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Toxicol Appl Pharmacol. 2018 Apr 15;345:94-102. doi: 10.1016/j.taap.2018.02.013. Epub 2018 Feb 21.

Time course of polyhexamethyleneguanidine phosphate-induced lung inflammation and fibrosis in mice.

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Systems Toxicology Center, Predictive Toxicology Department, Korea Institute of Toxicology, Daejeon 305-343, Republic of Korea.
Pathology Analytical Research Center, Korea Institute of Toxicology, Daejeon 305-343, Republic of Korea.
Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Chonbuk National University, Iksan, Republic of Korea. Electronic address:
Inhalation Toxicology Research Center, Korea Institute of Toxicology, Jeonbuk 580-185, Republic of Korea; Human and Environment Toxicology, University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address:


Pulmonary fibrosis is a chronic progressive disease with unknown etiology and has poor prognosis. Polyhexamethyleneguanidine phosphate (PHMG-P) causes acute interstitial pneumonia and pulmonary fibrosis in humans when it exposed to the lung. In a previous study, when rats were exposed to PHMG-P through inhalation for 3 weeks, lung inflammation and fibrosis was observed even after 3 weeks of recovery. In this study, we aimed to determine the time course of PHMG-P-induced lung inflammation and fibrosis. We compared pathological action of PHMG-P with that of bleomycin (BLM) and investigated the mechanism underlying PHMG-P-induced lung inflammation and fibrosis. PHMG-P (0.9 mg/kg) or BLM (1.5 mg/kg) was intratracheally administered to mice. At weeks 1, 2, 4 and 10 after instillation, the levels of inflammatory and fibrotic markers and the expression of inflammasome proteins were measured. The inflammatory and fibrotic responses were upregulated until 10 and 4 weeks in the PHMG-P and BLM groups, respectively. Immune cell infiltration and considerable collagen deposition in the peribronchiolar and interstitial areas of the lungs, fibroblast proliferation, and hyperplasia of type II epithelial cells were observed. NALP3 inflammasome activation was detected in the PHMG-P group until 4 weeks, which is suspected to be the main reason for the persistent inflammatory response and exacerbation of fibrotic changes. Most importantly, the pathological changes in the PHMG-P group were similar to those observed in humidifier disinfectant-associated patients. A single exposure of PHMG-P led to persistent pulmonary inflammation and fibrosis for at least 10 weeks.


Fibrosis; Inflammasome; Polyhexamethyleneguanidine phosphate; Pulmonary inflammation

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