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

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.

COVID-19 infection: the perspectives on immune responses

“…Although the nature of the clear jelly has yet to be determined, hyaluronan (HA) is associated with ARDS [12]; moreover, during SARS infection, the production and regulation of hyaluronan is defective. The levels of inflammatory cytokines (IL-1, TNF) are high in the lungs of COVID-19 patients and these cytokines are strong inducers of HA-synthase-2 (HAS2) in CD31 + endothelium, EpCAM + lung alveolar epithelial cells, and fibroblasts [13]. Importantly, HA has the ability to absorb water up to 1000 times its molecular weight.…”

Systematic review of COVID-19 autopsies: accelerated hyaluronan concentration as the primary driver of morbidity and mortality in high-risk COVID-19 patients: with therapeutic introduction of an oral hyaluronan inhibitor in the prevention of “Induced Hyaluronan Storm” Syndrome

“…Stating that "hyaluronic acid is the most powerful water(edema)-binding substance in the body", they put forth a "humoral" and "biochemical-physiological" hypothesis of ARDS [9] . Others have recently detailed the central role of hyaluronic acid in human respiratory disease, in which viral infections lead to marked and rapid increase in hyaluronic acid concentrations [10]- [12] .…”

Hyaluronan and Its Interactions With Immune Cells in the Healthy and Inflamed Lung

“…In the lung, the concentration of HA is elevated in the BALF of patients suffering from asthma ( 14 ), chronic obstructive pulmonary disease ( 48 ), interstitial pulmonary fibrosis ( 49 ), and other lung diseases [reviewed in ( 43 , 44 )]. In animal models, HA is upregulated in the bleomycin model of sterile injury ( 19 , 50 ), asthma (ova and cockroach allergen) ( 11 , 51 ), ozone-induced airway hyperreactivity ( 52 ), LPS-induced acute lung injury, and Escherichia coli ( 53 ), Klebsiella pneumoniae ( 54 ), or Influenza infection ( 55 ).…”

“…During this recovery period, the lung is more susceptible to bacterial infections. Recent work found that HA levels remain high in the lung tissue due to elevated HAS2 expression in epithelial, endothelial, and fibroblast cells ( 55 ). TSG-6 levels are also elevated and this generates a HC-modified HA matrix ( 55 ).…”

“…Recent work found that HA levels remain high in the lung tissue due to elevated HAS2 expression in epithelial, endothelial, and fibroblast cells ( 55 ). TSG-6 levels are also elevated and this generates a HC-modified HA matrix ( 55 ). Interestingly, a single dose of hyaluronidase at day 6 after influenza infection reduces the HA content in the lung, reduces the number of F4/80 + CD11b + CD11c lo macrophages and improves lung function at day 16 ( 55 ).…”