Dissertation
Lung inflammation and the deposition characteristics of inorganic particles in patients with lung cancer
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2020
DOI: 10.17077/etd.005391
Abstract
ABSTRACT
Background
Determining the precise nature of exposures in vivo has long been problematic and computer-controlled scanning electron microscopy (CCSEM) has been used to help address the nature of and to quantify the many particles deposited in the lung tumor tissue. The deposition of inorganic particles in the airway of lungs after inhalation has been linked to the development of lung cancer through mechanisms that involve the induction of chronic inflammation. These inorganic particles contribute to the development of chronic inflammation in the lung through the induction of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. The upregulation of the NLRP3 inflammasome has been linked to the development of lung cancer through laboratory experiments. This chronic inflammation can be tracked clinically by circulating biomarkers such as the erythrocyte sedimentation rate (ESR).
Objectives
The overall goal of this research was to explore potential associations between deposited inorganic particles in the lungs and mechanisms and markers of chronic inflammation. Paper 1 (Chapter 2) described the deposition characteristics of two inorganic particles, chromium and manganese, as well as the redox chemistry between them that contributes to their carcinogenicity. Paper 2 (Chapter 3) explored the association between inorganic particle deposition characteristics and the tracking of resulting inflammation by the ESR. Paper 3 (Chapter 4) explored the association between inorganic particle deposition in the lung tumor tissue and NLRP3 activation.
Methods
The central methodology in this research was the detection of inorganic particles deposited in lung tumor tissue of patients with lung cancer using CCSEM. Tissue was obtained from formalin-fixed paraffin-embedded (FFPE) blocks for paper 1 and fresh frozen blocks for papers 2 and 3 for analysis with CCSEM. Patient information was obtained via self-reported questionnaires in paper 1. Pulmonary function results and markers of inflammation were obtained via electronic medical record abstraction for the assessments of paper 2. NLRP3 activation was assessed for paper 3 in an assay for Caspase 1.
Results
Inorganic particle deposition in the lung tumor tissue can be reported by number and elemental makeup through the utilization of CCSEM. Analysis in paper 1 found that a higher lung burden of chromium and manganese was found in smokers versus never smokers, and in patients with emphysema. Chromium and manganese were shown to biopersist in the lung tumor tissue and were found to be located commonly on the same particle. Paper 2 demonstrated significant associations between ESR and aluminum, silica, and titanium. ESR was also associated with a decrease in the diffusion capacity of the lung for carbon monoxide (DLCO) and increase in the rate of tumor growth. In paper 3, cadmium was significantly associated with lower Caspase 1 tissue readings. More importantly, Caspase 1 levels in tumor tissue were significantly higher than in non-tumor adjacent tissue.
Conclusion
The mechanisms governing chronic inflammation in the lung tumor tissue as a result of inorganic particle deposition are complex and incompletely understood. Paper 1 concluded that manganese is commonly found on the same particle as chromium in lung tumor tissue, suggesting that it is frequently oxidizing chromium to its hexavalent carcinogenic state. Additionally, smoking is an important conduit for exposure to chromium and manganese. Paper 2 concluded that ESR is a good biomarker to track the effect of aluminum, silica, and titanium deposition in the lung tumor tissue and its association with chronic inflammation found in lung cancer. Finally, paper 3 concluded that the NLRP3 inflammasome is more activated in tumor tissue than in non-tumor adjacent tissue, suggesting that the inflammasome continues to mediate the tumor microenvironment even after tumorigenesis.
Details
- Title: Subtitle
- Lung inflammation and the deposition characteristics of inorganic particles in patients with lung cancer
- Creators
- Kristen Lindsey Coleman
- Contributors
- Patrick O'Shaughnessy (Advisor)R. William Field (Advisor)Alejandro Comellas (Committee Member)Charles Lynch (Committee Member)Diane Rohlman (Committee Member)Jessica Sieren (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Occupational and Environmental Health
- Date degree season
- Spring 2020
- DOI
- 10.17077/etd.005391
- Publisher
- University of Iowa
- Number of pages
- xii, 98 pages
- Copyright
- Copyright 2020 Kristen Lindsey Coleman
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 82-94).
- Public Abstract (ETD)
Background
A specialized microscope, called a computer-controlled scanning electron microscope (CCSEM), can be used to count all the particles deposited in the lung and to determine their elemental composition. Chronic inflammation in the lung also involves the nucleotide-biding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. The NLRP3 can be activated by particles and then generates other molecules that prolong inflammation. Inflammation can be monitored through a blood test called the erythrocyte sedimentation rate (ESR) that is elevated when inflammation exists.
Methods
Lung cancer tissue was obtained for use with the CCSEM to determine the number of particles as well as the particle’s chemical composition. The NLRP3 activation was determined using a Caspase 1 assay, which detects NLRP3 activation.
Results/Conclusion
The CCSEM results provided particle count and chemical composition for the lung tumor tissues. There was more chromium and manganese in the lungs of people who smoked as compared to non-smokers. Chromium and manganese were also shown to be retained in the lung tumor tissue and were also often found on the same dust particle. The ESR was higher in patients that had more aluminum, silica, and titanium in their lungs. The NLRP3 activation in tumor tissue was higher than in non-tumor tissue obtained from the same individual.
- Academic Unit
- Occupational and Environmental Health
- Record Identifier
- 9983968394502771
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