inflammation and injury and represents a promising therapeutic candidate for the treatment of radiation combined injury with sepsis.