呼吸道病原体不可分型的流感嗜血杆菌(NTHi)是慢性阻塞性肺疾病(COPD)恶化的最常见原因,其中过度的炎症反应是一个标志。由于当前药物的有限成功,迫切需要开发既安全又有效的新疗法。在这项研究中,我们探讨了石榴衍生肽Pug-1,Pug-2,Pug-3和Pug-4对NTHi诱导的炎症的调节潜力.我们的结果清楚地表明,Pug肽在不同程度上抑制NTHi诱导的IL-1β的产生,COPD的关键细胞因子,并表明这些作用与细胞毒性无关。Pug-4肽表现出最有效的抑制活性。这在所有研究的细胞类型中得到证实,包括鼠(RAW264.7)和人(分化的THP-1)巨噬细胞以及人肺上皮细胞(A549)。Pug-4显著降低TNF-α,在NTHi感染的A549细胞中还观察到NO和PGE2。此外,Pug-4强烈抑制核NF-κBp65蛋白和NF-κB靶基因的表达(通过IL-1β测定,TNF-α,iNOS和COX-2mRNA表达)在NTHi感染的A549细胞中。Pug-4抑制NLRP3和pro-IL-1β蛋白的表达,并抑制NTHi介导的caspase-1和成熟IL-1β的裂解。这些结果表明Pug-4通过NF-κB信号传导和NLRP3炎性体激活抑制NTHi诱导的炎症。我们的发现强调了Pug-4的显着抗炎活性,这是一种新鉴定的石榴肽,对抗NTH诱导的炎症。因此,我们强烈建议Pug-4肽作为治疗NTHi介导的炎症的抗炎药物的潜力。
The respiratory pathogen nontypeable Haemophilus influenzae (
NTHi) is the most common cause of exacerbation of chronic obstructive pulmonary disease (COPD), of which an excessive inflammatory response is a hallmark. With the limited success of current medicines there is an urgent need for the development of novel therapeutics that are both safe and effective. In this study, we explored the regulatory potential of pomegranate-derived peptides Pug-1, Pug-2, Pug-3, and Pug-4 on NTHi-induced inflammation. Our results clearly showed that to varying degrees the Pug peptides inhibited
NTHi-induced production of IL-1β, a pivotal cytokine in COPD, and showed that these effects were not related to cytotoxicity. Pug-4 peptide exhibited the most potent inhibitory activity. This was demonstrated in all studied cell types including murine (RAW264.7) and human (differentiated THP-1) macrophages as well as human lung epithelial cells (A549). Substantial reduction by Pug-4 of TNF-α, NO and PGE2 in
NTHi-infected A549 cells was also observed. In addition, Pug-4 strongly inhibited the expression of nuclear-NF-κB p65 protein and the NF-κB target genes (determined by IL-1β, TNF-α, iNOS and COX-2 mRNA expression) in NTHi-infected A549 cells. Pug-4 suppressed the expression of NLRP3 and pro-IL-1β proteins and inhibited
NTHi-mediated cleavage of caspase-1 and mature IL-1β. These results demonstrated that Pug-4 inhibited
NTHi-induced inflammation through the NF-κB signaling and NLRP3 inflammasome activation. Our findings herein highlight the significant anti-inflammatory activity of Pug-4, a newly identified peptide from pomegranate, against NTHi-induced inflammation. We therefore strongly suggest the potential of the Pug-4 peptide as an anti-inflammatory medicine candidate for treatment of NTHi-mediated inflammation.