Lisofylline ameliorates intestinal mucosal barrier dysfunction caused by ischemia and ischemia/reperfusion.
In an effort to determine whether treatment with lisofylline (LSF) ameliorates intestinal barrier dysfunction in rats subjected to mesenteric ischemia and reperfusion (I/R), regional mesenteric vessels were occluded for 60 min and then unclamped for 60 min more. In Protocol 1, intravenous LSF (15 mg/kg bolus then 10 mg/kg/h) was administered 5 min before ischemia. In Protocol 2, LSF (same dose) was given 1 min before reperfusion. Controls received an equivalent volume of Ringer's lactate solution. Permeability was assessed by determining the mucosal-to-serosal clearance of fluorescein isothiocyanate-conjugated dextran (4 kDa) in everted ileal gut sacs incubated ex vivo. In Protocol 1, LSF treatment during ischemia ameliorated mucosal barrier dysfunction; mean +/- SEM clearances for the LSF and Ringer's lactate solution groups after 60 min of ischemia were 34.4+/-6.1 and 64+/-7.1 nL/min/cm2, respectively; p = .007. Clearances after reperfusion were the same in the two groups. In Protocol 2, LSF treatment just before reperfusion ameliorated barrier dysfunction measured 60 min after the restoration of blood flow; clearances for the LSF and Ringer's lactate solution groups were 23.1+/-3.8 and 40.2+/-4.5 nL/min/cm2, respectively; p = .012. Treatment with LSF did not affect intestinal levels of reduced glutathione or adenosine triphosphate or the extent of histological damage to the mucosa after I/R. Nevertheless, villus height was greater in animals treated with LSF than RLS prior to ischemia in Protocol 1 (250+/-37 and 160+/-15 microm, respectively; p = .04) and during reperfusion in Protocol 2 (170+/-21 and 82+/-7 microm, respectively; p = .002). We conclude that LSF is effective in reducing both ischemia- and I/R-induced gut barrier dysfunction, possibly due to a mechanism related to preservation of villus height.
Wattanasirichaigoon
S
S
Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Menconi
M J
MJ
Delude
R L
RL
Fink
M P
MP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000503:physiopathology*; D007422:Intestines / Q000098:blood supply* / Q000473:pathology; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000188:drug therapy*
D000255:Adenosine Triphosphate; D005978:Glutathione; C025189:lisofylline; D010431:Pentoxifylline