Physiology of Brain InjuryCytokines and Perinatal Brain Damage
Section snippets
Infection distant from the brain can damage the developing brain
In a study completed more than 40 years ago, infants who had bacteria recovered from their cardiac blood at postmortem examination were estimated to be 34 times more likely to have histologic white matter damage than infants whose cardiac blood was sterile.6 No bacteria were found in the brain of any infant who had cerebral white matter damage. These observations led to the hypothesis that a circulating, noninfectious product of inflammation could lead to brain damage. The investigators tested
Which cytokines might be involved?
Cytokines, chemokines, and growth factors are ubiquitous signaling molecules that help orchestrate almost all bodily functions of growth and development and acute responses, such as fever and inflammation. An important aspect of cytokine biology is the high degree of overlap in source, target cell, and function. This redundancy makes it difficult to identify individual cytokines as “most important” in specific settings. In addition, some cytokines can have apparently contradicting functions.
Proposed mechanisms
Just as context is important for which cytokines are involved in perinatal brain damage causation, it is also important for how they might be involved. By this we refer to the experimental paradigm used to study cytokine actions in animal experiments of perinatal brain damage causation.
The following are examples of intricacies that should be kept in mind. First, the cytokine cascade in experimentally induced ischemia might differ in quality and in quantity from the cytokine response to
Two faces of neuroinflammation
What has recently been called the “dual role of inflammation in CNS disease”150 incorporates aspects of what we refer to as the interplay between proinflammatory challenge and endogenous protection responses.3 Multiple aspects of neuroimmune responses in the brain might help explain the purported ambivalent role of inflammation in the CNS, which is still not unanimously accepted in the neuroimmunology community.151 First, it is increasingly recognized that the immune system and the CNS overlap
Potential initiators of inflammation in fetuses and neonates
Some of the earliest experiments linking infection and cerebral white matter damage involved exposure of immature animals to endotoxin, or LPS. LPS binding to specific toll-like receptors (TLR) constitutes an early molecular event leading from endotoxin exposure to inflammation. The binding of endotoxin to TLR activates signal-transduction pathways that induce the expression of genes coding for various immune-response proteins, such as inflammatory cytokines. TLR and other pattern recognition
Genetic susceptibility to inflammation-related brain damage
There is increasing evidence that inherited cytokine or chemokine polymorphisms influence the risk for pre- and perinatal brain damage.179 Included are polymorphisms of genes regulating expression of proinflammatory cytokines and chemokines along with anti-inflammatory cytokines. Increased production of TNF-α is associated with an SNP at position −308 in the promoter region of the TNF-α gene. Patients who have this SNP have a sevenfold increase in the risk for central nervous system malaria180
Summary
More than 30 years ago, evidence from epidemiologic studies and experiments in animals indicated that infection remote from the brain is a potential cause of cerebral white matter damage in human neonates. Since that time, a large body of evidence has accumulated suggesting that the link between infection and brain damage involves various mediators of inflammation, including cytokines, chemokines, and immune cells. Inflammatory mediators also are involved in brain-damaging processes that follow
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