Release of proinflammatory and prothrombotic mediators in the brain and peripheral circulation in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

Abstract

Background and Purpose:We reported previously that stroke risk factors prepared the brain stem for the development of ischemia and hemorrhage and induced the production of tumor necrosis factor following an intrathecal injection of lipopolysaccharide, a prototypic monocyte-activating stimulus. This study evaluates whether blood or brain cells of hypertensive rats produce more proinflammatory and prothrombotic mediators than do blood or brain cells of normotensive rats.Methods: Levels of tumor necrosis factor, platelet-activating factor, 6-ketoprostaglandin F la , and thromboxane B 2 in the cerebrospinal fluid and blood of spontaneously hypertensive and normotensive Wistar-Kyoto rats were monitored before and after a challenge with lipopolysaccharide.Results: Little or no activity from these mediators was found in the cerebrospinal fluid or blood of saline-injected control animals. Intravenous administration of lipopolysaccharide (0.001, 0.1, and 1.8 nig/kg) produced dose-dependent increases in blood levels of all mediators in hypertensive rats. In normotensive rats the levels were less than in hypertensive rats and were not clearly dose-related. When lipopolysaccharide was injected intracerebroventricularly, more tumor necrosis factor was measured in the cerebrospinal fluid than in the blood, suggesting local synthesis of this cytokine. Levels of tumor necrosis factor and platelet-activating factor in the cerebrospinal fluid were higher in hypertensive than in normotensive rats. The thromboxane A 2 /prostacyclin ratio was not altered significantly between the two rat strains.Conclusions: It is suggested that the higher incidence of brain stem ischemia and hemorrhage after the intrathecal injection of lipopolysaccharide in hypertensive rats than in normotensive rats might be related to the higher levels of the two cytotoxic factors tumor necrosis factor and platelet-activating factor produced in response to such challenge.

Monocyte adhesion to cerebromicrovascular endothelial cells derived from hypertensive and normotensive rats

“…Enhanced monocyte interaction with endothelium in segments of the vasculature may signify the ease at which overall disturbances of endothelium can occur. This increased sensitivity of SHR EC may represent a mechanism by which hypertension acts as a predisposing factor for the development of thrombotic vascular disease (13,15,26).…”

“…Despite the fact that no significant variations were observed in the quantitative dependence on any particular adhesion pathway utilized by SHR or WKY EC (antibody-blocking experiments) other differences could exist in vivo, where endothelium is subjected to shear stress and factors other than just cytokines. Another in vivo difference not addressed in vitro is related to the finding of substantially greater numbers of monocytes in SHR, which would increase the number of cell interaction events (25)(26)(27). Additional sturlies may identify other mechanisms through which factors such as hypertension contribute to the initiation ofvascular injury and contribute to pathological changes seen in stroke and reperfusion injury.…”

“…These findings may indicate a mechanism at least partially responsible for increases in in vivo perivascular monocyte accumulation seen in hypertensive rats (15,27). Some of these effects may be mediated by the production of proinflammatory factors such as TNFa, which is produced in greater amounts by SHR than by WKY rats when injected with LPS (26,27). These observations indicate a possible mechanism by which hypertension may predispose to the development of disorders such as atherosclerosis as weil as stroke.…”

Inflammation: a mechanism of depression?

“…Brain damage also increases the expression of pro-infl ammatory cytokines [49] . TNF-α levels are elevated in various experimental models of brain injury [50] , including the administration of kainic acid [51] or lipopolysaccharide [52] , injection of the excitotoxin ibotenic acid [53] , closed head injury [54] , and traumatic head injury [55] . Specifically, IL-6…”

Characterization of the Microglial Response to Cerebral Ischemia in the Stroke-Prone Spontaneously Hypertensive Rat

“…6 Compared with WKY, mature SHR have significantly elevated neutrophil, monocyte, and lymphocyte counts in their blood, 7 with an abnormal degree of activation of these cells, and they produce higher levels of TNF and platelet-activating factor in cerebrospinal fluid after intravenous lipopolysaccharide administration. 8 Neutrophils have been proposed to contribute to ischemic injury, migrating to the site via a process of rolling and tethering to the blood vessel wall through the expression of adhesion molecules on their surface and on the endothelium of blood vessels. 5 Once adhered, neutrophils can cause damage not only by plugging blood vessels and reducing blood flow 9 but also by their release of cytotoxic substances at the endothelial surface or after migration into the brain.…”