Objective To evaluate the comprehensive protective effects of ulinastatin (UTI) on intestinal structure and function during sepsis and to explore whether UTI restores intestinal motility through mechanisms involving attenuation of interleukin-1β (IL-1β)–mediated inflammation. Methods A murine cecal ligation and puncture (CLP) model was established and mice received intravenous UTI. Primary outcomes included 7-day survival, time to first black stool, fecal output, small-intestinal transit, and blinded histopathology. Barrier integrity was assessed by Alcian Blue–Periodic Acid–Schiff staining for goblet-cell mucin and Claudin-1 immunofluorescence; inflammation by IL-1β, tumor necrosis factor (TNF)-α, and IL-6; and enteric nerve integrity by counting HuD-positive neurons and measuring PGP9.5-labeled nerve fibers. To assess direct effects, primary enteric neurons were stimulated with lipopolysaccharide or IL-1β in vitro . An IL-1β-neutralizing antibody (nAb) was used alone or with UTI to interrogate mechanism. Results UTI improved survival, shortened stool latency, increased pellet output, and enhanced transit after CLP. UTI attenuated intestinal injury, restored goblet-cell mucin production and Claudin-1 expression, and reduced systemic and colonic IL-1β, TNF-α, and IL-6. Moreover, UTI also increased the number of HuD + enteric neurons and preserved PGP9.5-labeled nerve fiber networks. In vitro , UTI preserved βIII-tubulin–defined neuronal morphology and reduced IL-1β secretion. IL-1β nAb reproduced the protective benefits on enteric nerve and intestinal motility; no significant additive benefits were observed when IL-1β nAb was combined with UTI. Conclusion UTI confers broad and integrated protection of the intestine during sepsis. These findings suggest that IL-1β–mediated inflammatory signaling plays a key role in UTI-induced enteric neuroprotection and restoration of intestinal motility.
Zailin Fu,Dingsheng Wang,Caiyun Zheng,Minghua Xie,Yifang Chen,Yi Zhou,Yan Huang,Ying Song,Weiyong Hong
Calcium overload, a notable instigator of acute pancreatitis (AP), induces oxidative stress and an inflammatory cascade, subsequently activating both endogenous and exogenous apoptotic pathways. However, there is currently lack of available pharmaceutical interventions to alleviate AP by addressing calcium overload. In the present study, the potential clinical application of liposome nanoparticles (LNs) loaded with 1,2‑bis(2‑aminophenoxy)ethane‑N,N,N',N'‑tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA‑AM), a cell‑permeant calcium chelator, was investigated as a therapeutic approach for the management of AP. To establish the experimental models in vitro, AR42J cells were exposed to high glucose/sodium oleate (HGO) to induce necrosis, and in vivo, intra‑ductal taurocholate (TC) infusion was used to induce AP. The findings of the present study indicated that the use of BAPTA‑AM‑loaded LN (BLN) effectively and rapidly eliminated excessive Ca2+ and reactive oxygen species, suppressed mononuclear macrophage activation and the release of inflammatory cytokines, and mitigated pancreatic acinar cell apoptosis and necrosis induced by HGO. Furthermore, the systemic administration of BLN demonstrated promising therapeutic potential in the rat model of AP. Notably, BLN significantly enhanced the survival rates of rats subjected to the TC challenge, increasing from 37.5 to 75%. This improvement was attributed to the restoration of pancreatic function, as indicated by improved blood biochemistry indices and alleviation of pancreatic lesions. The potential therapeutic efficacy of BLN in rescuing patients with AP is likely attributed to its capacity to inhibit oxidative stress, prevent premature activation of zymogens and downregulate the expression of TNF‑α, IL‑6 and cathepsin B. Thus, BLN demonstrated promising value as a novel therapeutic approach for promptly alleviating the burden of intracellular Ca2+ overload in patients with AP.
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