肺纤维化(PF)是一种危及生命的疾病,预后极差。由于PF病理机制的复杂性,填补这种未满足的医疗需求是具有挑战性的。许多肺部疾病与NF-κB和NLRP3炎性体的激活有关。考马斯亮蓝G-250(CBBG)被证明是一种安全的高选择性P2×7R拮抗剂,有希望使NLRP3炎性体失活。这是首次报道CBBG对博莱霉素诱导的大鼠肺纤维化的影响。我们的发现表明,CBBG导致博来霉素暴露的肺组织的组织学特征和氧化状态生物标志物的显着改善。此外,CBBG抑制胶原蛋白沉积,如羟脯氨酸分析后所示,TGF-β,PDGF-BB,TIMP-1、MMP-9、Col1a1、SMA和ICAM-1。它还表现出抗炎潜力,如通过测定TNF-α,IL-1β,IL-18、MCP-1在肺组织中的表达。在支气管肺泡灌洗中,总蛋白和LDH活性显著降低。CBBG的肺保护作用可能一方面归因于NLRP3炎性体的抑制,另一方面归因于NF-κB的失活。磷酸化p65的水平降低及其DNA结合活性以及TLR4的分析证实了NF-κB失活。作为抑制NLRP3炎性体组装的结果,胱天蛋白酶-1活性被抑制。最后,CBBG可以作为PF管理的主要或辅助疗法,因此它可能为未满足的医疗需求提供新方法的机会。
Pulmonary fibrosis (PF) is a life-threatening disorder with a very poor prognosis. Because of the complexity of PF pathological mechanisms, filling such an unmet medical need is challenging. A number of pulmonary diseases have been linked to the activation of NF-κB and the NLRP3 inflammasome. Coomassie brilliant blue G-250 (CBBG) is proved to be a safe highly selective P2×7R antagonist with promising consequent inactivation of NLRP3 inflammasome. This is the first report to investigate the effect of CBBG on the bleomycin-induced lung fibrosis in rats. Our findings revealed that CBBG resulted in a significant improvement in histological features and oxidative status biomarkers of bleomycin-exposed lung tissue. Additionally, CBBG repressed collagen deposition as indicated after the analysis of hydroxyproline, TGF-β, PDGF-BB, TIMP-1, MMP-9, Col1a1, SMA and ICAM-1. It also exhibited anti-inflammatory potential as revealed by the determination of TNF-α, IL-1β, IL-18, MCP-1 in the lung tissue. In the bronchoalveolar lavage, the total protein and the LDH activity were substantially reduced. The lung protective effects of CBBG might be attributed on the one hand to the inhibition of NLRP3 inflammasome and on the other hand to the inactivation of NF-κB. Decreased levels of phospho-p65 and its DNA-binding activity as well as the analysis of TLR4 confirmed NF-κB inactivation. Caspase-1 activity is suppressed as a consequence of inhibiting NLRP3 inflammasome assembly. To conclude, CBBG may act as a primary or adjuvant therapy for the management of PF and therefore it may pose an opportunity for a novel approach to an unmet medical need.