Inflammation in brain contusion

Detta är en avhandling från Stockholm : Karolinska Institutet, -

Sammanfattning: The immune system is essential for host defense against microbial pathogens and for wound healing processes. Inflammatory reactions, however, invariably cause tissue damage. Intracerebral inflammatory processes are known to be pathogenically important in condi tions such as multiple sclerosis and infectious meningitis, but they have not been extensive ly studied in traumatic brain injuries (TBI). Contusions are a form of TBI that frequently leads to delayed neurological deterioration. This study was undertaken to explore whether intracerebral inflammatory processes occur following cerebral contusions and to analyze the pathophysiological role of such processes. A maximal inflammatory response with infiltration of monocytes/macrophages, CD4 and CD8 positive T-lymphocytes, NK-cells, and MHC-II expression was detected four to six days after experimentally-induced contusions of the rat brain. Production of the proinflam matory cytokines interleukin (IL) -1-beta, tumor necrosis factor (TNF) -alpha and IL-6 showed similar temporal profiles, with maximal levels on day six after the trauma. Inflammatory activation persisted at least three months after the trauma. The development of edema was biphasic. The first peak occurred one day after the trauma. The second peak was detected five to seven days after the trauma and thus correlated in time with maximal inflammation. Anti-inflammatory treatment with dexamethasone, colchicine or chloroquine during the posttraumatic phase reduced inflammation and the delayed phase of edema. Cellular DNA-fragmentation in the perilesional zone, indicative of cell death, persisted for at least six days after the trauma. Microinjections of IL-1-beta into normal rat brain induced transient and dose-dependent neuronal DNA-fragmentation, encephalitis and vasogenic edema. Infiltrating inflammatory cells that strongly expressed nitric oxide synthase of the neuronal isoform correlated anatom ically and temporally with neuronal DNA-fragmentation, indicating a possible role of nitric oxide in mediating neuronal cytotoxicity. Microinjections of TNF-alpha caused a less pro nounced but more protracted vasogenic edema than IL-1-beta. Thus, these cytokines induced some of the pathogenic effects seen after contusions. Brain biopsies from patients undergoing surgery because of cerebral contusions were examined. We found intracerebral inflammation with monocytes/macrophages, CD4 and CD8 positive T-lymphocytes, MHC-II expression and IL-1-beta expression. The inflamma tion was more pronounced in patients who underwent surgery on days three to five than in those operated on within 24 hours after the trauma. Since the findings in humans and rodents are similar, the results of our experiments may be applicable also to man. The present study demonstrates that a pathogenically important delayed intracerebral inflammatory reaction occurs following cerebral contusions. The maximal inflammatory response correlates in time with a delayed deterioration frequently seen in the first week after a contusion. The persisting inflammatory activation also makes long-term effects on CNS physiology possible. Pharmacological modulation of the inflammatory response may improve the outcome.

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