Development of tissue damage, inflammation and resolution following stroke: An immunohistochemical and quantitative planimetric study

Clark, Robert K.; Lee, E.V.; Fish, C. J.; White, R. F.; Price, William J.; Jonak, Zdenka L.; Feuerstein, Giora; Barone, Frank C.

doi:10.1016/0361-9230(93)90124-t

Cited by 242 publications

(167 citation statements)

References 22 publications

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“…In this respect, histological studies of transient brain ischaemia in animal models of stroke have demonstrated an initial activation of glial cells within the first 48 h after the onset of stroke, whereas macrophage activation was detected a few days later [23]. Thus, the kinetics of IL-8 and GM-CSF production in CSF with a peak on day 2 in stroke patients, as observed in the present study, supports the glial cells as the main source of these cytokines.…”

Section: Discussionsupporting

confidence: 85%

Intrathecal release of pro- and anti-inflammatory cytokines during stroke

Tarkowski

Rosengren

Blomstrand

et al. 1997

Clinical and Experimental Immunology

198

151

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SUMMARYA growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of ischaemic brain damage. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines, such as IL-1b and IL-6 already within the first 24 h after the beginning of symptoms (Tarkowski et al., 1995). The aim of the present study was to investigate patterns of local inflammatory responses as a consequence of acute stroke. Thirty stroke patients were studied prospectively on days 0-3, 7-9, 21-26 and after day 90 with clinical evaluations, radiological assessments and analysis of cerebrospinal fluid (CSF) cytokine levels. In addition, 15 healthy control CSF samples were used. Significantly increased CSF levels of IL-8, granulocytemacrophage colony-stimulating factor (GM-CSF) and IL-10 were observed early during the stroke with a peak on day 2 for the proinflammatory cytokines IL-8 and GM-CSF, and on day 3 for the immunoregulatory cytokine IL-10. Patients with a brain infarct predominantly located in the white matter showed significantly higher levels of IL-8 in CSF than patients with an infarct mainly located in the grey matter. Also, high levels of intrathecal tumour necrosis factor-alpha (TNF-a) were associated with the presence of white matter disease. Our study demonstrates an intrathecal production of proinflammatory and immunoregulatory cytokines in patients with stroke, supporting the notion of localized immune response to the acute brain lesion. A better understanding of the inflammatory response in stroke may lead to new treatment strategies.

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Section: Discussionsupporting

confidence: 85%

Intrathecal release of pro- and anti-inflammatory cytokines during stroke

Tarkowski

Rosengren

Blomstrand

et al. 1997

Clinical and Experimental Immunology

198

151

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“…The increased sensitiv ity to ischemia seen in the striatum is similar to the findings of Clark et al (1993 ) and is likely due to the fact that the striatum lacks non-MCA collaterals, obtaining its entire supply of blood from the lentic ulate striate branch of MCA (Rieke et al , 1981;Coyle and Jokelainen, 1982). The size of the infarct also grew more rapidly in the striatum, but as with the cortex, the most dramatic change occurred be tween 6 and 12 h. It appears, then, that while patho genetic events proceed more rapidly in the striatum, a large area of ischemic tissue contains metaboli cally active cells even after 6 h. Minimally, then, it can be concluded that potential targets for thera peutic intervention are present even after prolonged occlusion of the vascular system.…”

Section: Discussionsupporting

confidence: 80%

“…Thus, they discounted the idea of a significant delay be tween ischemia and neuronal death (e. g. , Neder gaard, 1987;Nagasawa and Kogure, 1990;Nakano et al , 1990;Chiamulera et al , 1993 ;Clark et al , 1993). While a lack of substantial infarct within the first hours is mentioned in some reports, the obser vations were based on subjective impressions rather than quantitative data and statistical analyses (Osborne et al , 1987;Persson et al , 1989;Hakim et al , 1992;Clark et al , 1993). More recently, insight into some of the temporal events associated with focal infarct has come from studies employing occlusions of different durations in conjunction with quantitative histology.…”

mentioning

confidence: 99%

Time-Related Neuronal Changes following Middle Cerebral Artery Occlusion: Implications for Therapeutic Intervention and the Role of Calpain

Bartus

Dean

Cavanaugh

et al. 1995

J Cereb Blood Flow Metab

105

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Changes in neocortex and striatum were characterized over time following focal ischemia to the brain. Rats were subjected to permanent middle cerebral artery occlusion (MCA-O) and sacrificed 1, 3, 6, 12, or 24 h later. The affected tissue was processed for tetrazolium chloride (TTC) and cresyl violet staining, as well as for Western blots to detect calpain-induced spectrin proteolysis. Significant changes in cell size and spectrin breakdown occurred within the first hour of occlusion, with further, dramatic changes in these two early markers continuing over time. Initial evidence of cell loss was noted at 1 h postocclusion in the striatum and at 3 h in the neocortex. However, even in the center of the most affected portion of the neocortex, the majority of cells appeared to be intact through 6 h. By this time, a significant TTC-defined infarct also emerged. These quantitative data indicate that calpain-induced proteolysis occurs very soon after the ischemic insult, is correlated with earliest changes in cell hypotrophy, and precedes or occurs in tandem with evidence of significant cell loss. They also demonstrate that, while some cell loss occurs earlier than previously believed, the majority of cells remains morphologically intact well beyond what is typically thought to be the window of opportunity for intervention. The results thus raise the question of how long after the ischemic event pharmaceutic intervention might be employed to salvage substantial numbers of neurons.

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“…Clark et al (1993) demonstrated that the reduction in infarcted tissue corresponded to the time point at which macrophages became a dominant feature of the ischemic lesion, and was associated with a loss in hemispheric volume. Subsequently, it was postulated that the phagocytic activity of macrophages in the necrotic tissue is responsible for reducing the hemispheric volume by causing cavitation within the lesion, after cerebral ischemia (Clark et al, 1993). However, differences in the temporal progression of the cerebral infarct between the two studies could be attributed to the use of different models of ischemia or alternatively, differences in the strain of rat used.…”

Section: Discussionmentioning

confidence: 95%

Inflammatory Cell Infiltration after Endothelin-1-Induced Cerebral Ischemia: Histochemical and Myeloperoxidase Correlation with Temporal Changes in Brain Injury

Weston

Jones

Jarrott

et al. 2007

J Cereb Blood Flow Metab

128

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Accumulation of neutrophils in brain after transient focal stroke remains controversial with some studies showing neutrophils to be deleterious, whereas others suggest neutrophils do not contribute to ischemic injury. Myeloperoxidase (MPO) has been used extensively as a marker for quantifying neutrophil accumulation, but is an indirect method and does not detect neutrophils alone. To elucidate the interaction of macrophages in the neutrophil inflammatory response, we conducted double-label immunofluorescence in brain sections at 0, 1, 2, 3, 7, and 15 days after ischemia. Each of these results was obtained from the same animal to determine correlations between neutrophil infiltration and ischemic damage. It was found that MPO activity increased up to 3 days after cerebral ischemia. Dual-staining revealed that macrophages engulf neutrophils in the brain and that this engulfment of neutrophils increased with time, with 50% of neutrophils in the brain engulfed at 3 days and approximately 85% at 15 days (N = 5, P < 0.05). Interestingly, at 7 days the amount of dual-staining was decreased to 20% (N = 5, P < 0.05). Neutrophil infiltration was positively correlated with ischemic damage in both the cortex and striatum (r 2 = 0.86 and 0.80, respectively, P < 0.01). The results of this study indicate that the MPO from neutrophils phagocytized by macrophages may continue to contribute to the overall MPO activity, and that previous assessments that have utilized this marker to measure neutrophil accumulation may have miscalculated the number of neutrophils within the ischemic territory and hence their contribution to the evolution of the infarct at later time points. Thus any biphasic infiltration of neutrophils may have been masked by the accumulation of macrophages.

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Development of tissue damage, inflammation and resolution following stroke: An immunohistochemical and quantitative planimetric study

Cited by 242 publications

References 22 publications

Intrathecal release of pro- and anti-inflammatory cytokines during stroke

Intrathecal release of pro- and anti-inflammatory cytokines during stroke

Time-Related Neuronal Changes following Middle Cerebral Artery Occlusion: Implications for Therapeutic Intervention and the Role of Calpain

Inflammatory Cell Infiltration after Endothelin-1-Induced Cerebral Ischemia: Histochemical and Myeloperoxidase Correlation with Temporal Changes in Brain Injury

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