The inflammatory response in stroke

Abstract

Recent works in the area of stroke and brain ischemia has demonstrated the significance of the inflammatory response accompanying necrotic brain injury. Acutely, this response appears to contribute to ischemic pathology, and anti-inflammatory strategies have become popular. This chapter will discuss the current knowledge of the contribution of systemic and local inflammation in experimental stroke. It will review the role of specific cell types including leukocytes, endothelium, glia, microglia, the extracellular matrix and neurons. Intracellular inflammatory signaling pathways such as nuclear factor kappa beta and mitogen-activated protein kinases, and mediators produced by inflammatory cells such as cytokines, chemokines, reactive oxygen species and arachidonic acid metabolites will be reviewed as well as the potential for therapy in stroke and hypoxic-ischemic injury.

Figure 1. Inflammation following stroke

Brain ischemia is triggers inflammatory responses due to the presence of necrotic cells, generation of reactive oxygen species (ROS) and production of inflammatory cytokines even within neurons. These initiators lead to microglial activation which produce more cytokines causing upregulation of adhesion molecules in the cerebral vasculature. Chemokines lead to inflammatory cell chemotaxis to ischemic brain. Adhesion molecules mediate adhesion of circulating leukocytes to vascular endothelia and infiltration into the brain parenchyma. Once in the brain, activated leukocytes and microglia produce a variety of inflammatory mediators such as matrix metalloproteinases (MMPs), inducible nitric oxide synthase (iNOS) which generates nitric oxide (NO), cytokines and more ROS which lead to brain edema, hemorrhage and ultimately, cell death. MMPs are thought to mediate extracellular matrix disruption, a key event in brain edema and hemorrhage.

Figure 2. Ischemic activation of the arachidonic acid cascade

In the setting of cerebral ischemia, excess intracellular calcium (Ca_i²⁺) activates various lipases, including phospholipase A2 (PLA2) and phospholipase C (PLC) which breakdown both intracellular and membrane phospholipids and release arachidonic acid (AA). Both the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways are activated. The COX pathway converts AA to prostaglandin H2 (PGH2), a precursor prostaglandin. PGH2 is then metabolized to various eicosanoids, including prostacyclin (PGI2), thromboxane A2 (TXA2), prostaglandin E2 and prostaglandin D2. Eicosanoid family members have been shown to exert potent effect on brain vasomotor regulation and increase microvascular and BBB permeability. In the brain, they can act as neutrophil chemoattractants. AA can be also converted to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) by LOX-5. 5-HPETE is then metabolized to leukotriene A4 (LTA4) and B4 (LTB4). LTA4 is a precursor of cysteinyl leukotrienes (cysLTs). cysLTs are converted sequentially to leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene E4 (LTE4). Leukotrienes play multiple roles to mediate events such as chemoattraction, brain edema and BBB permeability.