Lee Jae-Won, Park Hyun Ah, Kwon Ok-Kyoung, Park Ji-Won, Lee Gilhye, Lee Hee Jae, Lee Seung Jin, Oh Sei-Ryang, Ahn Kyung-Seop
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Chungju-si, Chungbuk, 363-883, Republic of Korea.
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Chungju-si, Chungbuk, 363-883, Republic of Korea; College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, Republic of Korea.
Mol Immunol. 2017 Oct;90:150-157. doi: 10.1016/j.molimm.2017.07.012. Epub 2017 Aug 8.
NPS 2143, a novel and selective antagonist of calcium-sensing receptor (CaSR) has been reported to possess anti-inflammatory activity. In the present study, we examined the protective effect of NPS 2143 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). NPS 2143 pretreatment significantly inhibited the influx of inflammatory cells and the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung of mice with LPS-induced ALI. NPS 2143 decreased the levels of neutrophil elastase (NE) and protein concentration in the bronchoalveolar lavage fluid (BALF). NPS 2143 also reduced the production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the BALF and serum. In addition, NPS 2143 attenuated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased the activation of AMP-activated protein kinase (AMPK) in the lung. NPS 2143 also downregulated the activation of nuclear factor-kappa B (NF-κB) in the lung. In LPS-stimulated H292 airway epithelial cells, NPS 2143 attenuated the releases of IL-6 and MCP-1. Furthermore, NPS 2143 upregulated the activation of AMPK and downregulated the activation of NF-κB. These results suggest that NPS 2143 could be potential agent for the treatment of inflammatory diseases including ALI.
据报道，新型钙敏感受体（CaSR）选择性拮抗剂NPS 2143具有抗炎活性。在本研究中，我们检测了NPS 2143对脂多糖（LPS）诱导的急性肺损伤（ALI）的保护作用。NPS 2143预处理显著抑制了LPS诱导的ALI小鼠肺内炎症细胞的流入以及单核细胞趋化蛋白-1（MCP-1）的表达。NPS 2143降低了支气管肺泡灌洗液（BALF）中中性粒细胞弹性蛋白酶（NE）水平和蛋白浓度。NPS 2143还减少了BALF和血清中肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）等炎性细胞因子的产生。此外，NPS 2143减弱了肺中诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）的表达，并增强了肺中AMP激活的蛋白激酶（AMPK）的活性。NPS 2143还下调了肺中核因子-κB（NF-κB）的活性。在LPS刺激的H292气道上皮细胞中，NPS 2143减弱了IL-6和MCP-1的释放。此外，NPS 2143上调了AMPK的活性并下调了NF-κB的活性。这些结果表明，NPS 2143可能是治疗包括ALI在内的炎性疾病的潜在药物。
