Imipramine blocks acute silicosis in a mouse model.
Imipramine blocks acute silicosis in a mouse model.
复制标题
DOI：
10.1186/s12989-017-0217-1
复制
发表时间：
2017-09-11
影响因子：
10
通讯作者：
Holian A
中科院分区：
文献类型：
--
作者：
Biswas R;Trout KL;Jessop F;Harkema JR;Holian A
吸入结晶二氧化硅与肺部炎症和矽肺病有关。虽然矽肺病仍然是世界各地普遍存在的健康问题，但有效的治疗选择是有限的。丙咪嗪（IMP）是一种经FDA批准的三环抗抑郁药物，具有溶酶体促性。本研究的目的是评估IMP减少矽肺和阻断吞噬溶酶体膜渗透的潜力。研究了体外暴露于结晶二氧化硅±IMP的C57BL/6肺泡巨噬细胞（AM）的IL-1β释放、细胞毒性、颗粒摄取、溶酶体稳定性和酸性鞘磷脂酶活性。短期（24小时）小鼠体内研究中，除了体外培养AM细胞因子释放外，注射二氧化硅（±IMP）评估炎症和细胞因子释放。长期（6至10周）的小鼠体内研究，注射二氧化硅（±IMP）评估组织病理学、肺损伤和羟脯氨酸含量作为胶原积累的指标。IMP显著降低了二氧化硅诱导的细胞毒性和AM中成熟IL-1β的释放。在短期模型中，IMP在体内治疗减少了二氧化硅诱导的炎症。此外，在长期模型中，IMP可有效阻断二氧化硅诱导的肺损伤和胶原沉积。通过评估细胞过程，如颗粒摄取和酸性鞘磷脂酶活性，探索IMP减轻炎症的机制。综上所述，IMP对体外和体内暴露的二氧化硅具有抗炎作用。结果与IMP阻断二氧化硅诱导的吞噬溶酶体溶解，从而阻止细胞死亡和IL-1β释放一致。因此，IMP可以治疗二氧化硅诱导的炎症和随后的疾病进展，以及其他涉及吞噬溶酶体溶解的疾病。本文的在线版本（10.1186/s12989-017-0217-1）包含补充资料，仅供授权用户使用。
Inhalation of crystalline silica is associated with pulmonary inflammation and silicosis. Although silicosis remains a prevalent health problem throughout the world, effective treatment choices are limited. Imipramine (IMP) is a FDA approved tricyclic antidepressant drug with lysosomotropic characteristics. The aim of this study was to evaluate the potential for IMP to reduce silicosis and block phagolysosome membrane permeabilization. C57BL/6 alveolar macrophages (AM) exposed to crystalline silica ± IMP in vitro were assessed for IL-1β release, cytotoxicity, particle uptake, lysosomal stability, and acid sphingomyelinase activity. Short term (24 h) in vivo studies in mice instilled with silica (± IMP) evaluated inflammation and cytokine release, in addition to cytokine release from ex vivo cultured AM. Long term (six to ten weeks) in vivo studies in mice instilled with silica (± IMP) evaluated histopathology, lung damage, and hydroxyproline content as an indicator of collagen accumulation. IMP significantly attenuated silica-induced cytotoxicity and release of mature IL-1β from AM in vitro. IMP treatment in vivo reduced silica-induced inflammation in a short-term model. Furthermore, IMP was effective in blocking silica-induced lung damage and collagen deposition in a long-term model. The mechanism by which IMP reduces inflammation was explored by assessing cellular processes such as particle uptake and acid sphingomyelinase activity. Taken together, IMP was anti-inflammatory against silica exposure in vitro and in vivo. The results were consistent with IMP blocking silica-induced phagolysosomal lysis, thereby preventing cell death and IL-1β release. Thus, IMP could be therapeutic for silica-induced inflammation and subsequent disease progression as well as other diseases involving phagolysosomal lysis. The online version of this article (10.1186/s12989-017-0217-1) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
5.5
作者：
Beamer, Celine A.;Migliaccio, Christopher T.;Holian, Andrij
通讯作者：
Holian, Andrij
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
4.6
作者：
Hiraiwa K;van Eeden SF
通讯作者：
van Eeden SF
影响因子：
3.8
作者：
Jessop, Forrest;Hamilton, Raymond F.;Rhoderick, Joseph F.;Shaw, Pamela K.;Holian, Andrij
通讯作者：
Holian, Andrij
影响因子：
12.4
作者：
Hentze, H;Lin, XY;Porter, AG
通讯作者：
Porter, AG