Preclinical and clinical research on inflammation after intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is one of the most lethal stroke subtypes. Despite the high morbidity and mortality associated with ICH, its pathophysiology has not been investigated as well as that of ischemic stroke. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. For example, in preclinical ICH models, microglial activation has been shown to occur within 1 h, much earlier than neutrophil infiltration. Recent advances in our understanding of neuroinflammatory pathways have revealed several new molecular targets, and related therapeutic strategies have been tested in preclinical ICH models. This review summarizes recent progress made in preclinical models of ICH, surveys preclinical and clinical studies of inflammatory cells (leukocytes, macrophages, microglia, and astrocytes) and inflammatory mediators (matrix metalloproteinases, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron), and highlights the emerging areas of therapeutic promise.

Introduction

Intracerebral hemorrhage (ICH) results when a weakened blood vessel ruptures and bleeds into the surrounding brain. Spontaneous ICH accounts for 15–20% of all strokes and affects more than 2 million people worldwide each year (Qureshi et al., 2009, Ribo and Grotta, 2006). The prevalence of ICH is higher in certain populations, including blacks and Asians (Qureshi et al., 2009). Parts of the brain that are particularly vulnerable to ICH include the basal ganglia, cerebellum, brainstem, and cortex. Most cases of ICH are caused by primary hypertensive arteriolosclerosis and amyloid angiopathy (reviewed in Mayer and Rincon, 2005, Sutherland and Auer, 2006). Secondary ICH accounts for 15–20% of patients and usually results from vascular malformation, neoplasia, coagulopathy, and the use of thrombolysis in ischemic stroke (reviewed in Mayer and Rincon, 2005, Sutherland and Auer, 2006, Wang and Tsirka, 2005a). No matter the cause, the extravasated blood compresses the surrounding brain tissue, increasing the intracranial pressure. The prevalence of ICH is expected to increase slightly as improvements in blood pressure management are counteracted by the trends that favor ICH incidence, such as population aging, increasing use of thrombolytics and anticoagulants, and lack of effective prevention for cerebral amyloid angiopathy in the elderly.

The incidence of fatality is much higher among individuals who suffer ICH than among those who experience ischemic stroke. Those who do survive usually experience long-term physical and mental disability, although some patients can recover most neurologic function. Treatment for ICH is primarily support and control of general medical risk factors. The prognosis of ICH depends on the location, amount of bleeding, extent of subsequent brain swelling, the level of consciousness at admission, concomitant diseases, and the age of the patient. Interestingly, the data from a recent clinical ICH study indicate that the degree of perihematomal edema and subsequent edema expansion are positively correlated with the underlying hematoma size but are not major independent determinants in the outcome (Arima et al., 2009).

Although ICH research has received far less attention than has ischemic stroke (Donnan et al., 2010, NINDS, 2005), during the past few years, progress has been made toward identifying the roles of inflammatory signaling molecules, cells, and proteins in initiation and progression of post-ICH inflammation. We and others have reviewed the roles of cytokines, proteases, and reactive oxygen species (ROS) in ICH-induced brain injury (Aronowski and Hall, 2005, Wang and Doré, 2007b, Wang and Tsirka, 2005a, Xi et al., 2006). A recent review has highlighted the important functions of complement activation in ICH (Ducruet et al., 2009). The focus of this review will be primarily on recent progress made in the use of preclinical ICH models, understanding the changes in cellular components (leukocytes, microglia/macrophages, and astrocytes) and inflammatory mediators [matrix metalloproteinases (MMPs), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase (HO), and iron toxicity], and emerging opportunities for novel therapeutic strategies such as stem cell therapy.