Polyhexamethylene guanidine phosphate-induced necrosis may be linked to pulmonary fibrosis

Min Sung Kang, Sung Hwan Kim, Mi Jin Yang, Hyeon Young Kim, In Hyeon Kim, Jeong Won Kang, Hye Sook Choi, Seung Woo Jin, Eun Jung Park

Research output: Contribution to journalArticlepeer-review

Abstract

Following the humidifier disinfectant incident in Korea, polyhexamethylene guanidine phosphate (PHMG-P) has been used to establish lung fibrosis model animals. Herein, we investigated time-dependent changes after a single PHMG-P instillation (22 μg/lung) to identify the underlying pathogenesis and immune response involved in PHMG-P-induced lung fibrosis. Compared to control mice, body weight loss and blood biochemical and hematological changes were more remarkable in PHMG-P-instilled mice, an increase of total cell counts, infiltration of macrophages and neutrophils and necrotic cell death were also more notable in the lungs of PHMG-P-instilled mice. Pathological lesions were detected from Day 1 after exposure, deteriorating with time. In addition, secretion of anti-inflammatory mediators was rapidly inhibited from 6 h after exposure, and level of IL-24, a tissue repair-related cytokine, was up-regulated in the lungs of PHMG-P-instilled mice until Day 21 post-exposure. In vitro tests using BEAS-2B cells showed that PHMG-P disturbed structural and functional homeostasis of organelles and that intracellular ROS increase was considered as an important cause of PHMG-P-induced cell death. Additionally, co-culture with DNA, a polyanionic compound, clearly inhibited PHMG-P-induced necrosis, and increased IL-1β and TNF-α level and decreased IL-6 and IL-8 levels were observed following exposure to PHMG-P. Meanwhile, IL-8 secretion increased in cells exposed to PHMG-P-induced cell debris. Therefore, we suggest that necrotic cell debris may importantly contribute to the PHMG-P-induced inflammatory response and pathogenesis. In addition, PHMG-P-induced necrosis may be initiated by high affinity between PHMG-P and cell membrane.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalToxicology Letters
Volume362
DOIs
Publication statusPublished - 2022 Jun 1

Keywords

  • Cell death
  • Idiopathic pulmonary fibrosis
  • Inflammation
  • Necrosis
  • Polyhexamethylene guanidine
  • Tissue damage

ASJC Scopus subject areas

  • Toxicology

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