title: Treatment with the hyaluronic Acid synthesis inhibitor 4-methylumbelliferone suppresses LPS-induced lung inflammation.
abstract: Exposure to bacterial endotoxins, such as lipopolysaccharide (LPS), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for LPS-induced inflammation. In the current study, we investigated the potential use of the hyaluronic acid (HA) synthesis inhibitor 4-methylumbelliferone (4-MU) on LPS-induced acute lung inflammation. Culturing LPS-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from LPS-induced lung injury. Specifically, 4-MU treatment led to a reduction in LPS-induced hyaluronic acid synthase (HAS) messenger RNA (mRNA) levels, reduction in lung permeability, and reduction in proinflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target HA production may be an effective treatment for the inflammatory response following exposure to LPS.
authors.affiliation: Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St, Macon, GA, 31207, USA, mckallip_r@mercer.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McKallip
authors.forename: Hao
authors.initials: H
authors.lastname: Ban
authors.forename: Olga N
authors.initials: ON
authors.lastname: Uchakina
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis; D006923:Hymecromone / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D013154:Spleen / Q000166:cytology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D006923:Hymecromone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases