Regenerative arrest of inflamed peripheral nerves: role of nitric oxide

Inflammation can both support and hinder regeneration. In this work, we asked whether regeneration of peripheral nerve axons is facilitated or interrupted when it proceeds through a zone of local but nondirected inflammation. Regeneration was examined in new nerve bridges forming through conduits connecting transected rat sciatic nerves. The conduits, infused with lipopolysaccharide to generate a sterile and nondirected inflammatory response, had substantial rises in inducible nitric oxide (iNOS) mRNA synthesis. iNOS was expressed within macrophages just beyond the zone of axon regrowth. Under these conditions, there was complete interruption of regenerative bridge formation in all instances without axon regrowth across the transection. In a separate cohort, infusion of a broad-spectrum NOS inhibitor (Nomega-nitro-L-arginine-methyl ester) into the conduit salvaged bridge formation in a proportion (3/8) of rats. Our findings indicate that local inflammatory conditions inhibit regenerative events and that nitric oxide may contribute to these events.