Prevention of crystalline silica-induced inflammation by the anti-malarial hydroxychloroquine

Abstract Objectives: Inhalation of crystalline silica (cSiO2) remains a significant occupational hazard and may lead to the development of silicosis. When cSiO2 particles are phagocytized by alveolar macrophages, they cause disruption of the lysosomal membrane which results in cell death. There are currently no pharmaceutical treatments directed at this mechanism of disease; however, many existing pharmaceuticals, such as hydroxychloroquine (HCQ), become sequestered in the lysosome through an ion-trapping mechanism. The objective of this research was to determine whether HCQ can prevent cSiO2-induced toxicity by blocking LMP in alveolar macrophages. Materials and methods: This study assessed the ability of in vitro treatment with HCQ to block toxicity and lysosomal membrane permeability in cSiO2-exposed mouse bone-marrow derived macrophages. Additionally, C57Bl/6 mice were treated with HCQ by oral gavage before cSiO2 exposure, and the ability of HCQ to prevent lung injury and inflammation was assessed. Results: In vitro studies demonstrated that HCQ attenuated activation of the NLRP3 inflammasome and blocked LMP. Mice treated with HCQ in vivo showed a modest trend towards decreased cSiO2-induced toxicity. Ex vivo culture of alveolar macrophages collected from cSiO2-treated mice showed significantly less NLRP3 inflammasome activation after in vivo exposure to HCQ. Conclusions: Our findings suggest that hydroxychloroquine blocks LMP and can significantly decrease cSiO2-induced toxicity in vitro. HCQ may be a promising treatment for prevention of cSiO2-induced lung damage.