Preventive Effects of Valnemulin on Lipopolysaccharide-Induced Acute Lung Injury in Mice
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Preventive Effects of Valnemulin on LipopolysaccharideInduced Acute Lung Injury in Mice Zhibao Chen,1,2 Xuemei Zhang,3 Xiao Chu,1 Xiaozhe Zhang,1 Keji Song,2 Youshuai Jiang,2 Lu Yu,1,4 and Xuming Deng1,4
Abstract—Valnemulin reportedly regulates inflammatory responses in addition to its in vitro antibacterial activity. In this study, we established a mouse model of lipopolysaccharide (LPS)-induced inflammatory lung injury and investigated the effect of valnemulin (100 mg/kg) on acute lung injury (ALI) 8 h after LPS challenge. We prepared bronchoalveolar lavage fluid (BALF) for measuring protein concentrations, cytokine levels, and superoxidase dismutase (SOD) activity, and collected lungs for assaying wet-to-dry weight (W/D) ratios, myeloperoxidase (MPO) activity, cytokine mRNA expression, and histological change. We found that the pre-administration of valnemulin significantly decreases the W/D ratio of lungs, protein concentrations, and the number of total cells, neutrophils, macrophages, and leukomonocytes, and histologic analysis indicates that valnemulin significantly attenuates tissue injury. Furthermore, valnemulin significantly increases LPS-induced SOD activity in BALF and decreases lung MPO activity as well. In addition, valnemulin also inhibits the production of tumor necrosis factor-α, interleukin-6, and interleukin-1β, which is consistent with mRNA expression in lung. The results showed that valnemulin had a protective effect on LPS-induced ALI in mice. KEY WORDS: valnemulin; LPS; acute lung injury; cytokine.
trophils. The etiopathogenesis of endotoxin-induced ALI remains obscure and, to this point, has not been fully elucidated. It is generally accepted that ALI is an excessive, uncontrolled inflammatory response within the lung [1]. Acute respiratory distress syndrome (ARDS) is the most severe form of ALI, and it remains refractory to therapy. The pathogenesis of ALI/ARDS involves defective oxidation and inflammation, upregulation of adhesion molecules, increased production of chemokines, and excessive pulmonary cell apoptosis [2–4]. These syndromes are associated with the development of multiple organ dysfunction syndrome, which plays a pivotal role in the death of patients with multiple transfusions, shock, sepsis, and ischemia–reperfusion [4, 5]. Over the past several decades, various strategies for suppressing the inflammatory response have been tested in clinical trials for the treatment of ALI/ARDS. Unfortunately, these clinical trials have, thus far, been unsuccessful [6]. Lipopolysaccharide (LPS), a bacterial cell wall component, is known to induce the production of several inflammatory and chemotactic cytokines [7]. Intranasal administration of LPS is an accepted experimental model of ALI [8, 9], as LPS
INTRODUCTION Acute lung injury (ALI) is defined as a syndrome of acute and persistent lung inflammation with increased vascular permeability. It is characterized by inflammatory damage to the alveolar-capillary membrane and adhesion, activation, and sequestration of polymorphonuclear neu-
Zhibao Chen and
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