The Role of Hyaluronan Synthase 3 in Ventilator-induced Lung Injury

• Published in: American journal of respiratory and critical care medicine Vol. 172; no. 1; pp. 92 - 98
• Main Authors: Bai, Kuan-Jen, Spicer, Andrew P, Mascarenhas, Marcella M, Yu, Lunyin, Ochoa, Cristhiaan D, Garg, Hari G, Quinn, Deborah A
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 01.07.2005; American Lung Association; American Thoracic Society
• Subjects: Algorithms; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Chemokine CXCL2; D. Critical Care; Disease Models, Animal; Emergency and intensive respiratory care; Female; Glucuronosyltransferase - biosynthesis; Glucuronosyltransferase - genetics; Hyaluronan Synthases; Injuries of the thorax. Foreign bodies. Diseases due to physical agents; Intensive care medicine; Interleukin-8 - metabolism; Lung - enzymology; Lung Diseases - enzymology; Lung Diseases - etiology; Lung Injury; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Monokines - metabolism; Respiration, Artificial - adverse effects; Tidal Volume; Traumas. Diseases due to physical agents; Lung disease; Ventilator; Intensive care; knockout mice; Respiratory disease; Enzyme; Rodentia; Tidal volume; Synthase; Vertebrata; Mammalia; Mouse; Healing agent; Animal; Glycosaminoglycan; Antirheumatic agent; Hyaluronic acid; Mechanical ventilation; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200405-652OC

We recently found that low-molecular-weight hyaluronan was induced by cyclic stretch in lung fibroblasts and accumulated in lungs from animals with ventilator-induced lung injury. The low-molecular-weight hyaluronan produced by stretch increased interleukin-8 production in epithelial cells, and was accompanied by an upregulation of hyaluronan synthase-3 mRNA. We hypothesized that low-molecular-weight hyaluronan induced by high VT was dependent on hyaluronan synthase 3, and was associated with ventilator-induced lung injury. Effects of high VT ventilation in C57BL/6 wild-type and hyaluronan synthase-3 knockout mice were compared. Significantly increased neutrophil infiltration, macrophage inflammatory protein-2 production, and lung microvascular leak were found in wild-type animals ventilated with high VT. These reactions were significantly reduced in hyaluronan synthase-3 knockout mice, except the capillary leak. Wild-type mice ventilated with high VT were found to have increased low-molecular-weight hyaluronan in lung tissues and concomitant increased expression of hyaluronan synthase-3 mRNA, neither of which was found in hyaluronan synthase-3 knockout mice. We conclude that high VT induced low-molecular-weight hyaluronan production is dependent on de novo synthesis through hyaluronan synthase 3, and plays a role in the inflammatory response of ventilator-induced lung injury.