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Low Molecular Weight Hyaluronan from Stretched Lung Enhances Interleukin-8 Expression

Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston; Division of Pulmonary and Critical Care, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts; and Division of Critical Care Medicine, Medellín General Hospital and Pontifical Bolivarian University, Medellín, Colombia

Address correspondence to: Marcella M. Mascarenhas, Ph.D., Pulmonary and Critical Care Unit, Massachusetts General Hospital, 55 Fruit Street, Bulfinch-148, Boston, MA 02114. E-mail: mmascarenhas{at}partners.org

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, 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 that 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. Nonspecific inhibitors of HAS 3 (cyclohexamide and dexamethasone), a nonspecific inhibitor of protein tyrosine kinases (genistein), and a janus kinase 2 inhibitor (AG490) blocked stretch-induced HAS 3 expression and synthesis of LMW HA. Stretch-induced LMW HA from fibroblasts caused a significant dose-dependent increase in interleukin-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 proinflammatory cytokines in VILI.

Abbreviations: acute respiratory distress syndrome, ARDS • chondroitin sulfate, CS • extracellular matrix, ECM • extracellular signal–regulated kinase, ERK • hyaluronan, HA • hyaluronan synthase 3, HAS 3 • Hanks' buffered saline solution, HBSS • high molecular weight, HMW • interleukin, IL • Janus kinase, JAK • low molecular weight, LMW • lipopolysaccharide, LPS • macrophage inflammatory protein, MIP • polymerase chain reaction, PCR • proteoglycans, PGs • reverse transcription, RT • ventilator-induced lung injury, VILI

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