Intestinal manipulation (IM) during abdominal surgery triggers the influx of inflammatory cells, leading to postoperative
ileus. Prevention of this local muscle
inflammation, using
intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-1-specific
antibodies, has been shown to shorten postoperative
ileus. However, the
therapeutic use of
antibodies has considerable disadvantages. The aim of the current study was to evaluate the effect of
ISIS-3082, a mouse-specific
ICAM-1 antisense oligonucleotide, on postoperative
ileus in mice. Mice underwent a
laparotomy or a
laparotomy combined with IM
after treatment with
ICAM-1 antibodies, 0.1-10 mg kg(-1)
ISIS-3082, saline or ISIS-8997 (scrambled control
antisense oligonucleotides, 1 and 3 mg kg(-1)). At 24 h after surgery, gastric emptying of a 99mTC labelled semi-liquid meal was determined using scintigraphy. Intestinal
inflammation was assessed by
myeloperoxidase (MPO) activity in ileal muscle whole mounts. IM significantly reduced gastric emptying compared to
laparotomy. Pretreatment with
ISIS-3082 (0.1-1 mg kg(-1)) as well as
ICAM-1 antibodies (10 mg kg(-1)), but not ISIS-8997 or saline, improved gastric emptying in a dose-dependent manner. This effect diminished with higher doses of
ISIS-3082 (3-10 mg kg(-1)). Similarly,
ISIS-3082 (0.1-1 mg kg(-1)) and
ICAM-1 antibodies, but not ISIS-8997 or higher doses of
ISIS-3082 (3-10 mg kg(-1)), reduced manipulation-induced
inflammation. Immunohistochemistry showed reduction of
ICAM-1 expression with
ISIS-3082 only.
ISIS-3082 pretreatment prevents postoperative
ileus in mice by reduction of manipulation-induced local intestinal muscle
inflammation. Our data suggest that targeting
ICAM-1 using
antisense oligonucleotides may represent a new therapeutic approach to the prevention of postoperative
ileus.