Inhaled carbon monoxide suppresses the development of postoperative ileus in the murine small intestine
Inhaled carbon monoxide suppresses the development of postoperative ileus in the murine small intestine
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DOI：
10.1053/gast.2003.50060
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发表时间：
2003-02-01
期刊：
影响因子：
29.4
通讯作者：
Bauer, AJ
中科院分区：
文献类型：
--
作者：
Moore, BA;Otterbein, LE;Bauer, AJ
背景和目标：血红素氧合酶（HO-1）是血红素代谢的限速酶，其诱导对急性和慢性炎症中的损伤具有保护作用。吸入低水平的一氧化碳（CO），血红素代谢的副产品，具有抗炎作用等于HO-1诱导。本研究探讨了吸入CO是否对术后肠梗阻的发展具有保护作用。方法：采用手术麻醉和轻推法诱导小鼠小肠梗阻。动物在手术前1小时暴露于空气中的CO（250 ppm），并在手术后连续暴露24小时。结果如下：CO吸入可防止体外环肌收缩力的抑制，并显著改善体内胃肠传输。与对照组相比，术后3 - 6小时，促炎信使RNA（mRNA）表达（白细胞介素[IL]-6，IL-1 β，环氧合酶2 [考克斯-2]，诱导型一氧化氮[iNOS]）和抗炎介质（IL-10和HO-1）表达升高。一氧化碳处理可使IL-1 β和iNOS的峰值表达降低75%，但对IL-6或考克斯-2无影响。在用CO处理的操作小鼠中，HO-1表达较早（手术后3小时）达到峰值，并且水平比未暴露于CO的小鼠高300%。结论：这些结果表明，CO通过抑制炎症级联反应中的选择性成分和增强抗炎细胞因子IL-10的诱导来减轻术后肠梗阻。此外，HO-1的早期和增强的诱导可能通过保护免受自由基应激和通过直接在炎症部位增加CO的组织可用性来放大HO-1途径的抗炎作用。
Background & Aims: The induction of heme oxygenase (HO-1), the rate-limiting enzyme in heme metabolism, is protective against injury in acute and chronic inflammation. Inhalation of low levels of carbon monoxide (CO), a byproduct of heme metabolism, has anti-inflammatory effects equal to HO-1 induction. This study examined whether inhaled CO was protective against the development of postoperative ileus. Methods: Ileus was induced by surgical anesthesia and gentle manipulation of the mouse small intestine. Animals were exposed to CO (250 ppm) in air 1 hour before and continuously for 24 hours after surgery. Results: CO inhalation prevented the manipulation-induced suppression of circular muscle contractility in vitro, and significantly improved gastrointestinal transit in vivo. Proinflammatory messenger RNA (mRNA) expression (interleukin [IL]-6, IL-1beta, cyclooxygenase 2 [COX-2], inducible nitric oxide [iNOS]) and anti-inflammatory mediator expression (IL-10 and HO-1) were elevated 3 to 6 hours after surgery relative to controls. CO treatment reduced IL-1beta and iNOS peak expression by 75%, but not IL-6 or COX-2. In manipulated mice treated with CO, HO-1 expression peaked earlier (3 hours after surgery) and at levels 300% higher than in mice not exposed to CO. IL-10 expression at 3 hours also was 300% higher after CO treatment. Conclusions: These findings suggest that CO attenuates postoperative ileus by inhibiting selective elements within the inflammatory cascade and by enhanced induction of the anti-inflammatory cytokine IL-10. In addition, the early and enhanced induction of HO-1 potentially amplifies the anti-inflammatory effects of the HO-1 pathway by protection from free radical stress and by increasing the tissue availability of CO directly at the sites of inflammation.