Chronic E-Cigarette Use Increases Neutrophil Elastase and Matrix Metalloprotease Levels in the Lung

Am J Respir Crit Care Med. 2019 Dec 1;200(11):1392-1401. doi: 10.1164/rccm.201903-0615OC.


Rationale: Proteolysis is a key aspect of the lung's innate immune system. Proteases, including neutrophil elastase and MMPs (matrix metalloproteases), modulate cell signaling, inflammation, tissue remodeling, and leukocyte recruitment via cleavage of their target proteins. Excessive proteolysis occurs with chronic tobacco use and is causative for bronchiectasis and emphysema. The effect of e-cigarettes (vaping) on proteolysis is unknown.

Objectives: We used protease levels as biomarkers of harm to determine the impact of vaping on the lung.

Methods: We performed research bronchoscopies on healthy nonsmokers, cigarette smokers, and e-cigarette users (vapers), and determined protease levels in BAL. In parallel, we studied the effects of e-cigarette components on protease secretion in isolated human blood neutrophils and BAL-derived macrophages. We also analyzed the nicotine concentration in induced sputum and BAL.

Measurements and Main Results: Neutrophil elastase, MMP-2, and MMP-9 activities and protein levels were equally elevated in both vapers' and smokers' BAL relative to nonsmokers. In contrast, antiprotease levels were unchanged. We also found that exposure of isolated neutrophils and macrophages to nicotine elicited dose-dependent increases in protease release. After vaping, measurable levels of nicotine were detectable in sputum and BAL, which corresponded to the half-maximal effective concentration values for protease release seen in immune cells.

Conclusions: We conclude that vaping induces nicotine-dependent protease release from resident pulmonary immune cells. Thus, chronic vaping disrupts the protease-antiprotease balance by increasing proteolysis in lung, which may place vapers at risk of developing chronic lung disease. These data indicate that vaping may not be safer than tobacco smoking.

Keywords: BAL; nicotine; protease; sputum; vaping.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Biomarkers / analysis
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cotinine / analogs & derivatives
  • Cotinine / analysis
  • Female
  • Humans
  • Leukocyte Elastase / metabolism*
  • Lung / chemistry
  • Lung / drug effects*
  • Lung / enzymology
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinases / metabolism*
  • Neutrophils / drug effects
  • Neutrophils / enzymology
  • Nicotine / analysis
  • Nicotine / pharmacology
  • Vaping / adverse effects*


  • Biomarkers
  • hydroxycotinine
  • Nicotine
  • ELANE protein, human
  • Leukocyte Elastase
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Cotinine