title: Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses.
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.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Ha Ryong
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Inhalation Toxicology Research Center, Korea Institute of Toxicology, Jeongeup, 580-185, Korea.|Human and Environment Toxicology, University of Science and Technology, Daejeon, 305-350, Korea.
authors.forename: Kyuhong
authors.initials: K
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Chang We
authors.initials: CW
authors.lastname: Park
authors.affiliation: Inhalation Toxicology Research Center, Korea Institute of Toxicology, Jeongeup, 580-185, Korea.
authors.forename: Jeong Ah
authors.initials: JA
authors.lastname: Song
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Da Young
authors.initials: DY
authors.lastname: Shin
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Yong Joo
authors.initials: YJ
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea. khchung@skku.edu.
authors.forename: Kyu Hyuck
authors.initials: KH
authors.lastname: Chung
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques; D004202:Disinfectants; D006146:Guanidines / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D008168:Lung / Q000166:cytology; D008297:Male; D011014:Pneumonia / Q000139:chemically induced* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods
chemical_list: D000336:Aerosols; D004202:Disinfectants; D006146:Guanidines; D017382:Reactive Oxygen Species; C060540:polyhexamethyleneguanidine
keywords: Aerosol particles; Humidifier disinfectant; Polyhexamethylene guanidine phosphate; Pulmonary fibrosis