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Developing Therapeutics for the Prevention of Crystalline Silica-Induced Inflammation by Anti-Depressant Drugs

Andrij Holian, PhD, Professor, Director CEHS; Biostatistician: Raymond Hamilton, MS
Graduate Student: 
Rebekah Kendall, PhD Candidate, PreDoctoral-NRSA Recipient
SURP Student: 
Yaneiza González Altieri, SOT Intern, University of Puerto Rico at Aguadilla

Silicosis is a chronic inflammation disease where currently no cure is available. This disease occurred after exposure of silica (cSiO2) particles that affects the Lysosome Membrane Permeabilization (LMP) of the phagolysosome in macrophages. Resulting in a leakage of cathepsin and other proteases that activate the NLPRP3 inflammasome complex and secretion of the proinflammatory cytokines. This study was design to use two Food and Drug Administration (FDA) approved antidepressant drugs in mice macrophage cells as a treatment for silicosis to repurpose these drugs. Our hypothesis is that antidepressant drugs will decrease the silica-induced inflammation response in Murine Bone Marrow derived Macrophages (BMdM) and Alveolar Macrophages (AM) without causing cytotoxicity. BMDM and AM pre-treated with Fluvoxamine and Fluoxetine, respectively, for 30 minutes prior to cSiO2 exposure (50 µg/mL). cSiO2-exposed cells were seeded at 1x105 cells per well in a 96-well plate and incubated 24 hr (37ºC, 5% CO2). After 24 hr, cells and supernatants were assayed with Lactate Dehydrogenase (LDH, Promega) and MTS tetrazolium compound (MTS, Promega) assays to determine cytotoxicity. Supernatants were analysed by ELISA (R&D) for IL-1β levels. Using dose response results in BMdM we move on using a specific dose for AMs. As a result, the fluvoxamine (1 µM) and fluoxetine (5 µM) have reduction of the IL-1β and did not present cytotoxicity effect on both immune cells. In conclusion, both treatments reduced the crystalline silica-induced inflammation in mice immune cells without causing cytotoxicity. This FDA approved drugs could be repurpose as a treatment for chronic inflammation disease. Additional studies were needed to make sure that the proposed mechanism of the drugs is directly reducing the LMP and move on to human immune cells.