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Imipramine Blocks Acute Silicosis in a Mouse Model Rupa Biswas1†, Kevin L

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Imipramine Blocks Acute Silicosis in a Mouse Model Rupa Biswas1†, Kevin L Biswas et al. Particle and Fibre Toxicology (2017) 14:36 DOI 10.1186/s12989-017-0217-1 RESEARCH Open Access Imipramine blocks acute silicosis in a mouse model Rupa Biswas1†, Kevin L. Trout1†, Forrest Jessop1, Jack R. Harkema2 and Andrij Holian1* Abstract 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 (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. 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. Keywords: Silica, Silicosis, Particles, Imipramine, Macrophage, Lysosome, Inflammation, Toxicology Background silicosis develops after a few weeks to 5 years of high Silicosis is a lung disease caused by inhalation of crystal- concentration exposures [4]. Silicoproteinosis is a com- line silica and is most prevalent as a result of occupa- mon distinguishing pathology of acute silicosis, and tional exposures [1, 2]. The seriousness of the disease is these terms are often used interchangeably. Most forms reflected by the morbidity and disabling illnesses that of human silicosis are difficult to mimic experimentally continue to occur among workers [3]. Silicosis can be due to the long latency period for disease development, categorized into subtypes based on duration of exposure but animal models of silica exposure have been shown and associated pathology. In a general sense, chronic to produce similar characteristics in a more rapid time- silicosis develops after at least 10 years of low concentra- line [5–7]. Currently, treatment choices for silicosis are tion exposures, accelerated silicosis develops after 5- limited and accompanied by complex adverse outcomes 10 years of medium concentration exposures, and acute [4]. Therefore, it remains important to understand the mechanism of silica-induced inflammation and disease * Correspondence: [email protected] progression in order to develop effective therapeutics. † Equal contributors When respirable particulates of 2.5 μm or less deposit 1Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA in the pulmonary alveolus, they are cleared by alveolar Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Biswas et al. Particle and Fibre Toxicology (2017) 14:36 Page 2 of 13 macrophages (AM) and are predominantly contained in using AM from C57Bl/6 mice to evaluate the effect of IMP phagosomes [8, 9]. Lysosomes fuse with the phagosomes on IL-1β release and cytotoxicity. In vivo studies with to form phagolysosomes, in which lysosomal enzymes at- C57Bl/6 mice were conducted to determine if IMP could tempt to degrade phagocytosed particulates. However, a decrease silica-induced acute inflammation and pathology. number of particulates including silica cannot be degraded, Furthermore, we determined the potential of IMP as a which may contribute to phagolysosomal membrane protective and a therapeutic agent in a long-term crystal- permeabilization (LMP) [10, 11]. Nevertheless, the exact line silica exposure model. cause of particle-induced phagolysosomal instability is not clearly understood. Results LMP results in the release of lysosomal proteases to Imipramine inhibited silica-induced IL-1β release and the cytoplasm that have been reported to contribute to cytotoxicity in vitro cytotoxicity [12–16] and to trigger assembly of the Primary AM were used to evaluate the effects of IMP multiprotein complex, NLRP3 inflammasome [17]. The on IL-1β release and cytotoxicity. Isolated AM were function and regulation of inflammasomes has been treated ± IMP (25 μM) for 30 min and then exposed reviewed elsewhere [18–22]. NLRP3 inflammasome as- to LPS (20 ng/ml) ± silica (100 μg/ml). The results in sembly leads to activation of Caspase-1, which cleaves Fig. 1a show silica leads to a significant increase in pro-Interleukin (IL)-1β and pro-IL-18 to their active IL-1β release compared to cells treated with LPS only. forms. Another signal is required to activate the NF-κB IMP pretreatment significantly inhibited IL-1β release pathway, such as lipopolysaccharide (LPS), IL-1β,high in silica-exposed AM. Similar results were obtained mobility group box 1 (HMGB1) protein [23], or other using cell line THP-1 (Additional file 1: Figure S1), damage/pathogen-associated molecular patterns (DAMP/ which is a human monocytic leukemia line that is PAMP). NF-κB activation upregulates transcription of commonly used for particle toxicology studies in our inflammasome components, pro-IL-1β, and pro-IL-18. laboratory and others [29, 30]. These results demon- The release of mature IL-1β and IL-18 have been closely strate that IMP can significantly block silica-induced associated with acute inflammation and development of IL-1β release in vitro. lung fibrosis [24, 25]. It should be noted that although AM cytotoxicity was examined for two purposes: (1) inflammasome activation is typically considered to be the to determine whether the observed decrease in IL-1β primary mechanism for IL-1β processing, it has been sug- was due to any unexpected toxicity of IMP, and (2) to gested that there may also be smaller contributions from inflammasome-independent mechanisms in vivo [20]. Since LMP plays an important regulatory role in A 1000 *** NLRP3 inflammasome activation and subsequent in- *** No IMP flammation, blocking LMP would be a target for novel 800 IMP therapeutics for inflammatory diseases linked to lyso- 600 somal instability. For example, a drug or an agent that (pg/ml) can stabilize the lysosome and prevent membrane 400 permeabilization may have the potential to attenuate IL-1 200 downstream inflammation. A potential anti-LMP agent 0 is imipramine (IMP), a U.S Food and Drug Administra- LPS Silica+LPS tion approved tricyclic antidepressant drug with lysoso- B motropic properties [26]. Pretreatment with IMP has 150 No IMP been reported to attenuate the inflammatory response IMP and improve survival in an LPS-induced acute lung injury *** 100 * model [27]. In another study, the authors reported that ** IMP and surfactant synergistically suppressed acid sphin- gomyelinase (aSMase) activity in lung tissue, reduced cer- 50 amide generation, and improved pulmonary function in a Viable% cells newborn piglet lavage model [28]. However, IMP has not relative to control 0 been examined in models of particulate-induced inflamma- No Silica Silica tion. Therefore, the potential of IMP to inhibit inflamma- Fig. 1 In vitro IL-1β release and cytotoxicity in AM treated with silica ± tion following silica exposure was examined in this study. imipramine. AM treatment conditions include IMP for 30 min, followed We hypothesized that IMP will stabilize lysosomes, by exposure to LPS and silica for 24 h. a IL-1β release was measured by thereby decreasing NLRP3 inflammasome activation and ELISA. b MTS assay results are expressed as cell viability relative to no silica, no IMP control. n ≥ 3 mice per treatment condition downstream inflammation. In vitro studies were conducted Biswas et al. Particle and Fibre Toxicology (2017) 14:36 Page 3 of 13 evaluate the effect of IMP on silica-induced cytotoxicity. above. The lavaged cells were then cultured ex vivo for Isolated AM were pretreated ± IMP for 30 min then ex- 24 h ± LPS (20 ng/ml). There was a significant
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