Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury

Atsunori Nakao, Kei Kimizuka, Donna B. Stolz, Joao Seda Neto, Takashi Kaizu, Augustine M.K. Choi, Takashi Uchiyama, Brian S. Zuckerbraun, Michael A. Nalesnik, Leo E. Otterbein, Noriko Murase

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Abstract

Carbon monoxide (CO), a byproduct of heme catalysis by heme oxygenases, has been shown to exert anti-inflammatory effects. This study examines the cytoprotective efficacy of inhaled CO during intestinal cold ischemia/reperfusion injury associated with small intestinal transplantation. Orthotopic syngenic intestinal transplantation was performed in Lewis rats after 6 hours of cold preservation in University of Wisconsin solution. Three groups were examined: normal untreated controls, control intestinal transplant recipients kept in room air, and recipients exposed to CO (250 ppm) for 1 hour before and 24 hours after surgery. In air grafts, mRNA levels for interleukin-6, cyclooxygenase-2, intracellular adhesion molecule (ICAM-1), and inducible nitric oxide synthase rapidly increased after intestinal transplant. Histopathological analysis revealed severe mucosal erosion, villous congestion, and inflammatory infiltrates. CO effectively blocked an early up-regulation of these mediators, showed less severe histopathological changes, and resulted in significantly improved animal survival of 92% from 58% in air-treated controls. CO also significantly reduced mRNA for proapoptotic Bax, while it up-regulated anti-apoptotic Bcl-2. These changes in CO-treated grafts correlated with well-preserved CD31+ vascular endothelial cells, less frequent apoptosis/necrosis in intestinal epithelial and capillary endothelial cells, and improved graft tissue blood circulation. Protective effects of CO in this study were mediated via soluble guanylyl cyclase, because 1H-(1,2,4)oxadiazole (4,3-α) quinoxaline-1-one (soluble guanylyl cyclase inhibitor) completely reversed the beneficial effect conferred by CO. Perioperative CO inhalation at a low concentration resulted in protection against ischemia/reperfusion injury to intestinal grafts with prolonged cold preservation.

Original languageEnglish
Pages (from-to)1587-1598
Number of pages12
JournalAmerican Journal of Pathology
Volume163
Issue number4
DOIs
Publication statusPublished - Oct 1 2003
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Nakao, A., Kimizuka, K., Stolz, D. B., Neto, J. S., Kaizu, T., Choi, A. M. K., Uchiyama, T., Zuckerbraun, B. S., Nalesnik, M. A., Otterbein, L. E., & Murase, N. (2003). Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. American Journal of Pathology, 163(4), 1587-1598. https://doi.org/10.1016/S0002-9440(10)63515-8