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.
Highlights
Extracellular matrix provides physical support to tissues and orchestrates the differentiation, proliferation, migration, positioning and survival of resident and infiltrating immune cells
Using a self-resolving influenza infection model we show that hyaluronan persists due to HA-synthase 2 activity in non-immune cells, that macrophages are trapped within this matrix, that HA is significantly modified by addition of HCs from IαI and that the system can be reversed, leading to improved lung function, by administration of haluronidase intransally
We assessed whether hyaluronan accumulation was dependent on the severity of disease or the type of airway infection. 2, 5 or 8 plaque forming units of influenza A PR8 infection produced weight loss of different severity as expected (Fig. 1C)
Summary
Extracellular matrix provides physical support to tissues and orchestrates the differentiation, proliferation, migration, positioning and survival of resident and infiltrating immune cells. Organ-specific matrices provide tissue-specific training of cells that reside within; an interaction that changes profoundly during the tissue destruction and remodelling that occurs in many lung pathologies [1]. Hyaluronan (HA) is a glycosaminoglycan component of the extracellular matrix found at high concentrations in the lung [2,3,4,5]. In conditions of endoplasmic stress, viral infections, hyperglycaemia and adrenergic receptor stimulation, HA can form cable-like structures that disrupt tissue architecture and are more adhesive to inflammatory cells [11]
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