Shubayev V I, Myers R R
Department of Anesthesiology, University of California, 9500 Gilman Dr., La Jolla, San Diego, CA 92093 0629, USA.
Brain Res. 2000 Feb 7;855(1):83-9. doi: 10.1016/s0006-8993(99)02321-5.
Chronic constriction injury (CCI) to peripheral nerve causes a painful neuropathy in association with a process of axonal degeneration and endoneural remodeling that involves macrophage recruitment and local increase in extracellular proteases and tumor necrosis factor alpha (TNF-alpha). Cell surface activation of TNF-alpha from its transmembrane precursor, as well as sequestration of TNF-alpha receptors II and I, is performed by the zinc-dependent endopeptidase family of matrix metalloproteinases (MMPs). Among TNF-alpha-converting MMPs, basal lamina degrading gelatinases are thought to play a role in sciatic nerve injury. In the present study, we determined the forms of TNF-alpha involved in the development of CCI neuropathy in rats, using Western blot analysis, and the temporal correlation of TNF-alpha and TNFRI protein profiles with gelatinases activity at the site of peripheral nerve injury. We observed two peaks in TNF-alpha protein during the first week of CCI that correspond to previously reported peaks in painful behavior. We propose that the first peak at 6 h post-CCI is due to the local expression of the cytotoxic transmembrane 26 kDa TNF-alpha protein released by resident Schwann cells, mast cells and macrophages. This peak in TNF-alpha protein expression corresponds to an increase in gelatinase B (MMP-9) activity, which is greatly upregulated as early as 3 h following CCI to rat sciatic nerve. The second peak occurs at 5 days post-CCI, and may represent TNF-alpha protein released by hematogenously recruited macrophages. This peak is marked by the increase in active soluble 17 kDa TNF-alpha and by gelatinase A (MMP-2) upregulation. These observations suggest that there is a pathogenic role for the TNF-alpha-converting function of MMP-2 in painful CCI neuropathy. We conclude that severe nerve injury induces MMPs, TNF-alpha and TNFRI, which interactively control the privileged endoneurial environment and the pathogenesis of the painful neuropathies associated with the macrophage-dependent processes of Wallerian degeneration.
外周神经慢性压迫性损伤（CCI）会引发疼痛性神经病变，同时伴有轴突退变和神经内膜重塑过程，这一过程涉及巨噬细胞募集以及细胞外蛋白酶和肿瘤坏死因子α（TNF-α）在局部的增加。基质金属蛋白酶（MMPs）家族中的锌依赖性内肽酶可促使TNF-α从其跨膜前体进行细胞表面活化，并隔离TNF-α受体II和I。在可转化TNF-α的MMPs中，能降解基底膜的明胶酶被认为在坐骨神经损伤中发挥作用。在本研究中，我们通过蛋白质印迹分析确定了参与大鼠CCI神经病变发展过程的TNF-α形式，以及外周神经损伤部位TNF-α和TNFR I蛋白谱与明胶酶活性的时间相关性。我们观察到在CCI后的第一周，TNF-α蛋白出现两个峰值，这与先前报道的疼痛行为峰值相对应。我们认为，CCI后6小时出现的第一个峰值是由于驻留的施万细胞、肥大细胞和巨噬细胞释放的具有细胞毒性的26 kDa跨膜TNF-α蛋白的局部表达所致。TNF-α蛋白表达的这一峰值与明胶酶B（MMP-9）活性的增加相对应，在大鼠坐骨神经遭受CCI后3小时，明胶酶B活性就大幅上调。第二个峰值出现在CCI后5天，可能代表由血液中募集的巨噬细胞释放的TNF-α蛋白。这个峰值的标志是活性可溶性17 kDa TNF-α的增加以及明胶酶A（MMP-2）的上调。这些观察结果表明，MMP-2的TNF-α转化功能在疼痛性CCI神经病变中具有致病作用。我们得出结论，严重的神经损伤会诱导MMPs、TNF-α和TNFR I，它们相互作用以控制特殊的神经内膜环境以及与沃勒变性的巨噬细胞依赖性过程相关的疼痛性神经病变的发病机制。
