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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07142010-141346 |
| Date | 26 July 2010 |
| Creators | Shipley, Timothy W |
| Contributors | Karen A, Norris, PhD, Alison Morris, MD, MS, Todd Reinhart, ScD, Prabir Ray, PhD, Jerry Nau, MD, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-07142010-141346/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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