Presentation Type
Poster Presentation
Category
STEM (science, technology, engineering, mathematics)
Abstract/Artist Statement
Chronic respiratory disease remains a leading cause of death around the world, and recent events have only increased respiratory disease concerns. As such, there is a growing need for effective therapeutics to combat these and other chronic diseases. While the discovery and design of new pharmaceuticals can be a lengthy process there is an abundance of FDA approved drugs that can be repurposed for use in other than their originally intended uses. For example, the use of anti-depressants has been proposed as a potential therapy for COVID after a study showed that patients regularly taking anti-depressants had fewer COVID-caused hospitalizations and deaths. If the prescribed use of anti-depressants has the potential to lessen the impact of a respiratory disease such as COVID, we propose they can reduce the progression of other respiratory diseases such as the pervasive occupational-disease silicosis. Silicosis is a progressive lung disease marked by tissue scaring in the gas-air exchange regions of the lungs and currently there is no cure or effective therapy. While silicosis cases had been on the decline through efforts to change workplace conditions, there has been a troubling increase in atypical silicosis cases that result from brief, but highly concentrated amounts of crystalline silica being inhaled at the workplace. Occupations such as artificial stone countertop fabrication and sandblasting denim have seen an increase in silicosis cases. Because the progression of silicosis and other respiratory disease depends largely on unresolved inflammation, understanding the mechanisms of inflammation could provide a way to provide effective therapeutics. I propose that by using a variety of drugs classified as FIASMAs, the inflammation caused by silica in lung macrophages will be prevented. Macrophages have been demonstrated to the central regulatory cell in silicosis. Macrophages were pre-treated with the FIASMAs before they were exposed to crystalline silica and the resulting inflammation was significantly less when compared to the untreated cells (Fluvoxamine and Prozac decreased inflammation 86% and 71% respectively). To understand how these drugs can reduce inflammation, the effect of each of the drugs on the function of lysosomes was tested. Lysosomes are organelles responsible for digestion of the silica particles taken up by lung cells and are key to understanding how inflammation persists in lung diseases such as silicosis. Treating cells with FIASMA drugs decreased the function of degradative enzymes within the lysosomes (12% and 69% less than untreated cells), prevented the exit of cholesterol from the lysosomes (decreased by 15% and 24% from untreated cells), and prevented the permeability of the lysosomes caused by the silica particles (36% and 56% less than silica-caused permeability) by Fluvoxamine and Prozac, respectively. These results demonstrate that FIASMA drugs prevent silica particle caused inflammation in a macrophage cell model by reducing damage to the lysosomes, likely through the increased cholesterol in the lysosomes. The reduction of inflammation seen here suggests that FIASMA drugs should be further studied in respiratory disease models as potential therapeutic options to combat current and future human health crises.
Mentor Name
Andrij Holian
Personal Statement
The nature of my work is to understand the cellular mechanisms behind respiratory inflammation. This work has broad implications in global human health, especially considering current events. According to the American Lung Association, nearly 37 million people in the US live with chronic lung diseases while globally the World Health Organization estimates that respiratory disease leads to more than 8 million deaths per year. In the current pandemic, a majority of the 4.5 million deaths have been from respiratory distress. Respiratory disease is largely driven by unrelenting inflammation. Treatment for many inflammatory lung diseases treats the symptoms of the inflammation but is ineffective in reducing inflammation at its point of origin. My work will contribute to the understanding of cellular mechanisms in the persistence of inflammation. By understanding how inflammation persists, we can develop therapeutics that specifically reduce the production of inflammatory signals necessary for that persistence. One respiratory disease driven by the persistence of inflammatory signals is silicosis. Silicosis is a respiratory disease caused by the inhalation of silicon dioxide particles of a tiny enough size to get into the smallest portions of the lungs. These particles typically originate in occupations where dust is generated, such as mining, construction work, artificial stone countertop fabrication, or the sandblasting of denim jeans. In the lung, the inhaled silica particles interact with the macrophage cells and cause a cycle of cell death and inflammation. I use silica-caused inflammation to study the mechanisms of respiratory inflammation. By understanding even one component of respiratory inflammation, I hope to contribute to a greater understanding of respiratory inflammation in its entirety. The drugs I use in my research are FDA-approved drugs that are not currently used to treat silicosis, but I believe they have the potential to be used therapeutically for respiratory inflammation. In my work, I will show the efficacy of these drugs in preventing inflammation caused by silica and explore the impact of the drugs on the inner workings of lung macrophage cells and how that contributes to reduced inflammation. The therapeutic potential of these drugs in treating respiratory inflammation remains a gap of knowledge which is why I believe my research is of great importance to global human health. This reduction in inflammation seen in a silica exposure model points to the ability of these drugs to be used to prevent the onset of silicosis disease in those exposed to varying levels of silica in their occupations. Additionally, my research seeks to understand the cellular mechanisms impacted by these drugs and how that mitigates inflammation, leading to a greater understanding of respiratory inflammation and how to treat it. For this reason, I respectfully request your consideration for the Best of GradCon award.
Becky Kendall Video of Poster
Antidepressants reduce silica caused inflammation in lung macrophages
UC North Ballroom
Chronic respiratory disease remains a leading cause of death around the world, and recent events have only increased respiratory disease concerns. As such, there is a growing need for effective therapeutics to combat these and other chronic diseases. While the discovery and design of new pharmaceuticals can be a lengthy process there is an abundance of FDA approved drugs that can be repurposed for use in other than their originally intended uses. For example, the use of anti-depressants has been proposed as a potential therapy for COVID after a study showed that patients regularly taking anti-depressants had fewer COVID-caused hospitalizations and deaths. If the prescribed use of anti-depressants has the potential to lessen the impact of a respiratory disease such as COVID, we propose they can reduce the progression of other respiratory diseases such as the pervasive occupational-disease silicosis. Silicosis is a progressive lung disease marked by tissue scaring in the gas-air exchange regions of the lungs and currently there is no cure or effective therapy. While silicosis cases had been on the decline through efforts to change workplace conditions, there has been a troubling increase in atypical silicosis cases that result from brief, but highly concentrated amounts of crystalline silica being inhaled at the workplace. Occupations such as artificial stone countertop fabrication and sandblasting denim have seen an increase in silicosis cases. Because the progression of silicosis and other respiratory disease depends largely on unresolved inflammation, understanding the mechanisms of inflammation could provide a way to provide effective therapeutics. I propose that by using a variety of drugs classified as FIASMAs, the inflammation caused by silica in lung macrophages will be prevented. Macrophages have been demonstrated to the central regulatory cell in silicosis. Macrophages were pre-treated with the FIASMAs before they were exposed to crystalline silica and the resulting inflammation was significantly less when compared to the untreated cells (Fluvoxamine and Prozac decreased inflammation 86% and 71% respectively). To understand how these drugs can reduce inflammation, the effect of each of the drugs on the function of lysosomes was tested. Lysosomes are organelles responsible for digestion of the silica particles taken up by lung cells and are key to understanding how inflammation persists in lung diseases such as silicosis. Treating cells with FIASMA drugs decreased the function of degradative enzymes within the lysosomes (12% and 69% less than untreated cells), prevented the exit of cholesterol from the lysosomes (decreased by 15% and 24% from untreated cells), and prevented the permeability of the lysosomes caused by the silica particles (36% and 56% less than silica-caused permeability) by Fluvoxamine and Prozac, respectively. These results demonstrate that FIASMA drugs prevent silica particle caused inflammation in a macrophage cell model by reducing damage to the lysosomes, likely through the increased cholesterol in the lysosomes. The reduction of inflammation seen here suggests that FIASMA drugs should be further studied in respiratory disease models as potential therapeutic options to combat current and future human health crises.