Li Yubin, Wang Shaofei, Fan Jiajun, Zhang Xuesai, Qian Xiaolu, Zhang Xuyao, Luan Jingyun, Song Ping, Wang Ziyu, Chen Qicheng, Ju Dianwen
Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China.
Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
ACS Biomater Sci Eng. 2017 May 8;3(5):843-853. doi: 10.1021/acsbiomaterials.6b00790. Epub 2017 Apr 4.
Hepatotoxicity of cationic poly amidoamine (PAMAM) dendrimers is one of the most urgent challenges to their medicinal application. Recent studies have indicated that proinflammatory cytokines were critical in nanomaterials-induced toxicity. However, little is known about the roles and underlying regulatory mechanisms of proinflammatory cytokines in cationic PAMAM dendrimer-induced hepatotoxicity. Thus, the aim of the current study was to explore the role of proinflammatory cytokine tumor necrosis factor alpha (TNFα) in cationic PAMAM dendrimer-induced liver injury and its underlying mechanism and develop novel strategies to reduce hepatotoxicity of cationic PAMAM dendrimers through regulating TNFα. In this study, we verified the significant overexpression of TNFα in cationic PAMAM dendrimer-induced hepatotoxicity in mice and found that targeting TNFα by etanercept could protect against cationic PAMAM dendrimer-induced liver injury. Interestingly, etanercept suppressed cationic PAMAM dendrimer-induced inflammasome signaling as demonstrated by reduced activation of NALP3, cleavage of Caspase-1, and maturation of interleukin (IL)-1β. Moreover, suppression of NLRP3 inflammasomes by belnacasan could also protect against cationic PAMAM dendrimer-induced hepatotoxicity and TNFα-induced acute hepatotoxicity. Notably, targeting either TNFα or inflammasomes reduced autophagy activation in hepatotoxicity triggered by cationic PAMAM dendrimers. In general, these findings revealed that targeting TNFα could ameliorate cationic PAMAM dendrimer-induced hepatotoxicity via regulating NLRP3 inflammasome pathway, underscoring that TNFα antagonism by etanercept could be used as an effective pharmacological approach to control hepatotoxicity of cationic PAMAM dendrimers and thus providing novel therapeutic strategies for managing liver toxicity of nanomaterials via regulating inflammatory mediators.
阳离子聚酰胺胺（PAMAM）树枝状大分子的肝毒性是其药物应用面临的最紧迫挑战之一。最近的研究表明，促炎细胞因子在纳米材料诱导的毒性中起关键作用。然而，关于促炎细胞因子在阳离子PAMAM树枝状大分子诱导的肝毒性中的作用及潜在调控机制知之甚少。因此，本研究的目的是探讨促炎细胞因子肿瘤坏死因子α（TNFα）在阳离子PAMAM树枝状大分子诱导的肝损伤中的作用及其潜在机制，并通过调节TNFα开发降低阳离子PAMAM树枝状大分子肝毒性的新策略。在本研究中，我们证实了TNFα在阳离子PAMAM树枝状大分子诱导的小鼠肝毒性中显著过表达，并发现用依那西普靶向TNFα可预防阳离子PAMAM树枝状大分子诱导的肝损伤。有趣的是，依那西普抑制了阳离子PAMAM树枝状大分子诱导的炎性小体信号传导，表现为NALP3激活减少、半胱天冬酶-1裂解及白细胞介素（IL）-1β成熟。此外，贝那卡塞抑制NLRP3炎性小体也可预防阳离子PAMAM树枝状大分子诱导的肝毒性和TNFα诱导的急性肝毒性。值得注意的是，靶向TNFα或炎性小体均可降低阳离子PAMAM树枝状大分子引发的肝毒性中的自噬激活。总体而言，这些发现表明靶向TNFα可通过调节NLRP3炎性小体途径改善阳离子PAMAM树枝状大分子诱导的肝毒性，强调依那西普拮抗TNFα可作为控制阳离子PAMAM树枝状大分子肝毒性的有效药理学方法，从而为通过调节炎症介质管理纳米材料肝毒性提供新的治疗策略。
