Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation

Am J Physiol Lung Cell Mol Physiol. 2017 Aug 1;313(2):L267-L277. doi: 10.1152/ajplung.00354.2016. Epub 2017 May 11.


Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-mo-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations with light microscopy. Daily marijuana inhalation evoked severe bronchial hyperreactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, and neutrophil and macrophage infiltration developed after 1 mo of marijuana smoking; lymphocyte accumulation after 2 mo; macrophage-like giant cells, irregular or destroyed bronchial mucosa, goblet cell hyperplasia after 3 mo; and severe atelectasis, emphysema, obstructed or damaged bronchioles, and endothelial proliferation at 4 mo. Myeloperoxidase activity, inflammatory cell, and cytokine profile correlated with these changes. Airway hyperresponsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyperresponsiveness after 2 mo and significantly later caused inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyperresponsiveness, inflammation, tissue destruction, and emphysema, which are not mediated by the CB1 receptor.

Keywords: alveolitis; emphysema; inflammatory cytokines; myeloperoxidase activity; pneumonitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchi / drug effects
  • Bronchi / metabolism
  • Bronchial Hyperreactivity / chemically induced*
  • Bronchial Hyperreactivity / metabolism
  • Bronchoalveolar Lavage Fluid
  • Cannabis / adverse effects*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Inflammation / chemically induced*
  • Inflammation / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Pulmonary Emphysema / chemically induced*
  • Pulmonary Emphysema / metabolism
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Respiratory Hypersensitivity / chemically induced*
  • Respiratory Hypersensitivity / metabolism
  • Smoke / adverse effects*
  • Tobacco / adverse effects


  • Cytokines
  • Lipopolysaccharides
  • Receptor, Cannabinoid, CB1
  • Smoke