Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses LPS-Induced Lung Inflammation
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Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses LPS-Induced Lung Inflammation Robert J. McKallip,1,2 Hao Ban,1 and Olga N. Uchakina1
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. KEY WORDS: acute lung inflammation; LPS; hyaluronic acid; extracellular matrix.
INTRODUCTION Exposure to lipopolysaccharide resulting from infection with gram-negative bacteria can lead to lifethreatening complications due in large part to overactivation of the inflammatory response. This exaggerated response leads to accumulation of inflammatory cells and the production of a number of proinflammatory cytokines including IL-1β, IL-6, interferon gamma (IFNγ), and tumor necrosis alpha (TNF-α) systemically and in the lungs of infected patients [1]. Ultimately, the immune response initiated by lipopolysaccharide (LPS) can lead to endothelial cell injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and vascular collapse (shock) [1]. The development of ALI and ARDS can result in multiple organ failure and death of patients. The mortality rate in patients that develop ARDS is 35–40 % [2, 3]. In the USA alone, approximately 75,000 people die from 1
Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St, Macon, GA 31207, USA 2 To whom correspondence should be addressed at Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St, Macon, GA 31207, USA. E-mail: [email protected]
ALI and it is estimated that in the next 25 years, the number of deaths due to ALI in the USA will rise to close to 150,000 per year [2]. Unfortunately, the current treatments are mostly ineffective. Therefore, new therapies designed to treat the underlying cause of the injury while limiting any additional damage to the various affected organs are needed [4]. Modulation of the extracellular matrix can play an important role in the regulation of the inflammatory response. For example, a number of reports demonstrate that elevated levels of hyaluronic acid are a
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