Date of Award

2020

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Jerome Cantor

Second Advisor

John Wurpel

Third Advisor

Sandra Reznik

Abstract

To further understand the effect of superimposed lung inflammation on COPD, our laboratory developed a hamster model of COPD exacerbations using sequential intratracheal instillations of lipopolysaccharide (LPS) and elastase. Using this model, the superimposed inflammatory effect of LPS on elastase-induced emphysema was studied through morphological and biochemical parameters. Total leukocyte and percent neutrophil count in bronchoalveolar lavage fluid (BALF), and elastin-specific desmosine crosslinks (DID) were measured 48 hours after LPS treatment. Morphometric changes were evaluated with mean linear intercept (MLI) methods, and interstitial elastic fiber and lung surface area measurements 1 week post-LPS treatment. Compared to controls, animals treated with elastase/LPS showed a significant increase in BALF leukocytes (187 vs 47.7 x 104 cells), neutrophils (39 vs 4.8 percent), and free DID levels (182 vs 97 percent). Additionally, MLI was significantly elevated in the elastase/LPS group compared to controls (156.2 vs 81.7micrometer). Due to enhanced splaying and fragmentation of elastic fibers, interstitial elastic fiber surface area was significantly increased in animals treated with elastase/LPS than controls (49 vs 26 percent). On the other hand, lung surface area was decreased in elastase/LPS group compared to controls (17.8 vs 25.5 percent). Furthermore, intratracheal instillations of elastin peptides and LPS demonstrated significant effects on BALF neutrophils, free DID levels and leukocyte chemotactic properties. The results suggest that structural alterations in elastic fibers during exacerbations make them more susceptible to breakdown and may have a proinflammatory effect further accelerating loss of lung parenchyma and function.

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