American Journal of Respiratory and Critical Care Medicine
American Journal of Respiratory and Critical Care Medicine
5 years ago

The Role of Danger Signals in the Pathogenesis and Perpetuation of Critical Illness.

Choi, Ma, Pabon, Schenck
The innate immune system induces inflammation through induction of multiple pathways including the TNFα/NF-κB signaling as well as the NLRP3 inflammasome cascade activation with production of inflammatory molecules. Pathogen associated molecular patterns are immunogenic costimulatory molecules that can activate the innate immune system in the presence of foreign pathogens. These molecularly distinct, foreign, particles initiate inflammatory and cell death cascades of the innate immune response through the binding of pathogen recognition receptors such as toll like receptors. The concept of danger associated molecular patterns was proposed in the 1990s based on observations that noninfectious critical illness produces similar inflammatory reactions. Endogenous danger signals are commonly intracellular molecules, such as nuclear or mitochondrial nucleic acids, that have individual biologic roles in non-inflammatory states. However, once released into the extracellular space, these molecular patterns stimulate the innate immune response through binding of similar pathogen recognition receptors. Excessive release of danger signals during critical illness may create a self-perpetuating cycle of dysregulated inflammation, cell death, and subsequent distal organ injury. Danger signals have been correlated with numerous clinical outcomes in a variety of critical illnesses including sepsis, trauma, ventilator induced lung injury, and cardiac arrest. Here we highlight the most commonly reported endogenous danger signals in both animal and human studies and their potential role in the morbidity and mortality in the intensive care unit. In addition, we discuss current unanswered questions including the elucidation of downstream signaling cascades as well as therapeutic trials modulating the innate immune response through danger signal pathways.

Publisher URL: http://doi.org/10.1164/rccm.201612-2460PP

DOI: 10.1164/rccm.201612-2460PP

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