Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a major health concern, with high rates of mortality and morbidity and no highly effective clinical interventions. Basic research in animal models of ICH has provided insight into its complex pathology, in particular revealing the role of inflammation in driving neuronal death and neurologic deficits after hemorrhage. The response to ICH occurs in four distinct phases: (1) initial tissue damage and local activation of inflammatory factors, (2) inflammation-driven breakdown of the blood-brain barrier, (3) recruitment of circulating inflammatory cells and subsequent secondary immunopathology, and (4) engagement of tissue repair responses that promote tissue repair and restoration of neurologic function. The development of CNS inflammation occurs over many days after initial hemorrhage and thus may represent an ideal target for treatment of the disease, but further research is required to identify the mechanisms that promote engagement of inflammatory versus anti-inflammatory pathways. In this review, the authors examine how experimental models of ICH have uncovered critical mediators of pathology in each of the four stages of the inflammatory response, and focus on the role of the immune system in these processes.

Fig. 1

Time course of inflammatory and tissue repair responses after intracerebral hemorrhage (ICH). The onset of ICH causes inflammatory cell death, resulting in the release of proinflammatory factors. Neuronal death occurs rapidly after hemorrhage and continues for the first 3 days posthemorrhage. Expression of factors that regulate the blood–brain barrier (BBB), including matrix metalloproteinases, is first detected at 6 hours post-ICH, and increased BBB permeability is observed for an extended period after hemorrhage. The recruitment of peripheral leukocytes results in significant accumulation of blood-derived macrophages and neutrophils detected at 12 hours post-ICH and peaking at ~24 hours after hemorrhage. At 3 days after hemorrhage, the initiation of pathways involved in tissue repair and hematoma resolution can be detected; however, the duration of these processes remains unclear.