KMID : 1144420190340020133
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Acute and Critical Care 2019 Volume.34 No. 2 p.133 ~ p.140
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The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury
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Jang Eun-A
Kim Jin-Young Tin Tran Duc Song Ji-A Lee Seong-Heon Kwak Sang-Hyun
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Abstract
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Background: Overactivation of inflammatory cells, including macrophages and neutrophils, is associated with acute lung injury. BMS-470539 is a selective agonist of melanocortin 1 receptor, which triggers the inhibition of proinflammatory responses, suppressing neutrophil infiltration and protecting tissue. This study evaluated the effects of BMS-470539 on lipopolysaccharide-induced acute lung injury in a mouse model.
Methods: Mice received a subcutaneous injection of saline or BMS-470539 (18.47 mg/kg) 1 hour before an intratracheal injection of saline or lipopolysaccharide (20 ¥ìg). Mice were sacrificed to analyze the severity of pulmonary edema (lung wet-to-dry weight [W/D] ratio) and inflammatory responses (level of leukocytes, polymorphonuclear neutrophils [PMNs] and tumor necrosis factor alpha [TNF-¥á] in bronchoalveolar lavage fluid [BALF]), and neutrophil infiltration (myeloperoxidase activity). TNF-¥á activation was also measured in neutrophils from bone marrow. Survival was investigated in a second-hit sepsis mouse model.
Results: BMS-470539 improved sepsis-induced pulmonary edema, as demonstrated by a decreased W/D ratio (5.76%¡¾0.83% to 3.81%¡¾0.86%, P<0.05). The inflammatory response also improved, as shown by decreased levels of leukocytes (551¡¾116 to 357¡¾86¡¿10©÷/mm©ø, P<0.05), PMNs (51.52%¡¾16.23% to 18.41%¡¾7.25%, P<0.01), and TNF-¥á (550¡¾338 to 128¡¾52 pg/ml, P<0.01) in the BALF. BMS-470539 also improved the inflammatory response, as shown by TNF-¥á levels (850¡¾158 to 423¡¾59 pg/ml, P<0.01) in neutrophils. BMS-470539 downregulated neutrophil infiltration in the lung (myeloperoxidase: 654¡¾98 to 218¡¾89 U/g, P<0.001). Lastly, BMS improved the survival rate (0% to 70%, P<0.01) in a mice multiple organ failure model.
Conclusions: BMS-470539 improved lipopolysaccharide-induced acute lung injury and mortality in mice by affecting the inflammatory response.
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KEYWORD
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acute lung injury, cytokines, lipopolysaccharides, melanocortin 1 receptor
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