Systemic infection, inflammation and acute ischemic stroke
ABSTRACT Extensive evidence implicates inflammation in multiple phases of stroke etiology and pathology. In particular, there is growing awareness that inflammatory events outside the brain have an important impact on stroke susceptibility and outcome. Numerous conditions, including infection and chronic non-infectious diseases, that are established risk factors for stroke are associated with an elevated systemic inflammatory profile. Recent clinical and pre-clinical studies support the concept that the systemic inflammatory status prior to and at the time of stroke is a key determinant of acute outcome and long-term prognosis. Here, we provide an overview of the impact of systemic inflammation on stroke susceptibility and outcome. We discuss potential mechanisms underlying the impact on ischemic brain injury and highlight the implications for stroke prevention, therapy and modeling.
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- "and elevated levels of IL-1 can also affect patient susceptibility and severity of CNS injury (McColl et al., 2009; Denes et al., 2010). The overwhelming majority of patients presenting with ischemic or hemorrhagic stroke have one or more risk factors including obesity, hypertension, atherosclerosis, diabetes and infection, which account for 60–80% of stroke risk in the general population (Hankey, 2006; Emsley and Hopkins, 2008). "
Article: Interleukin-1 and acute brain injury[Show abstract] [Hide abstract]
ABSTRACT: Inflammation is the key host-defense response to infection and injury, yet also a major contributor to a diverse range of diseases, both peripheral and central in origin. Brain injury as a result of stroke or trauma is a leading cause of death and disability worldwide, yet there are no effective treatments, resulting in enormous social and economic costs. Increasing evidence, both preclinical and clinical, highlights inflammation as an important factor in stroke, both in determining outcome and as a contributor to risk. A number of inflammatory mediators have been proposed as key targets for intervention to reduce the burden of stroke, several reaching clinical trial, but as yet yielding no success. Many factors could explain these failures, including the lack of robust preclinical evidence and poorly designed clinical trials, in addition to the complex nature of the clinical condition. Lack of consideration in preclinical studies of associated co-morbidities prevalent in the clinical stroke population is now seen as an important omission in previous work. These co-morbidities (atherosclerosis, hypertension, diabetes, infection) have a strong inflammatory component, supporting the need for greater understanding of how inflammation contributes to acute brain injury. Interleukin (IL)-1 is the prototypical pro-inflammatory cytokine, first identified many years ago as the endogenous pyrogen. Research over the last 20 years or so reveals that IL-1 is an important mediator of neuronal injury and blocking the actions of IL-1 is beneficial in a number of experimental models of brain damage. Mechanisms underlying the actions of IL-1 in brain injury remain unclear, though increasing evidence indicates the cerebrovasculature as a key target. Recent literature supporting this and other aspects of how IL-1 and systemic inflammation in general contribute to acute brain injury are discussed in this review.Frontiers in Cellular Neuroscience 03/2015; 9. DOI:10.3389/fncel.2015.00018 · 4.18 Impact Factor
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- "Recent research has demonstrated that the inflammatory response accompanying necrotic brain injury plays an important role in stroke (McColl et al. 2009; Jin et al. 2010). Both neuroimmune and inflammatory reactions contribute to the development of stroke-induced cerebral injury (Wang et al. 2007) with complex relationships (Kriz and Lalancette-Hebert 2009). "
ABSTRACT: Whether the inflammatory response that accompanies acute ischemic stroke induces the kynurenine pathway is currently a matter of conjecture. Activation of this pathway may disturb active metabolites. The aim of this study was thus to characterize the catabolism of tryptophan and tyrosine in acute ischemic stroke (AIS) patients, and its association with cytokines, C-reactive protein, and glucose. Serum levels of 5-hydroxytryptamine, tryptophan catabolites, and competing amino acids and significant ratios of these were measured in 45 AIS patients and compared to those of 40 control subjects. Furthermore, associations between the serum levels of these biomarkers and serum levels of cytokines, C-reactive protein, and glucose were determined. Significantly lower levels of tryptophan and tyrosine in the stroke group indicate increased tryptophan and tyrosine oxidation in acute ischemic stroke, while significantly lowered tryptophan index and tyrosine index indicate a reduced capacity for the synthesis of 5-hydroxytryptamine and catecholamines in the brain, respectively. Furthermore, our findings indicate that the proinflammatory response in acute ischemic stroke may be responsible for a reduced capacity for the biosynthesis of brain catecholamines and mediate neurotoxic effects. Meanwhile, the anti-inflammatory IL-10 may exert a neuroprotective effect and prevent the putative reduced capacity for 5-hydroxytryptamine synthesis in the brain. These mechanisms may be involved in several sequelae following stroke, such as cognitive impairment, depression, and fatigue.Journal of Molecular Neuroscience 08/2013; 51(3). DOI:10.1007/s12031-013-0097-2 · 2.76 Impact Factor
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- "Various anti-inflammatory interventions have been shown to grant protection against brain injury, if administered within 3–6 h post-stroke. Centrally or peripherally expressed proinflammatory cytokines/chemokines such as IL-1, TNFα or RANTES (CCL5), proteases such as MMP-9, toll-like receptors such as TLR4 or TLR2, various immune cell populations such as T cells, macrophages, platelets or neutrophils have all been implicated in the development of ischemic brain injury, similarly to experimental models of ischaemic injury in peripheral tissues, such as myocardial infarction, kidney-or liver ischemia (Denes et al. 2010b, 2011b; McColl et al. 2009; Klingenberg and Hansson 2009; Dinarello 2011; Zhai et al. 2011). Although our understanding of how basic inflammatory mechanisms contribute to ischemic injury in the absence of comorbidities is far from complete, several recent review articles have addressed this issue in detail (Denes et al. 2010b; Iadecola and Anrather 2011; Chamorro et al. 2012). "
ABSTRACT: Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches.Journal of Neuroimmune Pharmacology 05/2013; 8(4). DOI:10.1007/s11481-013-9469-1 · 3.17 Impact Factor