GLP-2 Acutely Prevents Endotoxin-Related Increased Intestinal Paracellular Permeability in Rats
GLP-2 Acutely Prevents Endotoxin-Related Increased Intestinal Paracellular Permeability in Rats
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DOI：
10.1007/s10620-020-06097-6
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发表时间：
2020-01-31
影响因子：
3.1
通讯作者：
Kaunitz, Jonathan D.
中科院分区：
文献类型：
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作者：
Maruta, Koji;Takajo, Takeshi;Kaunitz, Jonathan D.
背景循环内毒素（脂多糖，LPS）增加肠道细胞旁通透性。我们假设胰高血糖素样肽-2（GLP-2）通过一种与其促神经营养作用无关的机制，急性降低LPS相关的肠细胞旁通透性增加。方法采用大鼠腹腔注射内毒素（5 mg/kg，ip）1-24 h后，通过门静脉内灌注FITC-葡聚糖4000（FD 4），观察小肠细胞旁通透性的变化。我们还检查了稳定的GLP-2类似物teduglutide（TDG）对FD 4渗透性的影响。结果LPS处理后6 h，FD 4进入PV的运动增加，但1 h或3 h时无明显变化，PV GLP-2水平升高，回肠粘膜促炎细胞因子和胰高血糖素原mRNA表达增加。与GLP-2受体拮抗剂联合给药可提高PV FD 4浓度。LPS处理后24 h的PV FD 4浓度高于LPS处理后6 h的FD 4浓度，LPS处理后6或12 h给予外源性GLP-2处理降低了PV FD 4浓度。LPS处理后3或6 h，TDG降低LPS处理后6 h测量的FD 4摄取。TDG相关的FD 4摄取减少被VPAC 1拮抗剂PG 97 -269或L-NAME逆转，而不是EGF或IGF 1受体抑制剂。结论全身性LPS可释放内源性GLP-2，降低LPS相关的通透性增加。外源性GLP-2给药的治疗窗至少在LPS处理后6-12小时内。外源性GLP-2治疗在预防与内毒素血症相关的细胞旁通透性增加方面具有价值。
Background Circulating endotoxin (lipopolysaccharide, LPS) increases the gut paracellular permeability. We hypothesized that glucagon-like peptide-2 (GLP-2) acutely reduces LPS-related increased intestinal paracellular permeability by a mechanism unrelated to its intestinotrophic effect. Methods We assessed small intestinal paracellular permeability in vivo by measuring the appearance of intraduodenally perfused FITC-dextran 4000 (FD4) into the portal vein (PV) in rats 1-24 h after LPS treatment (5 mg/kg, ip). We also examined the effect of a stable GLP-2 analog teduglutide (TDG) on FD4 permeability. Results FD4 movement into the PV was increased 6 h, but not 1 or 3 h after LPS treatment, with increased PV GLP-2 levels and increased mRNA expressions of proinflammatory cytokines and proglucagon in the ileal mucosa. Co-treatment with a GLP-2 receptor antagonist enhanced PV FD4 concentrations. PV FD4 concentrations 24 h after LPS were higher than FD4 concentrations 6 h after LPS, reduced by exogenous GLP-2 treatment given 6 or 12 h after LPS treatment. FD4 uptake measured 6 h after LPS was reduced by TDG 3 or 6 h after LPS treatment. TDG-associated reduced FD4 uptake was reversed by the VPAC1 antagonist PG97-269 or L-NAME, not by EGF or IGF1 receptor inhibitors. Conclusions Systemic LPS releases endogenous GLP-2, reducing LPS-related increased permeability. The therapeutic window of exogenous GLP-2 administration is at minimum within 6-12 h after LPS treatment. Exogenous GLP-2 treatment is of value in the prevention of increased paracellular permeability associated with endotoxemia.