ovalbumin and Stroke

Systemic 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.. We 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.. Systemic 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.. Our 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.

Topics: Anaphylaxis; Animals; Blood-Brain Barrier; Brain; Brain Edema; Brain Ischemia; Cerebral Infarction; Cytokines; Humans; Hypothermia, Induced; Infarction, Middle Cerebral Artery; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Ovalbumin; Stroke

Animals subjected to an inflammatory insult at the time of stroke are predisposed to the development of an inflammatory autoimmune response to brain. This response is associated with worse neurological outcome. Because induction of immunologic tolerance to brain antigens before stroke onset is associated with improved outcome, we sought to determine whether this paradigm could prevent the deleterious autoimmune response to brain provoked by an inflammatory stimulus at the time of ischemia.. Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin by intranasal administration before middle cerebral artery occlusion. At the time of reperfusion, all animals received lipopolysaccharide (1 mg/kg intraperitoneal). Behavioral tests were performed at set time intervals.. One month after middle cerebral artery occlusion, lymphocytes from the spleens of MBP-tolerized animals were less likely to evidence an autoimmune response and more likely to evidence a regulatory response (Treg) toward MBP than those from ovalbumin-tolerized animals. Animals that had an inflammatory response toward MBP (a Th1 response) performed worse on behavioral tests than those that did not. Fractalkine, a surrogate marker of inflammation, was elevated in animals with a Th1 response to MBP.. These data extend our previous findings and suggest that deleterious autoimmunity to brain antigens can be prevented by prophylactically inducing regulatory T-cell responses to those antigens.

Topics: Administration, Intranasal; Animals; Autoimmune Diseases of the Nervous System; Autoimmunity; Biomarkers; Chemokine CX3CL1; Encephalitis; Immune Tolerance; Immunity, Cellular; Immunotherapy; Infarction, Middle Cerebral Artery; Male; Myelin Basic Protein; Ovalbumin; Rats; Rats, Inbred Lew; Stroke; T-Lymphocytes, Regulatory; Treatment Outcome

Inflammatory and immune mechanisms can precipitate cerebrovascular thrombosis and hemorrhage. Immunologic tolerance can be induced to a specific antigen by intranasal instillation of that antigen. Lymphocytes tolerized in this way provide local immunosuppression on restimulation with the same antigen. This study tests whether tolerization of lymphocytes to E-selectin can suppress local vessel activation and prevent stroke.. Spontaneously hypertensive genetically stroke-prone rats (n=113) were distributed among the following studies: comparison of ischemic infarcts/intraparenchymal hemorrhages after single or repetitive tolerization schedules with ovalbumin, E-selectin, or PBS; comparison of E-selectin tolerization- and PBS tolerization-induced suppression of delayed-type hypersensitivity in animals subsequently sensitized to E-selectin; and comparison of PBS-, ovalbumin-, and E-selectin-tolerized groups (after intravenous lipopolysaccharide to activate vessels) regarding transforming growth factor-beta1-positive splenocyte counts, plasma interferon-gamma levels, anti-human E-selectin antibodies, endothelial intercellular adhesion molecule-1, and anti-endothelial cell antibodies.. Nasal instillation of E-selectin, which is specifically expressed on activated endothelium, potently inhibited the development of ischemic and hemorrhagic strokes in spontaneously hypertensive stroke-prone rats with untreated hypertension. Repeated schedules of tolerization were required to maintain the resistance to stroke. Suppression of delayed-type hypersensitivity to E-selectin and increased numbers of transforming growth factor-beta1-positive splenocytes showed that intranasal exposure to E-selectin induced immunologic tolerance. E-selectin tolerization also reduced endothelial activation and immune responses after intravenous lipopolysaccharide, as shown by marked suppression of intercellular adhesion molecule-1 expression, anti-endothelial cell antibodies on luminal endothelium, and plasma interferon-gamma levels compared with the control condition.. The novel findings in this study support further investigation of immunologic tolerance as applied to the prevention of stroke.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cerebral Hemorrhage; Drug Evaluation, Preclinical; E-Selectin; Genetic Predisposition to Disease; Hypersensitivity, Delayed; Immune Tolerance; Immunity, Innate; Immunity, Mucosal; Instillation, Drug; Lipopolysaccharides; Lymphocytes; Nasal Mucosa; Ovalbumin; Rats; Rats, Inbred SHR; Stroke; Survival Rate; Treatment Outcome