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Regulation of Silica-Induced Pulmonary Inflammation University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2014 Regulation of silica-induced pulmonary inflammation Rupa Biswas The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Biswas, Rupa, "Regulation of silica-induced pulmonary inflammation" (2014). Graduate Student Theses, Dissertations, & Professional Papers. 4394. https://scholarworks.umt.edu/etd/4394 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. Regulation of silica-induced pulmonary inflammation By Rupa Biswas At University of Montana Department of Biomedical and Pharmaceutical Sciences Center for Environmental Health Sciences Advisory Committee Members Andrij Holian, Ph.D., Chair Department of Biomedical and Pharmaceutical Sciences Kevan Roberts, Ph.D. Department of Biomedical and Pharmaceutical Sciences Howard Beall, Ph.D. Department of Biomedical and Pharmaceutical Sciences Christopher Migliaccio, Ph.D. Department of Biomedical and Pharmaceutical Sciences Stephen Lodmell, Ph.D. Division of Biological Sciences 1 Rupa Biswas Ph.D., June 2014 Toxicology Abstract Title: Regulation of silica-induced pulmonary inflammation Chairperson: Andrij Holian, Ph.D. Abstract Inhalation of crystalline silica for an extended period of time results in inflammation in the lungs, which plays a pivotal role in the development of silicosis, a progressive, inflammatory and fibrotic pulmonary disease. Inhaled silica particles are encountered by alveolar macrophages (AM) in the lungs. Previous studies have indicated the role of scavenger receptors in binding of environmental particles and also demonstrated that AM recognize and bind silica particles through class A scavenger receptors (SRA) expressed on their surface. MARCO (Macrophage Receptor with Collagenous Structure) is a SRA family receptor and the predominant receptor for recognition and binding of silica particles by alveolar macrophages (AM). Respirable silica particles are recognized by MARCO on AM and are internalized through phagocytosis by AM and subsequently contained in phagosomes. The lysosomes fuse with the phagosomes forming phagolysosomes and deliver the lysosomal enzymes for degradation of the particulates. However, silica cannot be degraded and induce lysosomal membrane permeabilization (LMP), by as yet unknown mechanism. LMP results in the release of lysosomal proteases, to the cytoplasm. This triggers the assembly of the NLRP3 (Nucleotide-binding domain, and Leucine-rich Repeat containing family, Pyrin domain containing) inflammasome assembly and further inflammation as a consequence. This project has focused on determining the relationship between MARCO and NLRP3 inflammasome activity and consequent downstream inflammation. Silica increased NLRP3 inflammasome activation and release of the pro-inflammatory cytokine, IL-1, to a greater extent in MARCO-/- AM 2 compared to wild type (WT) AM. A similar increase in NLRP3 inflammasome activation by silica was observed using MARCO Ab to block MARCO receptors in WT AM. Cathepsin B Inhibition (CA-074-Me), attenuated pro-inflammatory cytokine release. WT AM treated with cholesterol trafficking modifier U18666A decreased silica-induced NLRP3 inflammasome activation and MARCO null AM had reduced ability to sequester cholesterol following silica exposure. Taken together, this study demonstrates the critical role played by lysosomal membrane permeabilization (LMP) in triggering silica-induced inflammation and the contribution of MARCO in normal cholesterol uptake in macrophages, Therefore, in absence of MARCO, macrophages are susceptible to greater inflammatory response following silica exposure due to increased LMP. This project also determined the anti-inflammatory potential of imipramine to inhibit pulmonary inflammation following acute and chronic silica exposure. Anti-inflammatory potential of imipramine was evaluated in vitro in isolated AM from C57Bl/6 WT mice, and in acute and chronic in vivo silica exposure model. The in vitro results demonstrated that pretreatment with imipramine significantly attenuated cathepsin B activity and IL-1β release. In acute in vivo model, pretreatment with imipramine alleviated silica-induced inflammation, as was evident from the decrease in the chemokine KC and neutrophil infiltration. In the chronic in vivo exposure model used in the co-administration study, the protective effect of imipramine was validated by the histopathological analysis of lung tissues and the hydroxyproline quantification of silica- induced lung fibrosis. In the chronic exposure model used in the post-administration study, though imipramine treatment after four weeks of silica exposure attenuated the silica-induced lung injury, imipramine treatment after four weeks of silica exposure reduced the chronic pathological condition. These experiments establish that the pretreatment or concomitant treatment of imipramine was effective in alleviating silica-induced lung pathology, signifying that the early and acute phase of silica-induced 3 inflammation is a critical phase where potential therapeutics interventions could be effective. Taken together, this project elucidates the role of MARCO in silica-induced NLRP3 inflammasome activation and inflammation, and establishes the protective role of imipramine in silica-induced inflammation and disease progression. 4 Acknowledgements I would like to thank my mentor and chair of my advisory committee, Dr. Andrij Holian for his astute guidance, advice and support. With great pleasure, I would like to thank the members of my advisory committee Dr. Kevan Roberts, Dr. Howard Beall, Dr. Christopher Migliaccio and Dr. Stephen Lodmell, for their expert guidance and valuable inputs. I would like to thank Raymond F. Hamilton Jr and Britten Postman for their expertise and invaluable technical instructions. I would also like to thank Center for Environmental Health Sciences and Department of Biomedical Sciences and Pharmaceutical Sciences at the University of Montana for providing me the opportunity to acquire excellent scientific training at the state- of-the art research facility. With gratitude and love I would like to thank my dear parents, Jyotirmay and Bharati Biswas, and my beloved sister Neepa Biswas for their unconditional love, guidance, encouragement, support and most importantly, for being there for me whenever I needed them. I would also like to thank my dear husband, Anirban Ghosh for his love, support and occasional cheering. I am grateful to my family for believing in my potential. I would not be where I am today without the encouragement and support of my loving family. 5 Table of Contents Regulation of silica-induced pulmonary inflammation ...................................................................................... 1 Abstract ...................................................................................................................................................... 2 Acknowledgements .................................................................................................................................... 5 List of key abbreviations ............................................................................................................................ 8 List of publications and manuscript ........................................................................................................... 9 CHAPTER 1 - Introduction .......................................................................................................................... 10 Silica ......................................................................................................................................................... 10 Silicosis .................................................................................................................................................... 13 Classification of silicosis .......................................................................................................................... 13 Signs and Symptoms ................................................................................................................................ 14 Pathophysiology of silicosis ..................................................................................................................... 15 Prevalence of silicosis .............................................................................................................................. 16 Current treatment options for silicosis ..................................................................................................... 16 Particle exposure and respiratory system ................................................................................................. 17 Particle deposition in the respiratory system ............................................................................................ 18 Alveolar Cells in the alveolus .................................................................................................................. 19 Origin, differentiation, distribution and activation
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