Rationale for sequential extracorporeal therapy (SET) in sepsis

Table 3 Table 3

	Origin	Release mechanism	PRRs
Intracellular
ATP	Mitochondria	Injury	P2X₇
heat shock proteins	Cytosol	Apoptosis, necrosis	TLR2, TLR4, CD91
Histones	Nucleus	Apoptosis, necrosis	TLR2, TLR4, NLRP3
HMGB1	Nucleus, autophagosome	Apoptosis, necrosis, injury	TLR2, TLR4, TLR9, RAGE
mtDNA	Mitochondria	Trauma, injury	TLR9
Extracellular
Biglycan	Proteoglycan	MMP cleavage, de novo synthesis	TLR2, TLR4, NLRP3
Decorin	Proteoglycan	MMP cleavage, de novo synthesis	TLR2, TLR4
Fibrinogen	Extracellular matrix glycoprotein	Extravasation	TLR4
Fibronectin	Extracellular matrix glycoprotein	Metalloprotease, splicing, unfolding	TLR2, TLR4
Heparane sulphate	Glycosaminoglycan	Heparanase cleavage	TLR4, RAGE

Adapted from Frevert et al. [59]. The table summarises a selection of DAMPs that promote both adaptive and innate immunity signalling and inflammation. DAMPs represent endogenous sterile stimuli, which are released either from dying cells (e.g. histones, HMGB1) or the extracellular matrix (e.g. fibrinogen, fibronectin) and act through direct interaction with TLRs. The activation of TLRs triggers inflammation through the production of proinflammatory mediators and the recruitment of leukocytes to infection and injury sites
CD cluster of differentiation, DAMPs damage-associated molecular patterns, HMGB1 high-mobility group protein B1, mtDNA mitochondrial DNA, NLRP3 NOD-like receptor pyrin domain-containing 3, PRRs pattern recognition receptors, RAGE receptor for advanced glycation end products, TLRs toll-like receptors

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