Defective lung function following influenza virus is due to prolonged, reversible hyaluronan synthesis

TLDR

Viral infections can alter lung extracellular matrix, which is essential for mechanical stability and modulates inflammation, yet the role of hyaluronan—a key matrix component whose synthesis and degradation must be balanced—remains poorly understood, although hyaluronidase is already used clinically to disperse co‑injected materials. Intranasal exogenous hyaluronidase releases inter‑α‑inhibitor heavy chains, lowers lung hyaluronan, and restores lung function. After severe influenza infection, hyaluronan production is imbalanced, driven by hyaluronan synthase 2 from epithelial, endothelial, and fibroblast cells, with hyaluronan complexed with inter‑α‑inhibitor heavy chains that sequester CD44‑expressing macrophages; targeting this abnormal matrix production could reverse fibrotic changes.

Abstract

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.