Popovich P G, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes B T
Department of Medical Microbiology & Immunology, The Ohio State University College of Medicine and Public Health, 333 W. 10th Avenue, Columbus, Ohio, 43210, USA.
Exp Neurol. 1999 Aug;158(2):351-65. doi: 10.1006/exnr.1999.7118.
Traumatic injury to the spinal cord initiates a series of destructive cellular processes which accentuate tissue damage at and beyond the original site of trauma. The cellular inflammatory response has been implicated as one mechanism of secondary degeneration. Of the various leukocytes present in the spinal cord after injury, macrophages predominate. Through the release of chemicals and enzymes involved in host defense, macrophages can damage neurons and glia. However, macrophages are also essential for the reconstruction of injured tissues. This apparent dichotomy in macrophage function is further complicated by the overlapping influences of resident microglial-derived macrophages and those phagocytes that are derived from peripheral sources. To clarify the role macrophages play in posttraumatic secondary degeneration, we selectively depleted peripheral macrophages in spinal-injured rats during a time when inflammation has been shown to be maximal. Standardized behavioral and neuropathological analyses (open-field locomotor function, morphometric analysis of the injured spinal cord) were used to evaluate the efficacy of this treatment. Beginning 24 h after injury and then again at days 3 and 6 postinjury, spinal cord-injured rats received intravenous injections of liposome-encapsulated clodronate to deplete peripheral macrophages. Within the spinal cords of rats treated in this fashion, macrophage infiltration was significantly reduced at the site of impact. These animals showed marked improvement in hindlimb usage during overground locomotion. Behavioral recovery was paralleled by a significant preservation of myelinated axons, decreased cavitation in the rostrocaudal axis of the spinal cord, and enhanced sprouting and/or regeneration of axons at the site of injury. These data implicate hematogenous (blood-derived) macrophages as effectors of acute secondary injury. Furthermore, given the selective nature of the depletion regimen and its proven efficacy when administered after injury, cell-specific immunomodulation may prove useful as an adjunct therapy after spinal cord injury.
脊髓创伤会引发一系列破坏性细胞过程，这些过程会加剧创伤原发部位及以外的组织损伤。细胞炎症反应被认为是继发性变性的一种机制。损伤后脊髓中存在的各种白细胞中，巨噬细胞占主导。通过释放参与宿主防御的化学物质和酶，巨噬细胞会损伤神经元和神经胶质细胞。然而，巨噬细胞对于损伤组织的重建也至关重要。常驻小胶质细胞衍生的巨噬细胞和外周来源的吞噬细胞的重叠影响，使巨噬细胞功能的这种明显二分法更加复杂。为了阐明巨噬细胞在创伤后继发性变性中所起的作用，我们在炎症已被证明达到最大值的时间段内，选择性地清除了脊髓损伤大鼠的外周巨噬细胞。采用标准化行为和神经病理学分析（旷场运动功能、损伤脊髓的形态计量分析）来评估这种治疗的效果。从损伤后24小时开始，然后在损伤后第3天和第6天再次对脊髓损伤大鼠进行静脉注射脂质体包裹的氯膦酸盐，以清除外周巨噬细胞。以这种方式处理的大鼠脊髓内，撞击部位的巨噬细胞浸润明显减少。这些动物在地面运动时后肢使用情况有显著改善。行为恢复伴随着有髓轴突的显著保留、脊髓前后轴空泡形成减少以及损伤部位轴突发芽和/或再生增强。这些数据表明血源性（源自血液）巨噬细胞是急性继发性损伤的效应器。此外，鉴于清除方案的选择性及其在损伤后给药时已证实的疗效，细胞特异性免疫调节可能被证明是脊髓损伤后辅助治疗的有用方法。
