Danger Signals in the ICU

Abstract

Objectives: Sterile and infectious critical illnesses often result in vasoplegic shock and a robust systemic inflammatory response that are similar in presentation. The innate immune system is at the center of the response to both infectious and traumatic insults. Damage-associated molecular patterns are small molecules that are released from stressed or dying cells. Damage-associated molecular patterns activate pattern recognition receptors and coordinate the leading edge of the innate immune response. This review introduces the concept of damage-associated molecular patterns and how they activate a systemic inflammatory response, specifically in trauma, neurologic injury, and infection. It also explores how, when carried to extremes, damage-associated molecular patterns may even perpetuate multisystem organ failure.

Data sources: Basic and clinical studies were obtained from a PubMed search through August 2017.

Study selection: Articles considered include original articles, review articles, and conference proceedings.

Data extraction: An analysis of scientific, peer-reviewed data was performed. High quality preclinical and clinical studies adjudicated by the authors were included and summarized.

Data synthesis: Pattern recognition receptors respond to damage-associated molecular patterns and then activate inflammatory pathways. Damage-associated molecular patterns have been linked to the recruitment of sentinel leukocytes and the initiation of the inflammatory cascade. Damage-associated molecular patterns have been linked to many conditions in critical care illnesses. Preclinical models have added insight into how they may mediate distant organ dysfunction.

Conclusions: Damage-associated molecular pattern activation and release is an important research for intensive care practitioners. It will add to our understanding of the phase and state of the innate immune response to an insult. Early work is encouraging. However, only with improved understanding of damage-associated molecular pattern activation and function, we can perhaps hope to target damage-associated molecular patterns as diagnostic and/or therapeutic modalities in the future.

Figure 1

Proposed schema for the pathogenesis of damage-associated molecular pattern (DAMP) and pathogen-associated molecular pattern (PAMP) mediated local and distal organ injury during critical illness. Infection or sterile organ injury such as trauma, or pancreatitis leads to direct initial insult. Infection and local tissue injury releases PAMPs and DAMPs. PAMPs and DAMPs bind Toll-Like Receptors and Pathogen Recognition Receptors with subsequent cytokine and chemokine release. Activation of the innate immune system with neutrophil recruitment and T-cell activationwhich leads to resultant local and distant organ injury.