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

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.