The role of hyaluronan synthase 3 in ventilator-induced lung injury.
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.
Bai
Kuan-Jen
KJ
Pulmonary and Critical Care Unit, Massachusetts General Hospital, 55 Fruit Street, Bulfinch-148, Boston, MA 02114, USA.
Spicer
Andrew P
AP
Mascarenhas
Marcella M
MM
Yu
Lunyin
L
Ochoa
Cristhiaan D
CD
Garg
Hari G
HG
Quinn
Deborah A
DA
D000465:Algorithms; D000818:Animals; D054426:Chemokine CXCL2; D004195:Disease Models, Animal; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics; D000076002:Hyaluronan Synthases; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000201:enzymology*; D008171:Lung Diseases / Q000201:enzymology / Q000209:etiology; D055370:Lung Injury; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015846:Monokines / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D013990:Tidal Volume
D054426:Chemokine CXCL2; D016209:Interleukin-8; D015846:Monokines; D014453:Glucuronosyltransferase; C491356:Has3 protein, mouse; D000076002:Hyaluronan Synthases