Little is known about the impact of viral infections on lung matrix despite its important contribution to mechanical stability and structural support. The composition of matrix also indirectly controls inflammation by influencing cell adhesion, migration, survival, proliferation and differentiation. Hyaluronan is a significant component of the lung extracellular matrix and production and degradation must be carefully balanced. We have discovered an imbalance in hyaluronan production following resolution of a severe lung influenza virus infection, driven by hyaluronan synthase 2 from epithelial cells, endothelial cells and fibroblasts. Furthermore hyaluronan is complexed with inter-α-inhibitor heavy chains due to elevated TNF-stimulated gene 6 expression and sequesters CD44-expressing macrophages. We show that intranasal administration of exogenous hyaluronidase is sufficient to release inter-α-inhibitor heavy chains, reduce lung hyaluronan content and restore lung function. Hyaluronidase is already used to facilitate dispersion of co-injected materials in the clinic. It is therefore feasible that fibrotic changes following severe lung infection and inflammation could be overcome by targeting abnormal matrix production. Highlights • Influenza causes prolonged changes in hyaluronan due to increased synthase activity • Influenza induces persistent hyaluronan cross-linking by inter-alpha-inhibitor heavy chains • Pockets of persistent hyaluronan are associated with CD44-expressing macrophages • Digestion of hyaluronan with intranasal hyaluronidase restores lung function but upon cessation of treatment post-viral complications return
【저자키워드】 HA, hyaluronidase, HA synthase 2; 4MU, 4-methylumbelliferone; HYAL, hyaluronan; Has2,