PREVENTION OF CRYSTALLINE SILICA-INDUCED INFLAMMATION BY THE ANTI-MALARIAL HYDROXYCHLOROQUINE

Author

Rachel Dawn BurmeisterFollow

Year of Award

2019

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Andrij Holian

Commitee Members

Scott Wetzel, Chris Migliaccio

Keywords

hydroxychloroquine, crystalline silica, alveolar macrophages, silica inhalation, LMP, lysosomal membrane permeability

Subject Categories

Toxicology

Abstract

Exposure to inhaled crystalline silica (cSiO2) is common in occupations where there is cutting, milling, or grinding of cSiO2 containing material. The Occupational Safety and Health Administration estimates that over 2 million workers may be exposed to inhaled cSiO2 in the United States. Inhalation of cSiO2 causes acute and chronic inflammation and may lead pulmonary diseases such as silicosis, as well as an increased risk of developing autoimmune diseases.Unfortunately, treatment of cSiO2-induced lung diseases is limited and primarily focused on supportive care.

Inflammation caused by cSiO2 begins when, cSiO2 particles are phagocytized by alveolar macrophages. Interaction between the particle and lysosomal membrane results in damage to the phagolysosomal membrane; a state known as lysosomal membrane permeability (LMP). Leakage of lysosomal contents into the cytoplasm induces NLRP3 inflammasome activation leading to cell death and systemic inflammation. There are currently no pharmaceutical treatments that are directed at this mechanism of disease. Many existing pharmaceuticals become sequestered in the lysosome through an ion-trapping mechanism, and our laboratory aims to determine if these pharmaceuticals are capable of blocking permeabilization of the lysosomal membrane. Previously, our laboratory has shown that the tricyclic antidepressant, imipramine, blocks inflammatory cytokine production and toxicity in alveolar macrophages after exposure to cSiO2. The objective of this research is to determine whether another pharmaceutical, hydroxychloroquine, prevents cSiO2-induced toxicity by blocking LMP in alveolar macrophages. The ability to target the mechanism responsible for initiating particle-induced inflammation may lead to potential treatments and prevention strategies for people exposed to cSiO2.

Recommended Citation

Burmeister, Rachel Dawn, "PREVENTION OF CRYSTALLINE SILICA-INDUCED INFLAMMATION BY THE ANTI-MALARIAL HYDROXYCHLOROQUINE" (2019). Graduate Student Theses, Dissertations, & Professional Papers. 11356.
https://scholarworks.umt.edu/etd/11356