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  • Preclinical and clinical research indicates that inflammatio


    Preclinical and clinical research indicates that inflammation contributes to the progression of ICH injury. Therefore, there is a pressing need to develop interventions that can limit neuroinflammation and its detrimental effects on ML133 HCl pathway function. Inflammatory cytokines are secreted in the brain tissue after ICH, and growing evidence suggests that inflammatory reactions and cytokines play a very important role in the secondary injury process of ICH (Lan et al., 2017b, Wang, 2010, Wang and Dore, 2007b, Wu et al., 2010b, Zhou et al., 2014). Thus, modulating these cytokines may represent a new direction for the treatment of ICH (Chen et al., 2015c, Lan et al., 2017b, Wang, 2010). This review analyzes several cytokines involved in secondary injury after ICH that may be helpful for providing individualized clinical treatment and prognostication.
    The mechanism of ICH-induced brain injury
    Mechanism of inflammatory injury after ICH Inflammatory reactions contribute to the damage and repair of brain tissues after ICH (Lan et al., 2017b, Wang, 2010). Most research studies on inflammatory reactions in ICH have used animal models that are generated by cerebral injection of either collagenase or autologous blood, although both have shortcomings (Lan et al., 2017b, Mracsko and Veltkamp, 2014, Wang and Dore, 2007b, Zhu et al., 2014). Injection of autologous blood creates a single, large hematoma, but it cannot mimic rebleeding (MacLellan et al., 2008, Zhang et al., 2017). Injection of collagenase destroys the basement membrane of the small intracranial vessels, resulting in persistent bleeding, hematoma expansion (Wang and Dore, 2007b, Wang et al., 2015b), and increased intracranial pressure (Hiploylee and Colbourne, 2014) that resemble the conditions of clinical ICH (Lan et al., 2017b). Inflammation is a complex process that is mediated mainly by cellular and molecular components (Wang and Dore, 2007b). The cellular components include leukocytes, macrophages, astrocytes, T-cells, and microglia, whereas molecular components comprise prostaglandins, chemokines, cytokines, extracellular proteases, and ROS (Mracsko and Veltkamp, 2014, Wang, 2010, Wang and Dore, 2007b). After ICH, plasma proteins (thrombin, plasmin, fibrinogen, etc.) and hematoma components are released into brain tissue where they activate the complement (Hua et al., 2000), stress (Duan et al., 2016), hemostasis (Babu et al., 2012), and immune systems (Pennypacker, 2014). Together, these systems lead to inflammatory reactions, including inflammatory cell recruitment and activation, as well as inflammatory media release, which contributes to brain tissue injury and repair (Wang, 2010, Wang and Dore, 2007b, Wang and Tsirka, 2005a).
    Inflammatory cytokines in ICH secondary injury
    Strategies with potential translation from the laboratory to the clinic Inflammation is a dynamic process of injury and repair that responds to various stress and damage factors. Significant changes in cytokines associated with the basic inflammatory pathology occur in the ICH brain and may serve as new therapeutic targets (Chang et al., 2017, Lan et al., 2017b, Zhang et al., 2017). However, excessive inhibition of inflammation after ICH not only increases the risk of infection (Tapia-Perez et al., 2016), but also delays hematoma clearance and tissue repair (Zhang et al., 2017). Enhancement of overall inflammatory response will aggravate secondary brain injury after ICH (Zhou et al., 2014). Therefore, the key point of the therapeutic strategy is to regulate the balance of the proinflammatory and anti-inflammatory response in order to reduce brain damage and promote brain repair. This strategy can be achieved by increasing the anti-inflammatory cytokines and/or decreasing the proinflammatory cytokines. To date, research into the reduction of ICH injury by altering these cytokines has been conducted mostly in rodent models. Although these studies have focused on only a few cytokines, it is clear that the inhibition of proinflammatory cytokines or augmentation of anti-inflammatory cytokines can alleviate inflammatory reactions, reduce brain edema, increase stability of the BBB, reduce brain injury, and improve neurologic function (King et al., 2011, Lu et al., 2014, Masada et al., 2003, Mayne et al., 2001, Sinn et al., 2007, Yang et al., 2014). These animal studies are summarized in Table 2.