Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses

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• 作者：Ha Ryong Kim ; Kyuhong Lee ; Chang We Park ; Jeong Ah Song…
• 关键词：Polyhexamethylene guanidine phosphate ; Aerosol particles ; Humidifier disinfectant ; Pulmonary fibrosis
• 刊名：Archives of Toxicology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：90
• 期：3
• 页码：617-632
• 全文大小：1,880 KB
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• 作者单位：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)
  
  1. School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea
  2. Inhalation Toxicology Research Center, Korea Institute of Toxicology, Jeongeup, 580-185, Korea
  3. Human and Environment Toxicology, University of Science and Technology, Daejeon, 305-350, Korea
  
• 刊物主题：Pharmacology/Toxicology; Occupational Medicine/Industrial Medicine; Environmental Health; Biomedicine general;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-0738

文摘

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.