Review articleThe inflammatory response in stroke
Introduction
Stroke is one of the most frequent causes of death and disability worldwide, and has significant clinical and socioeconomic impact. Although different mechanisms are involved in the pathogenesis of stroke, there is increasing evidence showing that inflammation accounts for its progression, at least acutely (Barone and Feuerstein, 1999, Chamorro and Hallenbeck, 2006, Samson et al., 2005). A robust inflammatory reaction characterized by peripheral leukocyte influx into the cerebral parenchyma and activation of endogenous microglia follows focal cerebral ischemia (Becker, 1998, Davies et al., 1998, Hallenbeck, 1996, Morioka et al., 1993, Zheng and Yenari, 2004). Cessation of cerebral blood flow leads to energy depletion and necrotic neuron death, which can trigger immune responses ultimately leading to inflammatory cell activation and infiltration. Reperfusion of the occluded vessel, either due to compensation by the collateral circulation, or spontaneous or therapeutic recanalization leads to the generation of reactive oxygen species (ROS) either by reperfusion with oxygenated blood or production within brain and immune cells. ROS can then stimulate ischemic cells, even ischemic neurons, to secrete inflammatory cytokines and chemokines that cause, among other things, adhesion molecule upregulation in the cerebral vasculature and peripheral leukocyte recruitment, respectively. Once activated, inflammatory cells can release a variety of cytotoxic agents including more cytokines, matrix metalloproteinases (MMPs), nitric oxide (NO) and more ROS (Fig. 1). These substances may induce more cell damage as well as disruption of the blood-brain barrier (BBB) and extracellular matrix ((Danton and Dietrich, 2003, Emsley and Tyrrell, 2002). BBB disruption can further potentiate brain tissue injury and contribute to secondary ischemic brain damage by permitting serum elements and blood to enter the brain (Rosenberg, 1999, Siesjo and Siesjo, 1996). Secondary damage develops as a consequence of brain edema, post-ischemic microvascular stasis and vasomotor/hemodynamic deficits leading to hypoperfusion and post-ischemic inflammation, thus involving activation of microglia and brain infiltration of peripheral inflammatory cells (Dirnagl et al., 1999, Siesjo and Siesjo, 1996). This type of migration of peripheral circulating leukocytes into the brain could produce an amplification of inflammatory signal cascades, which will enhance the damage. These processes are especially pronounced during reperfusion when previously occluded vessels are opened and lead to massive influx of ROS and leukocytes into injured brain. Blocking various aspects of the inflammatory cascade has shown to ameliorate injury from experimental stroke (Han and Yenari, 2003), although this has yet to be demonstrated at the clinical level (Becker et al., 2001).
During the past few years, progress has been made towards identifying the roles of important inflammatory signaling molecules, cells and proteins in the process of initiation and development of post-ischemic inflammation. This review focuses on current findings and provides an update on the understanding of post-ischemic inflammation.
Section snippets
Cellular response to ischemic stroke
Inflammation is characterized by the accumulation of inflammatory cells and mediators in the ischemic brain. After ischemia onset, inflammatory cells such as blood-derived leukocytes and microglia are activated and accumulate within the brain tissue subsequently leading to inflammatory injury. Increasing evidence shows that astrocytes may also act as inflammatory cells responding to ischemic stroke.
Adhesion molecules
Adhesion molecules play a pivotal role in the infiltration of leukocytes into the brain parenchyma after stroke and may represent important therapeutic targets (see recent review by (Sughrue et al., 2004). Three major steps, rolling and adhesion and transendothelial migration of leukocytes, are involved in the access of leukocytes to the brain through the endothelial wall. Activated leukocytes, especially neutrophils, result in further damage of ischemic lesions through reperfusion or secondary
Cytokines
Cytokines are upregulated in the brain after a variety of insults including stroke, and are expressed not only in cells of the immune system, but production by resident brain cells, including glia and neurons, have been observed (Liu et al., 1994, Sairanen et al., 2001). The most studied cytokines related to inflammation in stroke are interleukin-1 (IL-1), TNF-α, interleukin-6 (IL-6), interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) (Han and Yenari, 2003). Among those cytokines,
Transcriptional regulation of inflammation
It is now well recognized that cerebral ischemia upregulates gene expression. Activation of several transcription factors has been documented in experimental stroke models. Some of these transcription factors are particularly involved in the inflammatory response, and will be discussed here.
Conclusion
Inflammation is increasingly recognized to be the key element in pathological progression of ischemic stroke. Whether inflammation is destructive or beneficial may depend on how severe the ischemia is and the stages of ischemia in which inflammatory responses contribute. Likely, early inflammatory responses may potentiate ischemic injury, while late responses may be important in recovery and repair. Future work should address the optimal timing of inflammation modulating interventions as well
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