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Int J Clin Exp Pathol 1(5):409-418;2008
Original Article
Gut Hyperpermiability after Ischemia and Reperfusion: Attenuation with Adrenomedullin
and its Binding Protein Treatment

Shinya Higuchi, Rongqian Wu, Mian Zhou, Corrado P. Marini, Thanjavur S. Ravikumar and Ping Wang

Department of Surgery North Shore University Hospital and Long Island Jewish Medical Center and  The Feinstein Institute for Medical
Research Manhasset, NY 11030.

Received 16 Oct 2007; accepted with revision 14 Nov 2007; available online 1 January 2008

Abstract: Ischemia bowel remains a critical problem resulting in up to 80% mortality. The loss of gut barrier function plays an important role.
Our previous studies have shown that administration of adrenomedullin (AM), a novel vasoactive peptide, and its binding protein (AMBP-1),
reduces the systemic inflammatory response and organ injury after systemic ischemia induced by hemorrhagic shock. However, it remains
unknown whether administration of AM/AMBP-1 preserves gut barrier function after gut ischemia reperfusion (I/R). We therefore hypothesized
that AM/AMBP-1 prevents structural and functional damages to the intestinal mucosa after gut I/R. To test this, gut ischemia was induced by
placing a microvascular clip across the superior mesenteric artery (SMA) for 90 min in male adult rats. After release of the SMA clamp, AM (12
μg/kg BW) and AMBP-1 (40 μg/kg BW) in combination or vehicle (1-ml normal saline) were administered intravenously over a period of 30 min.
The mucosal barrier function in the small intestine was assessed in an isolated everted ileum sac using fluorescein-isothiocyanate dextran
(FD4) at 4 h after AM/AMBP-1 treatment. FD4 clearance was used as a measure of gut permeability. In additional groups of animals, blood and
small intestine samples were collected at 4 h after the treatment. Morphological changes in the small intestine were assessed by H-E
staining. Serum concentrations of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, lactate and lactate
dehydrogenase were also assessed. The gene expression and protein levels of TNF-α in the small intestine were determined by RT-PCR and
ELISA, respectively. Our results showed that administration of AM/AMBP-1 significantly attenuated the development of intestinal mucosal
hyperpermeability during the reperfusion. Treatment with AM/AMBP-1 dramatically improved I/R-induced intestinal mucosal damages,
attenuated remote organ injury, and downregulated gene expression and protein levels of TNF-α in the small intestine. In conclusion, AM/AMBP-
1 attenuates structural and functional damages to the intestinal mucosa, and it appears to be a novel treatment for reperfusion injury after gut
ischemia. The beneficial effect of AM/AMBP-1 on gut barrier function after I/R is associated with downregulation of TNF-α. (IJCEP710003).

Key Words:  Ischemia-reperfusion, intestines, permeability, tissue injury, TNF-α

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Address all correspondence to: Ping Wang, M.D., Division of Surgical Research, The Feinstein Institute for Medical Research, 350 Community
Drive, Manhasset, NY 11030, Tel: (516) 562-3411, Fax: (516) 562-1022, E-mail: