Investigation of the protective effect of cilostazol on acute lung injury-mediated inflammation and in silico molecular modelling studies of inflammatory signalling pathway: a repurposing study.

IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Pranaya L Misar, Kishor V Otari
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引用次数: 0

Abstract

Acute lung injury i.e. ALI and its serious form acute respiratory distress syndrome (ARDS) are incurable medical conditions associated with significant global mortality and morbidity. The objective of the present research was to repurpose cilostazol, an antiplatelet drug with anti-inflammatory, antioxidant and antiapoptotic effect, as a potential approach for treatment of ALI. Its multifaceted effects make it promising candidate but its mechanism against ALI remains elusive. Hence it is needed to elucidate its mechanism of action to revealed its therapeutic potential and improve its clinical outcomes. This study investigated the potential inflammatory therapeutic targets of cilostazol with its protective effect against lipopolysaccharide (LPS)-induced ALI. We have identified 10 inflammatory target proteins of cilostazol i.e. PDK1, RAC1, PTK6, KDR, EGFR, endothelin-I, caspase-3, TNF-α, NF-κB1/BTK, a TLR/IRAK4 by molecular docking and validated by in vivo evaluation to demonstrate its therapeutic efficacy. In vivo experiment was performed in two sets; first to determine cellular inflammation by analysing the biomarkers in both lung homogenate and bronchoalveolar fluid and second set to study lung edema with dexamethasone as a standard. Additionally, respiratory parameters, related mRNA expressions and histopathology was evaluated. Our results, molecular docking showed that cilostazol binds to identified inflammatory target proteins with the same binding affinity as that of experimental inhibitors. In vivo, downregulated oxidative stress, and inflammation i.e. attenuated the pulmonary edema and vascular leakage, release of inflammatory mediators i.e. IL-6, TNF-α, NO, C-reactive protein (CRP), lactate dehydrogenase (LDH) myeloperoxidase (MPO), Krebs von den Lungen 6 (KL-6), and the recruitment of inflammatory cells; downregulated the m-RNA gene expressions of tumour necrosis factor alpha (TNF-α), nuclear factor kappa B( NF-kB), Toll-like receptor 4 (TLR4), Janus kinase/signal transducer, and activator of transcription 3 (JAK and STAT3); and improved total lung capacity in LPS-challenged rats. These findings revealed the cilostazol's efficacy as promising therapeutic agent for ALI by inhibiting the NF-κB/TLR4/JAK-STAT3 signalling pathway.

西洛他唑对急性肺损伤介导炎症的保护作用的研究和炎症信号通路的硅分子模拟研究:一项再利用研究。
急性肺损伤,即急性肺损伤及其严重形式的急性呼吸窘迫综合征(ARDS)是与全球死亡率和发病率显著相关的无法治愈的疾病。西洛他唑是一种具有抗炎、抗氧化和抗凋亡作用的抗血小板药物,本研究的目的是重新利用西洛他唑作为治疗ALI的潜在方法。其多方面的作用使其成为有希望的候选药物,但其抗ALI的机制尚不清楚。因此,有必要阐明其作用机制,以揭示其治疗潜力,改善其临床效果。本研究探讨西洛他唑的潜在炎症治疗靶点及其对脂多糖(LPS)诱导的ALI的保护作用。我们通过分子对接鉴定了西洛他唑的10种炎症靶蛋白PDK1、RAC1、PTK6、KDR、EGFR、内皮素- i、caspase-3、TNF-α、NF-κB1/BTK、TLR/IRAK4,并通过体内评价验证了其治疗效果。体内实验分两组进行;首先通过分析肺匀浆和支气管肺泡液中的生物标志物来确定细胞炎症,第二组以地塞米松为标准研究肺水肿。观察呼吸参数、相关mRNA表达及组织病理学变化。我们的研究结果,分子对接表明西洛他唑与已知的炎症靶蛋白结合,与实验抑制剂具有相同的结合亲和力。在体内,下调氧化应激和炎症,即减轻肺水肿和血管渗漏,炎症介质如IL-6、TNF-α、NO、c反应蛋白(CRP)、乳酸脱氢酶(LDH)、髓过氧化物酶(MPO)、Krebs von den Lungen 6 (KL-6)的释放和炎症细胞的募集;下调肿瘤坏死因子α (TNF-α)、核因子κ B(NF-kB)、toll样受体4 (TLR4)、Janus激酶/信号转导器、转录激活因子3 (JAK和STAT3)的m-RNA基因表达;并改善lps挑战大鼠的总肺活量。这些发现揭示了西洛他唑通过抑制NF-κB/TLR4/JAK-STAT3信号通路作为ALI治疗药物的前景。
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来源期刊
CiteScore
6.20
自引率
5.60%
发文量
142
审稿时长
4-8 weeks
期刊介绍: Naunyn-Schmiedeberg''s Archives of Pharmacology was founded in 1873 by B. Naunyn, O. Schmiedeberg and E. Klebs as Archiv für experimentelle Pathologie und Pharmakologie, is the offical journal of the German Society of Experimental and Clinical Pharmacology and Toxicology (Deutsche Gesellschaft für experimentelle und klinische Pharmakologie und Toxikologie, DGPT) and the Sphingolipid Club. The journal publishes invited reviews, original articles, short communications and meeting reports and appears monthly. Naunyn-Schmiedeberg''s Archives of Pharmacology welcomes manuscripts for consideration of publication that report new and significant information on drug action and toxicity of chemical compounds. Thus, its scope covers all fields of experimental and clinical pharmacology as well as toxicology and includes studies in the fields of neuropharmacology and cardiovascular pharmacology as well as those describing drug actions at the cellular, biochemical and molecular levels. Moreover, submission of clinical trials with healthy volunteers or patients is encouraged. Short communications provide a means for rapid publication of significant findings of current interest that represent a conceptual advance in the field.
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