Imipramine blocks acute silicosis in a mouse model

Background: 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. methods: 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 (24h) 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. results: 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. conclusions: 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. © 2017 the author(s).