We now know that stroke-induced damage often takes place long after the initial ischemic event has subsided. I thought a brief overview of some potential mechanisms accounting for this delayed onset damage would be interesting and helpful in understanding this complex process.
Until relatively recently all tissue damage associated with an infarct was presumed to have occurred within the first few hours following the event. After this time, all structural deficits were thought to be fixed, leading to few treatments targeted specifically at mechanisms of delayed damage. More recently, however, it has been shown that delayed mechanisms of damage can significantly increase the degree of tissue damage caused by acute, transient strokes.
Through the use of modern neuroimaging methods, it has been shown that there can be significant growth of the infarct for more that 24 hours after the initial event. Also, other neural damage resulting from the initial stroke has an even longer timeline. These recent elucidations clearly point out the need to better understand delayed mechanisms of damage and provide new brain protective strategies.
One key player, linked to delayed damage associated with acute stroke, is inflammation. Listed are a few of the central arguments for implicating inflammation in the delayed damage mechanism:
1.) Inflammatory cells can be found in the brain after stroke.
2.) Anti-inflammatory strategies can protect against experimental stroke.
3.) Disruption of genes linked to inflammation (iNOS, from posted review article) can protect against stroke.
4.) Inducing brain inflammation causes neural tissue damage.
The stroke-induced inflammatory response is a complex process usually taking place after blood flow has been restored. Reperfusion of the ischemic cells with oxygenated blood (either spontaneous or by means of TPA) induces formation of reactive oxygen species (ROS). These ROS can then stimulate the surrounding cells to secrete inflammatory cytokines, eventually leading to increased leukocyte infiltration into the brain. This type of prolonged stroke-induced inflammation in the brain can result in several detrimental effects. For one, infiltration and aggregation of leukocytes may directly lead to further injury through their secretion of harmful substances. Also, the blood brain barrier can be compromise by the activation of cytotoxic releasing inflammatory cells. This can lead to edema (an accumulation of fluid) in the brain, which can further exacerbate damage caused by low oxygen levels.
Due to the 3-hour timetable for TPA (tissue plasminogen activator) effectiveness, 95% of strokes cannot be treated specifically. Also, a study done by the WHO concluded that the best acute care for stroke patients can only slightly improve outcomes. Both of these statements further justify the continued research towards better understanding the many factors involved in delayed damage mechanisms associated with stroke-induced inflammation.
This accounts for the sudden onset of inflammation following and directly related to a stroke. Has anyone found information regarding chronic systemic inflammation and its role in stroke?
References:
Dirnagl, Ulrich, and Elger, Bernd. "Neuroinflammation in Stroke". Springer, 2004. Pg: 87-95.
Tang, Xian Nan, Wang, Qing, and Yenari, Midori A. "The Inflammatory Response in Stroke". J. Neuroimmunol. 184(1-2): 53-68.
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1 comment:
Im so glad you brought up the notion that inflammation and stroke can be both an acute and a chronic process. Our work and the work of others demonstrate the idea that acute inflammatory mechanisms contributes to injury immediately (minutes-days) after an ischemic stroke.
The other idea, that a chronic inflammatory condition can lead to ongoing damage of the brain after a stroke, or, could be a risk factor for a second stroke, has not been examined as thoroughly. For example, diabetes is now known as a chronic inflammatory disease (among other characteristics). Many inflammatory changes occur in diabetic patients. One of these changes is the cell type we study: the leukocyte. Leukocytes (PMNs) are known to be chronically activated in overweight diabetic patients (perhaps due chronically elevated inflammatory cytokines). We think there is a direct relationship between the extent of chronic inflammation (and PMN activation) and the extent of both acute brain damage after a stroke, as well as the risk for a second stroke. We hope to recieve grant funding to study this hypothesis.
Thanks for the thorough summary of this topic!
L. Ritter
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