Evolution of Cerebral Tumor Necrosis Factor-α Production During Human Ischemic Stroke

Abstract

Background and Purpose— Tumor necrosis factor-α (TNF-α) is detected in ischemic brain cells in experimental animal models and is believed to play an important role in apoptosis. However, the natural expression of TNF-α during human stroke is not known. Methods— We examined TNF-α immunohistochemistry and terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) in brain samples of stroke victims (n=16) after variable survival (15 hours to 18 days). Systemic TNF-α content from a separate cohort including severe or lethal stroke cases (n=26) was also assayed. Results— Neuronal TNF-α was demonstrated from 0.6 to 5.4 days after the onset of stroke symptoms, peaking bilaterally during days 2 and 3. Bilateral glial TNF-α immunoreactivity was detected during the acute phase, with the astrocytic TNF-α expression dominating in later phases and persisting contralaterally to the infarct in more matured phases (17 to 18 days). Invading inflammatory cells were TNF-α immunopositive beginning on the third day. Besides, vascular wall structures showed immunoreactivity sporadically. TNF-α levels were mostly nondetectable in peripheral blood. TUNEL labeling and TNF-α staining overlapped, although not completely, during the first days. Conclusions— The data support the hypothesis that TNF-α may be involved both in the acute propagation of inflammatory processes and cell death and possibly in the more delayed reconstitutive processes of human ischemic stroke.