Role of macrophages in the stimulation and regeneration of sensory nerves by transposed granulation tissue and temporal aspects of the response.

Application of granulation tissue, which is rich in macrophages, to a peripheral nerve induces a conditioning effect, in that it enhances the regeneration capability of peripheral nerves after a test crush lesion. The temporal aspects of this response and the role of macrophages and interleukin-1 beta (IL-1 beta) were studied in the sciatic nerves of 71 rats. Granulation tissue was implanted close to the sciatic nerve and test crush lesions were applied after various periods of time (0-21 days). Regeneration was evaluated after an additional two, three, four, or six days. Regeneration distances were longer in granulation-treated nerves than in nerves treated with subcutaneous tissue. Furthermore, in animals in which the test crush lesion was made at the same time as the granulation tissue was implanted (n = 6), regeneration distances were longer, 8.1 (0.8) mm compared with 7.2 (0.6), than those in which the crush was made after conditioning intervals of 3 (n = 6, 7.6 (0.4) compared with 6.9 (0.4), p = 0.03); 7 (n = 6, 7.4 (0.4) compared with 6.6 (0.1), p = 0.03); and 21 days [(n = 8, 7.2 (0.6) compared with 6.4 (0.5)]. Inactivation of the granulation tissue by freezing suppressed the conditioning effect. There were numerous ED1 and ED2 positive macrophages as well as positive staining for IL-1 beta in the granulation tissue on day 0. Positive staining for IL-1 beta was also seen in nerve fibres as well as in non-neuronal cells after a conditioning interval. The results suggest that regeneration is stimulated by factors released from the cells of the granulation tissue, and that the amount of factors released or the responsiveness of the regenerating nerve change during the conditioning interval.