Table 2.
Inflammatory markers associated with HT.
| Early HT (first 18 h of stroke onset) | ||
|---|---|---|
| Inflammatory marker | Source/mechanism | Role in HT |
| ROS (increase) | Intracellular mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase xanthine oxidases, cellular membrane receptors inflammatory mediators, astrocytes | Disrupt the NVU (endothelial-pericyte-astrocyte) leading to increase BBB degradation |
| HMGB1 | Microglia, astrocytes | Upregulates MMP-9 via TLR4. TNF, IL-1β |
| Peroxynitrite | Micro vessels, neurons and astrocytic end feet | Activate MMPs, disrupting vascular integrity |
| NF-κB | Astrocytes, microglia, and endothelial cells | Part of neutrophil infiltration pathway, upregulate cell adhesion molecules and inflammatory cytokines. |
| Leukocytes (increase) | Circulating leukocytes adhere to vascular endothelial cells following ischemia. Leukocyte adhesion and migration across the vasculature activates a number of signaling cascades (protein kinase C, focal adhesion kinase) that increase BBB permeability | Signaling cascade increased BBB permeability through ROS and MMP-9 expression. |
| MMP-9 (blood derived) (increase) | Leukocytes (Neutrophils) (not primary source). Mechanisms for MMP-9 activation following ischemia include: (1) ROS (2) TNF, IL-1β, and other cytokines that activate MMP-3 which converts proMMP-9 to active MMP-9 (3) actions of high mobility group box protein1 (HMGB1) on TLR4 receptors that then induce MMP-9 or (4) NF-κB induction of MMP-9 | Luminal side: acts on TJP (tight junction proteins) (claudin-5, occludin, ZO-1) and basal lamina proteins (fibronectin, lamina, collagen), taken into endothelial cells or acts on basal lamina to open the BBB. Inside brain: Neutrophils can release MMPs that act directly on TJPs and/or basal lamina to disrupt the NVU (endothelial-pericyte-astrocyte) |
| MMP-2 (brain derived) (increase) remains elevated for days post-stroke | Astrocytes, endothelial cells and leukocytes | MMP-2 mediates degradation of occludin (tight junction protein) |
| Leukocyte gene expression | Six genes identified through mRNA expression: amphiregulin (AREG), membrane-associated ring finger (C3HC4) 7 (MARCH7), SMAD family member 4 (SMAD4), inositol polyphosphate-5-phosphatase (INPP5D), multiple coagulation factor deficiency 2 (MCFD2) and vascular endothelial growth inhibitor (VEGI) | |
| Late HT (18–24 h of stroke onset) | ||
| Source | Role | |
| MMP-9 (Brain derived) (Increase) | MMP-9: astrocytes, neurons, microglia and endothelial cells. Activated by from ROS, TNF and IL-1β, HMGB1, NF-κB induction | Disruption of BBB |
| MMP-3 (Brain derived) (Increase) | MMP-3: pericytes and endothelial cells. MMP-3 acts on proMMP-9 to produce active MMP-9 and thus may promote HT | Disruption of BBB |
| Role of Vascular Remodeling | • A number of growth factors, MMPs and other molecules form new vessels and NVU • VEGF plays an important role in vascular remodeling and angiogenesis |
VEGF: early, promotes BBB disruption; later promotes BBB integrity and vascular function. MMPs: Promote new vessel formation and increased pericyte/endothelial expression of tight junction proteins (ZO-1, occludin, claudin-5) HMGB1: acts on endothelial progenitor cells to promote peri-infarct angiogenesis (beneficial role) |
| ROS | Act as signaling molecules to regulate cell growth, differentiation and angiogenesis. | |
BBB, blood-brain barrier; HMGB1, high mobility group box protein 1; IL, interleukin; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; NVU, neurovascular unit; ROS, reactive oxygen species; TLR, toll like receptor; TNF, tumor necrosis factor; TJP, tight junction protein; VEGF, vascular endothelial growth factor.