Abstract
Sepsis remains an important source of morbidity and mortality in children, despite the development of standardized care. In the last decades, there has been an increased interest in genetic and genomic approaches to early recognition and development of treatments to manipulate the host inflammatory response. This review will present a summary of the normal host response to infection and progression to sepsis, followed by highlighting studies with a focus on gene association studies, epigenetics, and genome-wide expression profiling. The susceptibility (or outcome) of sepsis in children has been associated with several polymorphisms of genes broadly involved in inflammation, immunity, and coagulation. More recently, gene expression profiling has been focused on identifying novel biomarkers, pathways and therapeutic targets, and gene expression-based subclassification. Knowledge of a patient’s individual genotype may, in the not-too-remote future, be used to guide tailored treatment for sepsis. However, at present, the impact of genomics remains far from the bedside of critically ill children.
Highlights
Introduction on Critically Ill Septic ChildrenThe unpredictability of response to infection among individuals is one of the most notable characteristics of infectious diseases
It may include the direct effects of the invading microorganisms or their toxic products, release of large quantities of proinflammatory mediators, complement activation, and host factors, as some individuals may be genetically susceptible to developing sepsis [1,2]
Toll-like receptors (TLRs) are going to trigger a signaling cascade, via the activation of cytosolic nuclear factor-kb (NF-kb)—the activated NF-kb will bind to transcription sites, inducing activation of a large set of genes involved in the host inflammatory response, such as proinflammatory cytokines, chemokines, and nitric oxide [2]; Activated polymorphonuclear leukocytes (PMNs) will express adhesion molecules that cause their aggregation and margination to the vascular endothelium—this process will be accelerated by the endothelium expressing adherence molecules to attract leukocytes, followed by a series of steps to migrate to the injury site
Summary
The recognition and binding to microbial components by innate immune cells, by activated macrophages, marks the initiation of the host response to an infection. The binding of immune cell surface receptors to microbial components is responsible for the activation of several processes, including: Toll-like receptors (TLRs) are going to trigger a signaling cascade, via the activation of cytosolic nuclear factor-kb (NF-kb)—the activated NF-kb will bind to transcription sites, inducing activation of a large set of genes involved in the host inflammatory response, such as proinflammatory cytokines (tumor necrosis factor alpha [TNFα], interleukin-1 [IL-1]), chemokines (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]), and nitric oxide [2]; Activated polymorphonuclear leukocytes (PMNs) will express adhesion molecules that cause their aggregation and margination to the vascular endothelium—this process will be accelerated by the endothelium expressing adherence molecules to attract leukocytes, followed by a series of steps (rolling, adhesion, diapedesis, and chemotaxis) to migrate to the injury site. The regulation of the inflammatory processes, including adherence, chemotaxis, phagocytosis of invading bacteria, bacterial damaging, and phagocytosis of debris from injured tissue, is going to depend on the equilibrium of proinflammatory and anti-inflammatory mediators
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