Bench-to-bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury

Maria T Kuipers, Tom van der Poll, Marcus J Schultz, Catharina W Wieland, Maria T Kuipers, Tom van der Poll, Marcus J Schultz, Catharina W Wieland

Abstract

Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non-infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill.

Figures

Figure 1
Figure 1
Damage-associated molecular patterns and Toll-like receptors. Toll-like receptor (TLR) signaling is illustrated as discussed in the text. TLR2 (in association with TLR1 or TLR6) and TLR4 are located at the cell surface. TLR3, TLR7/8 and TLR9 are found in the endosome. All TLRs except TLR3 recruit myeloid-differentiation primary response protein 88 (MyD88) as an adaptor protein, TLR3 and TLR4 recruit Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) protein. TLR signaling pathways lead to NF-κB activation and/or type I interferon (IFN) expression. Endogenous TLR activators are listed based on the receptors they can activate. HMGB1, high-mobility group box-1; IRF, interferon regulatory factor; LDL, low-density lipoprotein; ssRNA, single-strand RNA.
Figure 2
Figure 2
Damage-associated molecular patterns and the NLRP3 inflammasome. The NLRP3 inflammasome is a multiprotein complex with an important role in the production of mature IL-1β and IL-18. Activation of NF-κB - for example, via Toll-like receptor (TLR) signaling - is necessary for the production of pro-IL-1β and pro-IL-18 (signal 1). Pathogen-derived factors as well as damage-associated molecular patterns (DAMPs) - including uric acid, ATP, biglycan, and hyaluronan (HA) - can activate NLRP3 (signal 2). How these various stimuli activate NLRP3 is not completely elucidated. Three intracellular features are associated with NLRP3 activation: (a) potassium efflux, (b) increased reactive oxygen species (ROS) levels, and (c) lysosomal damage and the release of cathepsin B. Catabolism of HA leads to the release of small oligosaccharide fragments. How these fragments exactly activate NLRP3 is unclear. Activated NLRP3 assembles with adaptor protein apoptosis-associated speck-like protein (ASC) and pro-caspase-1 to form active caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their mature form. MyD88, myeloid-differentiation primary response protein 88.

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