Jang Eun-A, Kim Jin-Young, Tin Tran Duc, Song Ji-A, Lee Seong-Heon, Kwak Sang-Hyun
Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School and Hospital, Gwangju, Korea.
Brain Korea 21 Project, Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Korea.
Acute Crit Care. 2019 May;34(2):133-140. doi: 10.4266/acc.2019.00507. Epub 2019 May 31.
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.
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 μg). 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-α] in bronchoalveolar lavage fluid [BALF]), and neutrophil infiltration (myeloperoxidase activity). TNF-α activation was also measured in neutrophils from bone marrow. Survival was investigated in a second-hit sepsis mouse model.
BMS-470539 improved sepsis-induced pulmonary edema, as demonstrated by a decreased W/D ratio (5.76%±0.83% to 3.81%±0.86%, P<0.05). The inflammatory response also improved, as shown by decreased levels of leukocytes (551±116 to 357±86×10²/mm³, P<0.05), PMNs (51.52%±16.23% to 18.41%±7.25%, P<0.01), and TNF-α (550±338 to 128±52 pg/ml, P<0.01) in the BALF. BMS-470539 also improved the inflammatory response, as shown by TNF-α levels (850±158 to 423±59 pg/ml, P<0.01) in neutrophils. BMS-470539 downregulated neutrophil infiltration in the lung (myeloperoxidase: 654±98 to 218±89 U/g, P<0.001). Lastly, BMS improved the survival rate (0% to 70%, P<0.01) in a mice multiple organ failure model.
BMS-470539 improved lipopolysaccharide-induced acute lung injury and mortality in mice by affecting the inflammatory response.
包括巨噬细胞和中性粒细胞在内的炎症细胞过度激活与急性肺损伤相关。BMS-470539是促黑素细胞激素1受体的选择性激动剂，可触发对促炎反应的抑制，抑制中性粒细胞浸润并保护组织。本研究评估了BMS-470539对脂多糖诱导的小鼠急性肺损伤模型的影响。
小鼠在气管内注射生理盐水或脂多糖（20μg）前1小时皮下注射生理盐水或BMS-470539（18.47mg/kg）。处死小鼠以分析肺水肿的严重程度（肺湿重与干重[W/D]比值）和炎症反应（支气管肺泡灌洗液[BALF]中白细胞、多形核中性粒细胞[PMN]和肿瘤坏死因子α[TNF-α]的水平），以及中性粒细胞浸润（髓过氧化物酶活性）。还测定了骨髓中性粒细胞中的TNF-α激活情况。在二次打击脓毒症小鼠模型中研究存活率。
BMS-470539改善了脓毒症诱导的肺水肿，W/D比值降低证明了这一点（从5.76%±0.83%降至3.81%±0.86%，P<0.05）。炎症反应也得到改善，BALF中白细胞水平（从551±116降至357±86×10²/mm³，P<0.05）、PMN水平（从51.52%±16.23%降至18.41%±7.25%，P<0.01）和TNF-α水平（从550±338降至128±52pg/ml，P<0.01）降低表明了这一点。BMS-470539还改善了炎症反应，骨髓中性粒细胞中TNF-α水平（从850±158降至423±59pg/ml，P<0.01）降低证明了这一点。BMS-470539下调了肺中的中性粒细胞浸润（髓过氧化物酶：从654±98降至218±89U/g，P<0.001）。最后，BMS提高了小鼠多器官功能衰竭模型中的存活率（从0%提高到70%，P<0.01）。
BMS-470539通过影响炎症反应改善了脂多糖诱导的小鼠急性肺损伤和死亡率。
