期刊
GUT
卷 52, 期 9, 页码 1278-1285出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gut.52.9.1278
关键词
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资金
- NHLBI NIH HHS [R01 HL060234, HL55330, HL60234, R01 HL055330] Funding Source: Medline
- NIAID NIH HHS [AI42365] Funding Source: Medline
- NIDDK NIH HHS [DK54232, R01 DK054232] Funding Source: Medline
- NIGMS NIH HHS [GM-53789, GM-58241, P50 GM053789, R01 GM058241] Funding Source: Medline
Background: Intestinal transplantation provokes an intense inflammatory response within the graft muscularis that causes intestinal ileus. We hypothesised that endogenously produced anti-inflammatory substances could be utilised as novel therapeutics. Therefore, we tested the protective effects of inhaled carbon monoxide ( CO) and an endogenous haeme oxygenase 1 (HO-1) anti-inflammatory mediator on transplant induced inflammatory responses and intestinal ileus in the rat. Methods: Gastrointestinal transit of non-absorbable FITC labelled dextran and in vitro jejunal circular muscle contractions were measured in controls and syngeneic orthotopic transplanted animals with and without CO inhalation ( 250 ppm for 25 hours). Inflammatory mRNAs for interleukin (IL)-6, IL-1beta, tumour necrosis factor alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide ( iNOS), cyclooxygenase 2 (COX-2), and IL-10 were quantified by real time reverse transcriptase-polymerase chain reaction and HO-1 by northern blot. Histochemical stains characterised neutrophil infiltration and enterocyte apoptosis. Results: Transplantation delayed transit and suppressed jejunal circular muscle contractility. Transplantation induced dysmotility was significantly improved by CO inhalation. Transplantation initiated a significant upregulation in IL-6, IL-1beta, TNF-alpha, ICAM-1, iNOS, COX-2, and HO-1 mRNAs with the graft muscularis. CO inhalation significantly decreased expression of IL- 6, IL-1beta, iNOS, and COX-2 mRNAs. CO also significantly decreased serum nitrite levels (iNOS activity). Conclusions: CO inhalation significantly improved post-transplant motility and attenuated the inflammatory cytokine milieu in the syngeneic rat transplant model. Thus clinically providing CO, the end product of the anti-inflammatory HO-1 pathway, may prove to be an effective therapeutic adjunct for clinical small bowel transplantation.
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