Leukemia inhibitory factor enhances the regeneration of transected rat sciatic nerve and the function of reinnervated muscle.
The cytokine leukemia inhibitory factor (LIF) favors the survival and growth of axons in vitro and in vivo. Fibronectin has been shown to enhance nerve regeneration when added in combination with various growth factors including LIF. The goal of this study was to evaluate the effect of LIF plus fibronectin on the regeneration of transected nerve and functional recovery of reinnervated skeletal muscle, in one experimental model of peripheral nerve repair, at two recovery times. The rat sciatic nerve was cut at mid-thigh level and a silicone cuff containing either saline (control), LIF, or LIF plus fibronectin (L+F) was used to bridge the proximal and distal nerve stumps leaving a 1 cm gap between them. Rats were then explored at 6 or 12 weeks following the initial surgery. Regenerating nerves were assessed by measuring the diameter of myelinated axons, conduction velocity, and number of myelinated fibers. Muscle reinnervation was assessed by measuring muscle mass, force of contraction, and histologically for changes in muscle fiber type (type I and type II). In this report we demonstrate that at 6 weeks there were significant increases in 1) nerve conduction velocity, 2) myelinated axon diameter, and 3) number of myelinated axons over that of control (saline-treated) animals. Both LIF groups demonstrated a shift in type II muscle fiber area compared to saline-treated controls, with the L+F group having a significant increase in muscle mass. At 12 weeks there was an improved recovery over and above that demonstrated at 6 weeks. Muscle mass was 65% and 42% greater than control for LIF and L+F, respectively. Force of contraction, conduction velocity, myelinated fiber number, and diameter were also significantly greater for both LIF- and L+F-treated rats than saline-treated rats. These results demonstrate that LIF significantly improves the regeneration of damaged peripheral nerves and the preservation of muscle viability, resulting in greatly enhanced recovery of skeletal muscle function.
Tham
S
S
Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne, Australia.
Dowsing
B
B
Finkelstein
D
D
Donato
R
R
Cheema
S S
SS
Bartlett
P F
PF
Morrison
W A
WA
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004553:Electric Conductivity; D006131:Growth Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D018482:Muscle, Skeletal / Q000294:innervation*; D009186:Myelin Sheath / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines