Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size

Abstract

BackgroundSystemic inflammation impairs outcome in stroke patients and experimental animals via mechanisms which are poorly understood. Circulating inflammatory mediators can activate cerebrovascular endothelium or glial cells in the brain and impact on ischaemic brain injury. One of the most serious early clinical complications of cerebral ischaemia is brain oedema, which compromises survival in the first 24-48 h. It is not understood whether systemic inflammatory challenges impair outcome after stroke by increasing brain injury only or whether they have direct effects on brain oedema, cerebrovascular inflammation and blood-brain barrier damage.MethodsWe used two different systemic inflammatory stimuli, acute endotoxin treatment and anaphylaxis to study mechanisms of brain injury after middle cerebral artery occlusion (MCAo). Ischaemic brain injury, blood-brain barrier damage and oedema were analysed by histological techniques. Systemic cytokine responses and inflammatory changes in the brain were analysed by cytometric bead array, immunofluorescence, in situ hibridization and quantitative real-time PCR.ResultsSystemic inflammatory challenges profoundly impaired survival in the first 24 h after experimental stroke in mice, independently of an increase in infarct size. Systemic lipopolysaccharide (LPS) dose-dependently increased mortality (50-100%) minutes to hours after cerebral ischaemia. Acute anaphylactic challenge in ovalbumin-sensitised mice affected stroke more seriously when induced via intraperitoneal administration compared to intravenous. Both LPS and anaphylaxis induced inflammatory changes in the blood and in the brain prior to experimental stroke. Plasma cytokine levels were significantly higher after LPS, while increased IL-10 levels were seen after anaphylaxis. After MCAo, both LPS and anaphylaxis increased microglial interleukin-1α (IL-1α) expression and blood-brain barrier breakdown. LPS caused marked granulocyte recruitment throughout the ipsilateral hemisphere. To investigate whether reduction of ischaemic damage can improve outcome in systemic inflammation, controlled hypothermia was performed. Hypothermia reduced infarct size in all treatment groups and moderately improved survival, but failed to reduce excess oedema formation after anaphylaxis and LPS-induced neuroinflammation.ConclusionsOur results suggest that systemic inflammatory conditions induce cerebrovascular inflammation via diverse mechanisms. Increased brain inflammation, blood-brain barrier injury and brain oedema formation can be major contributors to impaired outcome in mice after experimental stroke with systemic inflammatory stimuli, independently of infarct size.

A Novel SPECT-Based Approach Reveals Early Mechanisms of Central and Peripheral Inflammation after Cerebral Ischemia

“…Recent data suggest that peripheral inflammatory stimuli (induced by LPS or the proinflammatory cytokine interleukin-1) could alter cerebral perfusion, lead to larger BBB injury or cerebral edema after stroke that might happen independently of increases in infarct size. 19,33,34 In fact, we have found reduced 99mTc-HMPAO uptake in the cerebal cortex early (2 hours) after experimental stroke that was further reduced by preceding systemic inflammation. In contrast, systemic inflammation did not significantly reduce cerebral perfusion and did not augment BBB injury in the striatum (infarct core), where cerebral blood flow was maximally reduced during MCAo.…”

“…31 Underlying systemic inflammation due to old age, chronic diseases or infection results in markedly impaired outcome after stroke in patients and in experimental animals. 7,[17][18][19]32 However, mechanisms by which systemic inflammation impacts on brain injury are improperly understood. Recent data suggest that peripheral inflammatory stimuli (induced by LPS or the proinflammatory cytokine interleukin-1) could alter cerebral perfusion, lead to larger BBB injury or cerebral edema after stroke that might happen independently of increases in infarct size.…”

Antigen Presentation After Stroke

“…Experimental models of stroke have shown that various systemic inflammatory mechanisms exacerbate brain damage and worsen functional deficits. The mechanisms by which systemic inflammation exhacerbates cerebral ischemia are diverse, including reduced reperfusion after vessel recanalization [105], increased BBB injury, and edema formation [106]. Raising systemic inflammation in experimental ischemia through IL-1β administration, or in IL-10-deficient mice, or in mice with chronic infection that have a T helper 1 (Th1)-polarized immune response, has been associated to increased disruption of tight junction proteins and basal lamina collagen, increased platelet aggregation, microvascular injury, increased MMP activation, and increased mortality after experimental ischemia [102,107,108].…”

Streptococcus pneumoniae worsens cerebral ischemia via interleukin 1 and platelet glycoprotein Ibα

“…Similarly, increased BBB injury was evident in infected mice with even smaller infarcts, supporting our earlier observations that systemic inflammatory mechanisms could mediate inflammation and injury in the brain independently of changes in infarct size. 40 Vascular activation after infection, and increased platelet aggregation in infected mice after cerebral ischemia, suggested that inflammatory signals in the brain might be mediated by activated platelets. According to a recent study, S. pneumoniae can induce platelet aggregation in a strain-specific manner via toll-like receptor 2, which is dependent on GPIIb/IIIa, but is not affected by aspirin.…”