S100A8/A9 and S100A9 reduce acute lung injury

S100A8 and S100A9 are myeloid cell‐derived proteins that are elevated in several types of inflammatory lung disorders. Pro‐ and anti‐inflammatory properties are reported and these proteins are proposed to activate TLR4. S100A8 and S100A9 can function separately, likely through distinct receptors but a systematic comparison of their effects in vivo are limited. Here we assess inflammation in murine lung following S100A9 and S100A8/A9 inhalation. Unlike S100A8, S100A9 promoted mild neutrophil and lymphocyte influx, possibly mediated in part, by increased mast cell degranulation and selective upregulation of some chemokine genes, particularly CXCL‐10. S100 proteins did not significantly induce proinflammatory mediators including TNF‐α, interleukin‐1β (IL‐1β), IL‐6 or serum amyloid A3 (SAA3). In contrast to S100A8, neither preparation induced S100A8 or IL‐10 mRNA/protein in airway epithelial cells, or in tracheal epithelial cells in vitro. Like S100A8, S100A9 and S100A8/A9 reduced neutrophil influx in acute lung injury provoked by lipopolysaccharide (LPS) challenge but were somewhat less inhibitory, possibly because of differential effects on expression of some chemokines, IL‐1β, SAA3 and IL‐10. Novel common pathways including increased induction of an NAD+‐dependent protein deacetylase sirtuin‐1 that may reduce NF‐κB signalling, and increased STAT3 activation may reduce LPS activation. Results suggest a role for these proteins in normal homeostasis and protective mechanisms in the lung.

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