ABSTRACT
ADX – adrenalectomized; BBB – blood-brain barrier; CNS – central nervous system; CORT – corticosterone; bFGF – basic fibroblast growth factor; EAE – experimental autoimmune encephalomyelitis; EGF – epidermal growth factor; ELISA – enzyme-linked immunosorbant assay; GFAP – glial fibrillary acidic protein; GS – glutamine synthetase; HPA-axis – hypothalamic-pituitary adrenal-axis; IFN-– interferon-; IHC – immunohistochemistry; IL-1 – Interleukin; IL-1ra – IL-1 receptor antagonist; LIF – leukemia inhibitory factor; LIX – LPS-induced CXC chemokine; LPS – lipopolysaccharide; MCP-1 – monocyte chemoattractant protein-1; MHC – major histocompatibility complex; MIP-1 – macrophage inflammatory protein-1; MPTP – 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NGF – nerve growth factor; NO – nitric oxide synthase; OVX – ovariectomized; RANTES – regulated upon normal T-cell activation expressed and secreted; ROS – reactive oxygen species; SDS – sodium dodecylsulfate; T3 – triiodothyronine; TGF- – transforming growth factor-; TMT – trimethyl tin; TNF- – tumor necrosis factor-
Over the last twenty years, considerable evidence has accumulated to suggest that gliosis represents a homotypic response of astrocytes and microglia to all types of nervous system injury, including damage resulting from exposure to chemicals or chemical mixtures. The astrocytic component of this response, often referred to as “reactive” gliosis or astrogliosis, has received the most attention and is the subject of numerous reviews (Martin and O’Callaghan, 1996; Kimelberg and Norenberg, 1994; Norenberg, 1994; Eng and Ghirnikar, 1994; Norton et al., 1992; Perry and Andersson, 1992; Eng et al., 1992; Kimelberg and Norenberg, 1989; Malhotra et al., 1990; Eng, 1988a; Eng and DeArmond, 1981). Most of the progress in characterizing reactive gliosis over the years can be traced to the discovery of GFAP, the major protein of astrocyte intermediate filaments (Eng, 1988b; Eng, 1985; Eng et al., 1985). Astrocytes accumulate intermediate filaments when they become reactive (Eng, 1988b; Eng, 1987; Brock and O’Callaghan, 1987; Aono et al., 1985; Smith et al., 1984; Amaducci et al., 1981), therefore, by definition, reactive astrocytes show an enhanced expression of GFAP. Immunohistochemistry of GFAP has been widely utilized to monitor astrocytic responses to neural injury and has firmly established GFAP as the key biomarker of reactive gliosis. Although less prevalent in the literature, GFAP analysis by immunoblot and immunoassay also has been used to establish, quantitatively, the features of reactive gliosis (Norton et al., 1992; Aono et al., 1985; O’Callaghan, 1993; O’Callaghan
et al., 1995). We have used the latter approach to document regional differences in GFAP expression and the utility of GFAP as a marker of the dose-, time-, and region-dependent damage resulting from exposure to broad classes of known and suspected neurotoxic agents. Our purpose here is not to revisit these topics, but rather, it is to review and challenge some commonly held views on the nature of the astrocyte response to CNS injury. Specifically, we will discuss the potential role of GFAP in gliosis, conflicting data obtained from in vitro vs. in vivo analysis of “reactive” astrocytes, and the relative contribution of hypertrophy and hyperplasia to reactive gliosis. Because descriptions of cytokine and hormonal regulation of astroglial responses pervade the in vitro and in vivo literature, cytokine and hormonal effectors will be discussed as they relate to each feature of gliosis. Gliosis in the developing nervous system also will be examined along with the merits of analysis of gliosis by GFAP immunohistochemistry vs. GFAP immunoassay. Understanding the features of the astroglial response to injury is critical for the accurate use of GFAP as a biomarker for detecting and quantifying neurotoxicity and for designing effective strategies for neuroprotection or neurotrophic support following neurotoxic exposures.
