Introduction
Stroke
Inflammatory mediators
| Neurotoxicity | Neuroprotection | Effects of hypothermia | |
---|---|---|---|---|
1. Cytokines | IL-1β | Endogenous pyrogen Promotion gliosis Increase neurotoxic mediators Increase Ca2+ in neurons Edema formation BBB breakdown Priming endothelium for leukocyte adherence | Increase survival promoting factors Induction of IL-1ra | Reduction increased levels |
TNF-α | Inhibition glutamate uptake Promotion gliosis Increase neurotoxic mediators Increase Ca2+ signaling in neurons Stimulation apoptosis of endothelial cells Edema formation BBB breakdown Priming endothelium for leukocyte adherence Increase NF-κB activation | Increase neurotrophic factors Control extracellular Ca2+ Mediation neuronal plasticity Activation repair processes of cerebral microvasculature Induction anti-apoptotic factors Induction anti-oxidants Ischemic tolerance induction | Reduction TNF-α levels Less expression TNF receptor 1 Less NF-κB activation
Reflection:
Varying properties of soluble and membrane-bound form
Region-specific concentration and action
Receptor-specific action
| |
IL-6 | Endogenous pyrogen Attraction T lymphocytes | Induction IL-1ra | Reduction IL-6 | |
TGF-β | Increase β-amyloid precursor Increase glial scar formation | Reduction gliosis Less inflammatory mediators Suppressed release ROS Less brain edema Inhibition neutrophil adherence Reduction apoptosis Induction IL-1ra Promotion angiogenesis |
Reflection:
Neuroprotection limited to penumbra
| |
IL-10 | Less release cytokines and expression receptors Attenuation astrocytic activation | |||
2. HMGB Family | HMGB1 | Stimulation inflammatory mediators Activation microglia Increase NF-κB activation | Reduction of brain and plasma HMGB1 Reduction of NF-κB activation | |
3. Chemokines | CINC, MCP-1, MIP-1, MRF-1, fractalkine | Regulation and migration of leukocyte trafficking Stimulation BBB permeability Stimulation phagocytosis Increase cytokine secretion Stimulation apoptosis | Scavenge and repair necrotic tissue Angiogenesis | Downregulation MCP-1 |
4. Free oxygen radicals | ROS, NO | Lipid peroxidation Stimulation inflammatory response Disruption protein biochemistry | Suppressed oxidative stress | |
NO | Induction iron loss of cells Inhibition enzymes DNA replication Stimulation expression inflammatory mediators | Vasodilator | Reduction nNOS No influence iNOS
Reflection:
Different response in acute and chronic phase
| |
5. MMPs | MMP-9 (and -2) | BBB breakdown Stimulation leukocyte adherence and transmigration Vasogenic edema Hemorrhagic transformation | Stimulation plasticity, recovery and repair Clearance necrotic cell debris | Reduction MMP-9 No effect on MMP-2
Reflection:
Contribution to recovery late after injury
|
Adhesion molecules
| ||||
1. Selectins | E- and P-selectin | Slow down neutrophils and monocytes Promotion rolling over endothelium | Inhibition E-selectin | |
P-selectin | Enhancement platelet binding to neutrophils and monocytes | |||
L-selectin | Guide unstimulated leukocytes | No effect on L-selectin | ||
2. CAMs | ICAM-1and2, VCAM-1 | Stronger attachment leukocytes to endothelium Stimulation diapedesis | ||
3. Integrins | LFA-1, Mac-1, CD11c | Stimulation adhesion to endothelium Stimulation conformational changes leukocytes for diapedesis | No effect on LFA-1 Delayed upregulation of Mac-1 and CD11c | |
Cellular inflammatory response
| ||||
1. Glia | Microglia | Phagocytosis to clear dead cells Production inflammatory and cytotoxic mediators | Production neurotrophic factors Facilitation neurogenesis and plasticity Less release toxic mediators Scavenge and removal necrotic debris | Reduction of activation
Reflection:
Different subsets have different roles
|
Astrocytes | Production inflammatory and cytotoxic mediators Production chemokines Formation glial scar tissue Enhancement oxidative stress Release glutamate | Production neurotrophic factors Glial scar isolates damaged tissue | ||
2. Endothelial cells (BBB) | BBB breakdown: Hyperpermeability to macromolecules Vasogenic edema Increase intracranial pressure Stimulation inflammatory mediators and adhesion molecules Astrocyte detachment | Reduction BBB disruption for large molecules | ||
3. Leukocytes | Neutrophils | Release pro-inflammatory and cytotoxic mediators Stimulation lipid peroxidation Release proteolytic enzymes Damage endothelial cell membrane Increase BBB permeability Post-ischemic edema No-reflow phenomenon | Less infiltration | |
Monocytes | Generation superoxide anions Release pro-inflammatory cytokines | Removal necrotic cell debris and neutrophils | Less infiltration |