Published ahead of print on March 24, 2005, doi:10.1164/rccm.200405-652OC Am. J. Respir. Crit. Care Med., Volume 172, Number 1, July 2005, 92-98 A more recent version of this article appeared on July 1, 2005
Submitted on May 19, 2004 The Role of Hyaluronan Synthase 3 in Ventilator-Induced Lung InjuryKuan-Jen Bai1,1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Taipei Medical University, Wan-Fang Hospital, Taipei, Taiwan; Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 2 Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, TX, USA, 3 Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA * To whom correspondence should be addressed. E-mail: dquinn1{at}partners.org.
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 tidal volume was dependent on hyaluronan synthase 3, and was associated with ventilator-induced lung injury. Effects of high tidal volume 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 tidal volume. These reactions were significantly reduced in hyaluronan synthase 3 knockout mice, except the capillary leak. Wild-type mice ventilated with high tidal volume 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 tidal volume 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. Key words: tidal volume, mice, knockout, hyaluronic acid, ventilators
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