A mechanistic study of cigarette smoke-induced COPD in C57BL/6 mice: The impact of switching to pMRTP

      Veljkovic, E.; Phillips, B.; Peck, M. J.; Buettner, A.; Vuillaume, G.; Hoeng, J.; Peitsch, M. C.

      Conference date
      Mar 23, 2014
      Conference name
      Society of Toxicology (SOT) 2014

      In this study, the impact on the development of emphysema/COPD following inhalation of aerosol from two tobacco products, a reference cigarette (3R4F) and a prototypic modified risk tobacco product (pMRTP), was evaluated in C57BL/6 mice. The mice were exposed to an aerosol from 3R4F (750 µg/l TPM, 34.4 µg/l nicotine), pMRTP (nicotine concentration-matched) or filtered air (sham) for 4 hours per day, 5 days per week, up to 7 months. After 2 months of exposure to 3R4F, switching and cessation groups were exposed to pMRTP or filtered air, respectively. To analyze the progression of emphysema, evaluations of inflammation, pulmonary function, and various histopathological and molecular changes (transcriptomics and lipidomics) were performed at months 1, 2, 3, 4, 5 and 7. Exposure to 3R4F induced molecular, cellular and physiological modifications in lungs leading to emphysematous changes. Animals exposed to pMRTP exhibited negligible changes in all parameters assessed. Both cessation and switching groups showed a reversal of the inflammatory and functional responses induced by 3R4F smoke. Histopathological evaluation revealed a slowdown in the progression of emphysematous changes in switching and cessation groups. Smoking cessation or switching resulted in the rapid recovery at the transcription level. The lipid profiles in lung, liver and plasma similarly showed a clear 3R4F effect, with minimal changes associated with pMRTP exposure, and recovery near to sham-exposed levels following either switching or cessation. These data demonstrate that exposure to pMRTP for up to 7 months resulted in a response similar to fresh air-exposed animals using a battery of physiological and molecular measures. Furthermore, following a 2-month 3R4F cigarette smoke exposure period, both cessation and switching to a pMRTP aerosol resulted in the reversal or stabilization of parameters assessed.