Carbocisteine inhibits oxidant-induced apoptosis in cultured human airway epithelial cells

Respirology. 2009 Sep;14(7):1027-34. doi: 10.1111/j.1440-1843.2009.01594.x. Epub 2009 Aug 2.

Abstract

Background and objective: Increased oxidant levels have been associated with exacerbations of COPD, and L-carbocisteine, a mucolytic agent, reduces the frequency of exacerbations. The mechanisms underlying the inhibitory effects of L-carbocisteine on oxidant-induced COPD exacerbations were examined in an in vitro study of human airway epithelial cells.

Methods: In order to examine the antioxidant effects of L-carbocisteine, human tracheal epithelial cells were treated with L-carbocisteine and exposed to hydrogen peroxide (H(2)O(2)). Cell apoptosis was assessed using a cell death detection ELISA, and the pathways leading to cell apoptosis were examined by measurement of caspase-3 and caspase-9 by western blot analysis with fluorescent detection.

Results: The proportion of apoptotic cells in human tracheal epithelium was increased in a concentration- and time-dependent manner, following exposure to H(2)O(2). Treatment with L-carbocisteine reduced the proportion of apoptotic cells. In contrast, H(2)O(2) did not increase the concentration of LDH in supernatants of epithelial cells. Exposure to H(2)O(2) activated caspase-3 and caspase-9, and L-carbocisteine inhibited the H(2)O(2)-induced activation of these caspases. L-carbocisteine activated Akt phosphorylation, which modulates caspase activation, and the inhibitors of Akt, LY294002 and wortmannin, significantly reversed the inhibitory effects of L-carbocisteine on H(2)O(2)-induced cell apoptosis.

Conclusions: These findings suggest that in human airway epithelium, L-carbocisteine may inhibit cell damage induced by H(2)O(2) through the activation of Akt phosphorylation. L-carbocisteine may have antioxidant effects, as well as mucolytic activity, in inflamed airways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Carbocysteine / pharmacology*
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cells, Cultured
  • DNA Fragmentation / drug effects
  • Dose-Response Relationship, Drug
  • Expectorants / pharmacology*
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Respiratory Mucosa / cytology*
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism
  • Time Factors
  • Trachea / cytology*
  • Trachea / drug effects
  • Trachea / metabolism

Substances

  • Expectorants
  • Carbocysteine
  • Hydrogen Peroxide
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
  • Caspase 9