Abstract
Because S-adenosylmethionine (AdoMet) is required by Pneumocystis carinii in vitro, Pneumocystis infection depletes plasma AdoMet of rats and humans, nicotine reduces AdoMet of guinea pig lungs, and smoking correlates with reduced episodes of Pneumocystis pneumonia (PCP) in AIDS patients, we tested the effect of nicotine treatment on PCP using a rat model. Intraperitoneal infusion of 400 microg of R-(+) nicotine kg(-1) h(-1) intraperitoneal for 21 days caused a 15-fold reduction in lung AdoMet although neither plasma nor liver were changed. Infusion of 4 and 400 microg kg(-1) h(-1) into immunosuppressed rats, beginning when rats were inoculated with P. carinii, caused 85 and 99.88% reductions, respectively, in P. carinii cysts at sacrifice 21 days later; P. carinii nuclei were reduced by 91.2 and >99.99%, respectively. This effect was reversed by concomitant administration of AdoMet with nicotine. Treatment with AdoMet alone increased infection intensity. We conclude that AdoMet is a critical and limiting nutrient for Pneumocystis thus can serve as a therapeutic target for PCP. Regarding the mechanism, nicotine treatment caused no change in rat lung activity of AdoMet synthesizing methionine ATP transferase activity nor was there any evidence of increased AdoMet utilization for methylation reactions. Except of a doubling of putrescine, nicotine treatment also did not change lung polyamine content. However, key polyamine anabolic and catabolic enzymes were upregulated, and there were corresponding changes in polyamine metabolic intermediates. We conclude that chronic nicotine treatment increases lung polyamine catabolic/anabolic cycling and/or excretion leading to increased AdoMet-consuming polyamine biosynthesis and depletion of lung AdoMet.
Highlights
Pneumocystis is a fungal pathogen that infects the lungs of immunocompromised mammals causing a severe pneumonia known as PCP1 (Pneumocystis pneumonia)
Because S-adenosylmethionine (AdoMet) is required by Pneumocystis carinii in vitro, Pneumocystis infection depletes plasma AdoMet of rats and humans, nicotine reduces AdoMet of guinea pig lungs, and smoking correlates with reduced episodes of Pneumocystis pneumonia (PCP) in AIDS patients, we tested the effect of nicotine treatment on PCP using a rat model
Delivery of Nicotine to Rat Lungs via Intraperitoneal Infusion—Since systemic nicotine had been reported to reduce lung AdoMet of guinea pigs [29], and systemic administration seemed more relevant for possible clinical application, we chose peritoneal delivery rather than delivering nicotine directly to the lungs
Summary
Pneumocystis is a fungal pathogen that infects the lungs of immunocompromised mammals causing a severe pneumonia known as PCP1 (Pneumocystis pneumonia). AdoMet, and PCP began when we associated our findings that Pneumocystis requires AdoMet in culture and depletes plasma AdoMet in the rat model of PCP [22] with the results of a broad clinical study reporting a negative correlation between smoking and recurrent PCP [46] and older work showing a dramatic, lung-specific AdoMet reduction in guinea pigs treated with nicotine [29] From these associations, we developed the hypothesis that smoking protects against PCP by the action of nicotine causing a reduction in lung AdoMet. Here we report rat model data supporting this hypothesis and data suggesting the mechanism involved in the effect of nicotine on lung AdoMet
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