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.

Keywords:

• Alveolar macrophages
• crystalline silica
• hydroxychloroquine
• lysosomal membrane permeabilization
• inflammation

Acknowledgments

The authors thank the core scientists, Mary Buford and Britten Postma (Inhalation and Pulmonary Physiology Core) and Pam Shaw (Fluorescence Cytometry Core).

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by NIH CoBRE grant P30 GM103338 and NIH grant R01 ES027353. Also funding was received from the National Institute of Environmental Health Sciences.