Differential responses of intrinsic and extrinsic innervation of smooth muscle cells in rat colitis.

Intestinal smooth muscle cells receive neural input from axons that originate within the intestine, as well as from axons of extrinsic origin. In the inflamed intestine, altered motility may arise from damage to the axon/smooth muscle cell relationship, but the extent of change is unknown. Western blotting, histology and immunocytochemistry were used in the TNBS model of colitis in the rat to evaluate intrinsic and extrinsic axon numbers, which were then correlated with circular smooth muscle cell (CSMC) number during the time course from the acute onset of colitis to apparent recovery, at Day 35 post TNBS. Total axon profiles in the circular smooth muscle layer were reduced by nearly 50% on Day 4 of colitis, to 428 +/- 82 axons/section from 757 +/- 125 in control (n = 8-14 animals). The intrinsic innervation density (axon number per CSMC) dropped sharply by Day 2 to less than 30% of control. Although CSMC number nearly tripled during colitis, innervation density was restored to control levels by Day 6 due to a coordinated three-fold increase in axon number. The subpopulation of extrinsic axons expressing tyrosine hydroxylase showed a unique pattern during colitis, with no initial decrease in axon number, followed by axonal proliferation between Days 6 and 16 post-TNBS. We conclude that loss of intrinsic axons is an early event in colitis, and although reversed by axonal proliferation, transient denervation may promote CSMC hyperplasia as seen in earlier work in vitro. Axonal proliferation of both intrinsic and extrinsic axons is identified as a major homeostatic mechanism, with distinct patterns of damage and repair suggesting a structural basis for the altered motility seen in the inflamed colon.