Functional impairment of enteric smooth muscle and nerves caused by chronic intestinal allograft rejection regresses after FK506 rescue.
We have previously demonstrated that subclinical chronic rejection (CR) induces structural and functional alterations in enteric smooth muscle and nerves in a rat model of small intestinal transplantation. This study was designed to investigate the effect of prolonged FK506 rescue therapy on these sequelae of CR. Immunohistochemistry of BrdU-labeled muscle cells demonstrated that active proliferation of intestinal smooth muscle caused by CR was successfully aborted by FK506 rescue therapy after a period of 30 days (control = 0.14 +/- 0.09; CR = 30.4 +/- 1.73; rescue = 2.4 +/- 0.63 cells/jejunal cross-section, P < 0.01). However, FK506 did not reverse the already established increase in muscular thickness (control = 92 +/- 2.4; CR = 193 +/- 10.6; rescue = 188 +/- 8.1 microns) due to CR. Bethanechol stimulated circular muscle contractility was improved markedly with rescue therapy (maximal contractile force reached 39.5% of control values in CR grafts and 68.8% after rescue). Rescue therapy did not reverse the loss of NADPH-diaphorase positive myenteric ganglia (control = 37 +/- 1.4; CR = 28 +/- 2.9; rescue = 23 +/- 1.7 ganglia/cross-section). Despite the persistent loss of ganglia, inhibitory junction potentials (IJPs) improved significantly returning to control values with FK506 (control = 10 +/- 0.5; CR = 5 +/- 0.3; CR rescue = 10 +/- 0.7 mV; IJPs recorded at 1 pulse/150V/0.75 ms). Although structural changes in enteric smooth muscle and myenteric neurons induced by CR were not reversed, the progression of subclinical CR can be effectively curbed by FK506 rescue therapy. The improvement in muscular mechanics and inhibitory neural innervation is probably due to the cessation of infiltrating immunocytes and sprouting of remaining myenteric nerves.
Heeckt
P F
PF
Department of Surgery, University of Pittsburgh Medical Center, Pennsylvania 15261.
Lee
K K
KK
Halfter
W M
WM
Schraut
W H
WH
Bauer
A J
AJ
D000818:Animals; D002908:Chronic Disease; D006084:Graft Rejection / Q000503:physiopathology* / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology / Q000502:physiology; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000294:innervation* / Q000502:physiology*; D009469:Neuromuscular Junction / Q000502:physiology; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D009435:Synaptic Transmission / Q000502:physiology; D016559:Tacrolimus / Q000627:therapeutic use*
D016559:Tacrolimus