Polymorphonuclear Leukocyte Behavior in a Nonhuman Primate Focal Ischemia Model

Ember, Julia A.; Zoppo, Gregory J. del; Mori, Etsuro; Thomas, W. S.; Copeland, Brian R.; Hugli, Tony E.

doi:10.1038/jcbfm.1994.137

Cited by 30 publications

(26 citation statements)

References 26 publications

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“…A causative involvement of MMP-9 in these events remains to be tested. (Hibbs et aI., 1985;Kjeldsen et aI., 1992;Vartio and Baumann, 1989) and increase early during MCAO in this model (Ember et a!., 1994), no clear correlation between MMP-9 activity and leukocyte count could be seen here.…”

mentioning

confidence: 65%

Matrix Metalloproteinases Increase Very Early during Experimental Focal Cerebral Ischemia

Heo

Lucero

Abumiya

et al. 1999

J Cereb Blood Flow Metab

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514

459

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Summary: Microvascular integrity is lost during focal cere bral ischemia. The degradation of the basal lamina and extra cellular matrix are, in part, responsible for the loss of vascular integrity. Matrix metalloproteinases (MMPs) may play a pri mary role in basal lamina degradation. By using a sensitive modification of gelatin zymography, the authors investigated the activity of MMP-2 and MMP-9 in frozen lO-f.Lm sections of ischemic and nonischemic basal ganglia and plasma samples of 27 non-human primates after middle cerebral artery occlusion/ reperfusion (MCAO/R) for various periods. The gelatinolytic activities were compared with parallel cell dUTP incorporation in the ischemic zones of adjacent sections. In the brain, the integrated density of MMP-2 increased significantly by 1 hour 624after MCAO and was persistently elevated thereafter. Matrix metalJoproteinase-2 expression was highly correlated with the extent of neuron injury and the number of injured neurons (r = 0.9763, SE = 0.004, 2P < 0.0008). Matrix metalloproteinase-9 expression only was significantly increased in subjects with hemor rhagic transformation. In plasma, only MMP-9 increased transiently at 2 hours of MCAO. These findings highlight the early potential role of MMP-2 in the degradation of basal lamina leading to neuronal injury, and an association of MMP-9 with hemorrhagic transformation after focal cerebral ischemia. Key Words: Matrix metalloproteinase-Cerebral ischemia-Zymography-Neuron injury-Hemorrhagic trans formation-Basal lamina.

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mentioning

confidence: 65%

Matrix Metalloproteinases Increase Very Early during Experimental Focal Cerebral Ischemia

Heo

Lucero

Abumiya

et al. 1999

J Cereb Blood Flow Metab

Self Cite

514

459

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“…11 In stroke models, additional factors such as exposure to anesthetics and surgery may impair leukocyte functions and, thus, may contribute to the increased risk of infection. 18 However, in contrast to MCAO mice, shamoperated animals neither showed a relevant attenuation of immune responsiveness nor developed spontaneous bacterial infections 11 indicating that the surgical procedures and anesthetics do not play a major role in the impaired antibacterial defenses after stroke in this model.…”

Section: Discussionmentioning

confidence: 99%

Stroke Propagates Bacterial Aspiration to Pneumonia in a Model of Cerebral Ischemia

Prass

Braun

Dirnagl

et al. 2006

Stroke

176

144

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Background and Purpose-Bacterial pneumonia is the most common cause of death in patients sustaining acute stroke and is believed to result from an increased aspiration. Recently, stroke-induced immunodeficiency was described in a mouse model of cerebral ischemia, which is primarily caused by overactivation of sympathetic nervous system. We tested if stroke-induced immunodeficiency increases the risk of pneumonia after aspiration in a newly developed model of poststroke pneumonia. Methods-Experimental stroke in mice was induced by occlusion of the middle cerebral artery (MCAO) for 60 minutes.Aspiration pneumonia was induced by intranasal application of 20 L of a defined suspension of Streptococcus pneumoniae in phosphate-buffered saline 4 or 14 days after MCAO. Treatment comprised moxifloxacin (100 mg/kg body weight, six times every 2 hours after operation) or propranolol (30 mg/kg body weight, immediately before as well as 4 and 8 hours after MCAO). Readout was lung histology and bacterial counts in lung and blood. Results-Nasal inoculation of only 200 colony-forming units of S pneumoniae caused severe pneumonia and bacteremia after experimental stroke, whereas 200 000 colony-forming units are needed to induce comparable disease in sham animals. Aspiration pneumonia in stroke animals outlasted acute stroke state but was preventable by ␤-adrenoreceptor blockade. Key Words: aspiration Ⅲ mice Ⅲ pneumonia Ⅲ Streptococcus pneumoniae Ⅲ stroke T he prognosis of stroke depends mainly on the incidence of complications. 1 Bacterial pneumonia is the most frequent severe complication 1-3 and the most common cause of death in patients sustaining a stroke. 4 Furthermore, its incidence correlates with the severity of stroke 5 and is associated with poor outcome. 6 However, even minor strokes, without clinical symptoms, may be complicated by pneumonia. 7 The risk for pneumonia is highest in the acute state of stroke, but it remains increased for up to several months during rehabilitation. 8 Reduction of bulbar reflexes, drowsiness, the bedridden patient's state, and subsequent aspiration are considered to account for the high incidence of bacterial pneumonia after stroke. However, aspiration alone cannot explain the high incidence of stroke-associated pneumonia. 9 Aspiration occurs in healthy adults during sleep without inducing pneumonia. 10 The reasons for the high incidence of pneumonia in patients sustaining a stroke are still incompletely understood. Conclusions-ExperimentalRecently, we described stroke-induced immunodeficiency in a mouse model of cerebral ischemia, 11 which is mainly caused by sympathetic nervous system overactivation and results in spontaneous bacterial infections resulting from impaired cell-mediated immune responses. In a newly developed model of poststroke pneumonia, we tested whether stroke-induced immunodeficiency increases the risk of pneumonia after aspiration. To induce pneumonia, we used Streptococcus pneumoniae as a result of its clinical relevance. Elderly and persons with coexisting diseases ...

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“…The possibility that leukocyte alterations in experimental models may be determined by the surgical procedures used to induce the ischemic insult or by anesthesia has been refuted in a nonhuman primate model. 153 Moreover, the use of shamoperated animals (ie, animals in which all of the phases of the surgical procedure except artery occlusion are reproduced) makes it possible to control for the influence of surgery and anesthesia. Some of the substantial advantages of experimental models are the following: (1) The possibility of knowing the exact time of onset of ischemia means that the temporal pattern of the expression of the molecules under study can be investigated; (2) Access to brain tissue for pathological observation is simple; (3) New drugs can be tested.…”

Section: Relevance Of Animal Modelsmentioning

confidence: 99%

Cytokines and Cell Adhesion Molecules in Cerebral Ischemia

Pantoni

Sarti

Inzitari

1998

ATVB

124

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Abstract-The possibility of reopening an occluded cerebral artery by means of thrombolysis has renewed interest in a number of the several mechanisms that are active during acute cerebral ischemia. Over recent years, it has become apparent that leukocytes play a central role not only during the healing stage of brain infarction but also during the early phases of cerebral ischemia, when it is postulated that these cells produce harmful effects, particularly in the presence of reperfusion. This review is based on the critical analysis of more than 150 publications dealing with the role of leukocytes and some inflammatory mediators (cytokines, chemokines, and adhesion molecules) in cerebral ischemia. Animal studies indicate that leukocyte involvement is promoted by a variety of inflammatory molecules produced immediately after the onset of cerebral ischemia. Considerable experimental evidence suggests that these mediators play a key role in the progression from ischemia to irreversible injury (ie, cellular death and necrosis). However, the precise role of each molecule alone remains to be further elucidated as well as in relation to the complex network existing among different mediators. Progress in our understanding of the inflammatory mechanisms operating in cerebral ischemia has enabled the testing of new compounds with promising results in animals; in contrast, one recent controlled trial of an anti-leukocyte molecule in acute stroke patients showed negative results. This discrepancy may derive in part from our incomplete understanding of the complexity of the inflammatory mechanisms involved in cerebral ischemia. Our analysis suggests that until sufficient knowledge of the underlying disease mechanisms is acquired, more care should be taken when testing new and potentially efficacious drugs in stroke patients.

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Polymorphonuclear Leukocyte Behavior in a Nonhuman Primate Focal Ischemia Model

Cited by 30 publications

References 26 publications

Matrix Metalloproteinases Increase Very Early during Experimental Focal Cerebral Ischemia

Matrix Metalloproteinases Increase Very Early during Experimental Focal Cerebral Ischemia

Stroke Propagates Bacterial Aspiration to Pneumonia in a Model of Cerebral Ischemia

Cytokines and Cell Adhesion Molecules in Cerebral Ischemia

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