Date of Award

2023

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Jerome O Cantor

Second Advisor

John Wurpel

Third Advisor

Francis Schanne

Abstract

The mechanical properties of lung elastic fibers are derived from the specialized features of their core elastin protein, which contains distensible, coiled peptides that store the energy needed to expel air from the lungs. Elastin crosslinks provide structural support for the fibers and play an important role in determining the morphologic features of the lung. Degradation of elastic fibers in lung disease is associated with the release of desmosine, a unique amino acid that can be readily identified and quantified in body fluids and solid tissue using LC–MS-MS. The purpose of this study was to explore the role of desmosine as a biomarker for emphysematous changes in both animal and human models of COPD. Female Golden Syrian hamsters were exposed to either secondhand cigarette smoke or normal room air for 4 hours a day over a period of 3 days. 24 hours following exposure, hamsters were injected intraperitoneally with either 200 μg lipopolysaccharide injections in 0.1 mL saline or saline alone. Following euthanasia, hamster lung tissue was collected and evaluated for desmosine content and airspace enlargement. Hamster BALF was also collected and assessed for leukocyte and neutrophil content. Human lung tissue was collected postmortem from decedents with or without a clinical history of lung disease. This tissue was then evaluated for desmosine content and airspace enlargement. In addition to these studies, authentic human plasma, urine, and sputum samples collected from a previous clinical trial were evaluated for desmosine content. Desmosine content from both human and hamster models of COPD were measured using a novel LC–MS-MS technique that was developed for the quantification of desmosine in body fluids and solid tissue simultaneously. Significant increases in desmosine content and airspace enlargement were seen in the lungs of hamsters exposed to cigarette smoke and lipopolysaccharide. BALF leukocytes and neutrophils were concomitantly increased in this exposure group. Similar increases in desmosine content and airspace enlargement were seen in the lungs of human decedents with COPD. Based on these morphological and biochemical findings, desmosine is a sensitive indicator of alveolar wall injury and elastic fiber degradation in COPD.

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