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Temple University

1. Moncada Benavides, Camilo Andres. EFFECT OF NICOTINE ON LUNG S-ADENOSYLMETHIONINE AND PNEUMOCYSTIS PNEUMONIA DEVELOPMENT.

Degree: PhD, 2012, Temple University

Biochemistry

Infection with "Pneumocystis" causes a ≥ 99% depletion of plasma S-adenosylmethionine (AdoMet) levels in both "Pneumocystis" pneumonia (PcP) animal models and patients. AdoMet is a critical cellular metabolic intermediate, with a pivotal role as methyl donor in a myriad of biochemical processes and necessary for the synthesis of the essential polyamines spermidine and spermine. In the target tissue of "Pneumocystis", the lung, levels of AdoMet were previously shown to be depleted experimentally using nicotine. Here we show that chronic administration of nicotine in an animal model of PcP resulted in decreased lung AdoMet content. Since "Pneumocystis" is dependent on this metabolite, PcP burden was also relived. We hypothesized that the underlying mechanism behind nicotine-induced AdoMet depletion was an increased consumption of AdoMet through the polyamine pathway where the increased activity of N-1-spermidine/spermine acetyl transferase raises the catabolic / anabolic cycling of polyamines, a process that utilizes AdoMet. In a critical test of our hypothesis, we found that blockage of polyamine metabolism via inhibition of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) hinders the effect of nicotine on lung AdoMet levels. Further support is provided by metabolite analyses showing nicotine to cause a strong diversion of AdoMet toward polyamine synthesis and away from methylation reactions; these shifts are also reversed by inhibition of ODC. Because the nicotine effect on "Pneumocystis" is so striking, we considered the possibility of tissue specificity. Using laser capture microdissection (LCM), we collected samples of lung alveolar regions (site of infection) and respiratory epithelium for controls. We found nicotine to cause increased ODC activity in alveolar regions but not airway epithelium; we conclude that tissue specificity likely contributes to the effect of nicotine on "Pneumocystis" pneumonia. Our studies demonstrate the feasibility of pharmacological manipulation of the polyamine pathway in order to reduce AdoMet levels in the lung and prompted the assessment of compounds alternative to nicotine with the potential to achieve a comparable effect. In vitro evaluation of the polyamine analog DENSPM along with putrescine in type II alveolar cell lines, indicates that although such a combination has the potential to induce polyamine flux, an apparent competition for the same polyamine transport system impairs simultaneous uptake of both compounds at effective concentrations. In conclusion, we showed that chronic nicotine administration causes reduction of AdoMet levels in rat lung following 21 days of treatment, by a mechanism involving the induction of polyamine flux, which is responsible of increased AdoMet utilization for polyamine biosynthesis. According to LCM-based analysis, this effect seems to be confined to the alveolar regions of the lung.

Temple University – Theses

Advisors/Committee Members: Merali, Salim, Chong, Parkson Lee-Gau, Soprano, Dianne R., Collins, Jimmy H., Yarlett, Nigel.

Subjects/Keywords: Biochemistry; Laser Capture Microdissection; Lung; Nicotine; Pneumocystis; Polyamines; S-Adenosylmethionine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Moncada Benavides, C. A. (2012). EFFECT OF NICOTINE ON LUNG S-ADENOSYLMETHIONINE AND PNEUMOCYSTIS PNEUMONIA DEVELOPMENT. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,206623

Chicago Manual of Style (16th Edition):

Moncada Benavides, Camilo Andres. “EFFECT OF NICOTINE ON LUNG S-ADENOSYLMETHIONINE AND PNEUMOCYSTIS PNEUMONIA DEVELOPMENT.” 2012. Doctoral Dissertation, Temple University. Accessed September 25, 2020. http://digital.library.temple.edu/u?/p245801coll10,206623.

MLA Handbook (7th Edition):

Moncada Benavides, Camilo Andres. “EFFECT OF NICOTINE ON LUNG S-ADENOSYLMETHIONINE AND PNEUMOCYSTIS PNEUMONIA DEVELOPMENT.” 2012. Web. 25 Sep 2020.

Vancouver:

Moncada Benavides CA. EFFECT OF NICOTINE ON LUNG S-ADENOSYLMETHIONINE AND PNEUMOCYSTIS PNEUMONIA DEVELOPMENT. [Internet] [Doctoral dissertation]. Temple University; 2012. [cited 2020 Sep 25]. Available from: http://digital.library.temple.edu/u?/p245801coll10,206623.

Council of Science Editors:

Moncada Benavides CA. EFFECT OF NICOTINE ON LUNG S-ADENOSYLMETHIONINE AND PNEUMOCYSTIS PNEUMONIA DEVELOPMENT. [Doctoral Dissertation]. Temple University; 2012. Available from: http://digital.library.temple.edu/u?/p245801coll10,206623

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