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Archives of Toxicology

, Volume 90, Issue 3, pp 617–632 | Cite as

Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses

  • Ha Ryong Kim
  • Kyuhong Lee
  • Chang We Park
  • Jeong Ah Song
  • Da Young Shin
  • Yong Joo Park
  • Kyu Hyuck ChungEmail author
Organ Toxicity and Mechanisms

Abstract

Polyhexamethylene guanidine (PHMG) phosphate was used as a disinfectant for the prevention of microorganism growth in humidifiers, without recognizing that a change of exposure route might cause significant health effects. Epidemiological studies reported that the use of humidifier disinfectant containing PHMG-phosphate can provoke pulmonary fibrosis. However, the pulmonary toxicity of PHMG-phosphate aerosol particles is unknown yet. This study aimed to elucidate the toxicological relationship between PHMG-phosphate aerosol particles and pulmonary fibrosis. An in vivo nose-only exposure system and an in vitro air–liquid interface (ALI) co-culture model were applied to confirm whether PHMG-phosphate induces inflammatory and fibrotic responses in the respiratory tract. Seven-week-old male Sprague–Dawley rats were exposed to PHMG-phosphate aerosol particles for 3 weeks and recovered for 3 weeks in a nose-only exposure chamber. In addition, three human lung cells (Calu-3, differentiated THP-1 and HMC-1 cells) were cultured at ALI condition for 12 days and were treated with PHMG-phosphate at set concentrations and times. The reactive oxygen species (ROS) generation, airway barrier injuries and inflammatory and fibrotic responses were evaluated in vivo and in vitro. The rats exposed to PHMG-phosphate aerosol particles in nanometer size showed pulmonary inflammation and fibrosis including inflammatory cytokines and fibronectin mRNA increase, as well as histopathological changes. In addition, PHMG-phosphate triggered the ROS generation, airway barrier injuries and inflammatory responses in a bronchial ALI co-culture model. Those results demonstrated that PHMG-phosphate aerosol particles cause pulmonary inflammatory and fibrotic responses. All features of fibrogenesis by PHMG-phosphate aerosol particles closely resembled the pathology of fibrosis that was reported in epidemiological studies. Finally, we expected that PHMG-phosphate infiltrated into the lungs in the form of aerosol particles would induce an airway barrier injury via ROS, release fibrotic inflammatory cytokines, and trigger a wound-healing response, leading to pulmonary fibrosis. A simultaneous state of tissue destruction and inflammation caused by PHMG-phosphate had whipped up a “perfect storm” in the respiratory tract.

Keywords

Polyhexamethylene guanidine phosphate Aerosol particles Humidifier disinfectant Pulmonary fibrosis 

Notes

Acknowledgments

This work was partly supported by the Korea Environmental Industry and Technology Institute (Grant Number: 2012001370006).

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Ha Ryong Kim
    • 1
  • Kyuhong Lee
    • 2
    • 3
  • Chang We Park
    • 1
  • Jeong Ah Song
    • 2
  • Da Young Shin
    • 1
  • Yong Joo Park
    • 1
  • Kyu Hyuck Chung
    • 1
    Email author
  1. 1.School of PharmacySungkyunkwan UniversitySuwonKorea
  2. 2.Inhalation Toxicology Research CenterKorea Institute of ToxicologyJeongeupKorea
  3. 3.Human and Environment ToxicologyUniversity of Science and TechnologyDaejeonKorea

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