Shipley, Timothy W
(2010)
Pneumocystis Colonization and Chronic Obstructive Pulmonary Disease in a Simian Model of HIV Infection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Potent anti-retroviral therapy has transformed HIV infection from an acute to a chronic disease. Consequently, diseases previously not prevalent in HIV+ persons have emerged. For example, HIV-infected persons are at increased risk for developing COPD. Pneumocystis (Pc), a fungal opportunistic pathogen, has been associated with HIV and COPD. Pc colonization- the presence of Pc in subjects without clinical symptoms of Pneumocystis pneumonia- is increased in COPD patients. Furthermore, HIV+ individuals are at elevated risk for both Pc colonization and emphysema. Together, these observations suggest that COPD in HIV+ individuals involves Pc colonization. We used a simian/human immunodeficiency virus (SHIV) model of HIV infection to study pulmonary effects of Pc colonization. SHIV-infected/Pc-colonized monkeys developed obstructive pulmonary disease characterized by increased emphysematous tissue and bronchial-associated lymphoid tissue. Elevated Th2 cytokines and pro-inflammatory mediators in bronchoalveolar lavage fluid coincided with Pc colonization and pulmonary function decline. These results indicate that Pc colonization may be a risk factor for development of HIV-associated COPD.Gene expression profiles in the lung tissue of these animals evaluated by microarray analysis revealed differential expression of 243 genes in the obstructed SHIV/Pc monkeys compared to SHIV-only monkeys with normal lung function. Potentially relevant differentially expressed genes included genes involved in inflammation, protease/antiprotease balance, redox balance and tissue homeostasis, thus indentifying factors and pathways involved in early development of SHIV-associated COPD and revealing several novel, possible therapeutic targets.In a second cohort of animals, airway obstruction development associated with Pc colonization was recapitulated. To directly correlate pulmonary function decline with presence of Pc, a subset of the Pc-colonized monkeys was treated with the anti-Pc drug, TMP-SMX, after significant airway obstruction had occurred. No further pulmonary function decline was observed in either the treated or untreated animals up to a year after initiating TMP-SMX treatment. These results indicate that Pc-associated induction of airway obstruction takes place early after onset of colonization followed by an extended period of containment of the effects of Pc.These results demonstrate a key role for Pc in the early development of SHIV-associated COPD. Furthermore, they reveal multiple potential mediators of Pc-induced airway obstruction.
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Details
Item Type: |
University of Pittsburgh ETD
|
Status: |
Unpublished |
Creators/Authors: |
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ETD Committee: |
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Date: |
26 July 2010 |
Date Type: |
Completion |
Defense Date: |
23 June 2010 |
Approval Date: |
26 July 2010 |
Submission Date: |
14 July 2010 |
Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
Institution: |
University of Pittsburgh |
Schools and Programs: |
School of Medicine > Immunology |
Degree: |
PhD - Doctor of Philosophy |
Thesis Type: |
Doctoral Dissertation |
Refereed: |
Yes |
Uncontrolled Keywords: |
COPD; Emphysema; HIV; SHIV; Siman Model |
Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-07142010-141346/, etd-07142010-141346 |
Date Deposited: |
10 Nov 2011 19:51 |
Last Modified: |
19 Dec 2016 14:36 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/8374 |
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