Potential toxicity of polymyxins in human lung epithelial cells

Maizbha U Ahmed, Tony Velkov, Yu-Wei Lin, Bo Yun, Cameron J Nowell, Fanfan Zhou, Qi Tony Zhou, Kim Chan, Mohammad A K Azad, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

Inhaled polymyxins are of considerable utility in achieving optimal exposure in the respiratory tract for the treatment of lung infections caused by multidrug-resistant Gram-negative pathogens. Current inhaled polymyxin therapy is empirical, and often large doses are used that may lead to potential pulmonary adverse effects. This study aimed to investigate the effect of polymyxins on human lung epithelial (A549) cells. The viability of A549 cells was examined after treatment with polymyxins by flow cytometry. Activation of caspases 3, 8, and 9, expression of Fas ligand (FasL), loss of mitochondrial membrane potential, and mitochondrial oxidative stress induced by polymyxin B were evaluated. The concentration of polymyxin B required to induce 50% of maximal cell death was 1.74 mM (95% confidence interval, 1.60 to 1.90 mM). Colistin was at least 2-fold less toxic than polymyxin B, while colistimethate was nontoxic. With 2.0 mM polymyxin B, 30.6% 11.5% (mean standard deviation) of the cells were apoptotic at 8 h and this increased to 71.3% 3.72% at 24 h. Concentration-And time-dependent activation of caspases 3, 8, and 9 was evident, while the activation of caspase 9 was more dramatic. Furthermore, polymyxin B caused concentration-And time-dependent FasL expression, production of mitochondrial reactive oxygen species, and changes in mitochondrial membrane potential. This is the first study to demonstrate that both extrinsic death receptor and intrinsic mitochondrial pathways are involved in polymyxininduced toxicity in A549 cells. This knowledge base is critical for the development of novel strategies for the safe and effective inhalation therapy of polymyxins against Gram-negative "superbugs".

Original languageEnglish
Article numbere02690-16
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017

Keywords

  • Apoptosis
  • Mitochondria
  • Polymyxin
  • Pulmonary delivery
  • Respiratory toxicity

Cite this

Ahmed, Maizbha U ; Velkov, Tony ; Lin, Yu-Wei ; Yun, Bo ; Nowell, Cameron J ; Zhou, Fanfan ; Zhou, Qi Tony ; Chan, Kim ; Azad, Mohammad A K ; Li, Jian. / Potential toxicity of polymyxins in human lung epithelial cells. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 6.
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abstract = "Inhaled polymyxins are of considerable utility in achieving optimal exposure in the respiratory tract for the treatment of lung infections caused by multidrug-resistant Gram-negative pathogens. Current inhaled polymyxin therapy is empirical, and often large doses are used that may lead to potential pulmonary adverse effects. This study aimed to investigate the effect of polymyxins on human lung epithelial (A549) cells. The viability of A549 cells was examined after treatment with polymyxins by flow cytometry. Activation of caspases 3, 8, and 9, expression of Fas ligand (FasL), loss of mitochondrial membrane potential, and mitochondrial oxidative stress induced by polymyxin B were evaluated. The concentration of polymyxin B required to induce 50{\%} of maximal cell death was 1.74 mM (95{\%} confidence interval, 1.60 to 1.90 mM). Colistin was at least 2-fold less toxic than polymyxin B, while colistimethate was nontoxic. With 2.0 mM polymyxin B, 30.6{\%} 11.5{\%} (mean standard deviation) of the cells were apoptotic at 8 h and this increased to 71.3{\%} 3.72{\%} at 24 h. Concentration-And time-dependent activation of caspases 3, 8, and 9 was evident, while the activation of caspase 9 was more dramatic. Furthermore, polymyxin B caused concentration-And time-dependent FasL expression, production of mitochondrial reactive oxygen species, and changes in mitochondrial membrane potential. This is the first study to demonstrate that both extrinsic death receptor and intrinsic mitochondrial pathways are involved in polymyxininduced toxicity in A549 cells. This knowledge base is critical for the development of novel strategies for the safe and effective inhalation therapy of polymyxins against Gram-negative {"}superbugs{"}.",
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Potential toxicity of polymyxins in human lung epithelial cells. / Ahmed, Maizbha U; Velkov, Tony; Lin, Yu-Wei; Yun, Bo; Nowell, Cameron J; Zhou, Fanfan; Zhou, Qi Tony ; Chan, Kim; Azad, Mohammad A K; Li, Jian.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 6, e02690-16, 01.06.2017.

Research output: Contribution to journalArticleResearchpeer-review

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