Effect of Nicotine on Lung S-Adenosylmethionine and Development of Pneumocystis Pneumonia

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 g 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 g 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.

Community-acquired lung respiratory infections in HIV-infected patients: microbial aetiology and outcome

“…A recent report by GORDIN et al [14] found, in a follow-up study, that actively smoking HIVinfected patients who had interrupted HAART had an increased risk of bacterial pneumonia. The effect of smoking on the development of PCP is consistent with data from by SHIVJI et al [15] who showed that Sadenosylmethionine, a critical cellular metabolic intermediate necessary for P. jirovecii growth, is significantly reduced by nicotine exposure. This finding clearly explains the reduced rate of PCP among smoking AIDS patients [15].…”

S-Adenosylmethionine as a Biomarker for the Early Detection of Lung Cancer

“…22 In contrast, infusion of nicotine into the rat depletes lung AdoMet levels by increasing lung polyamine catabolic/anabolic cycling and/or excretion. 23 We noted that the highest (fourfold) levels of plasma AdoMet were in lung cancer patients who actually had significantly lower pack-years of smoking than our high-risk smokers (Figs 1 , 2) consistent with the concept that lung cancer rather than smoking elevated AdoMet. Skelly and colleagues 24 have published results of plasma AdoMet concentrations in a variety of human infectious diseases (bacterial pneumonia, tuberculosis, asymptomatic HIV, cryptococcosis), finding levels similar to our control subjects (100 to 150 nmol/L) and demonstrated a decline after treatment.…”

Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells

“…Blanchet et al 92 observed that nicotineinduced inhibition of macrophage function may actually protect against infl ammatory lung processes such as HP by decreasing the number of alveolar macrophages in the lungs of experimental animals and decreasing infl ammatory cytokine production. Further, Shivji et al 93 reported recently that chronic nicotine exposure results in a reduction of lung S-adenosylmethionine (AdoMet), which is required for growth of Pneumocystitis carinii . As such, smoking and nicotine protect against Pneumocystitis .…”