Low molecular weight hyaluronan from stretched lung enhances IL-8 expression

Mechanical ventilation has been shown to cause ventilator-induced lung injury (VILI), probably by overdistending or stretching the lung. Hyaluronan (HA), a component of the extracellular matrix (ECM), in low molecular weight (LMW) forms has been shown to induce cytokine production. LMW HA is produced by hyaluronan synthase 3 (HAS 3). We found that HAS 3 mRNA expression was upregulated and LMW HA accumulated in an animal model of VILI. We hypothesized that stretch-induced LMW HA production that causes cytokine release in VILI was dependent on HAS 3 mRNA expression. We explored this hypothesis with in vitro lung cell stretch. Cell stretch induced HAS 3 mRNA expression and LMW HA in fibroblasts. Non-specific inhibitors of HAS 3 (cyclohexamide and dexamethasone), a non-specific inhibitor of protein tyrosine kinases, (genistein) and a janus kinase 2 inhibitor (AG490), blocked stretchinduced HAS 3 expression and synthesis of LMW HA. Stretch-induced LMW HA from fibroblasts caused a significant dose-dependent increase in IL-8 production both in static and stretched epithelial cells. These results indicated that de novo synthesis of LMW HA was induced in lung fibroblasts by stretch via tyrosine kinase signaling pathways, and may play a role in augmenting induction of pro-inflammatory cytokines in VILI.