Metabolomic study on bleomycin and polyhexamethylene guanidine phosphate-induced pulmonary fibrosis mice models

Seo, Chan; Kim, Sunghwan; Lee, Hyeon‐Seong; Ji, Moongi; Min, Jeuk; Son, Young–Jin; Kim, In-Hyeon; Lee, Kyuhong; Paik, Man‐Jeong

doi:10.1007/s11306-019-1574-6

Cited by 22 publications

(13 citation statements)

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“…These results were supported by conventional chest CT and histopathologic analysis. It is well-established that PHMG induces lung inflammation and fibrosis in the rodent model [ 4 – 9 ]. However, this is the first study showing that PHMG causes lung cancer in a rodent model.…”

Section: Discussionmentioning

confidence: 99%

“…Since their commercial introduction, an estimated eight million people have been exposed to humidifier disinfectant-chemicals that are added to humidifier water to prevent microorganism growth [ 1 ]. The major component involved was polyhexamethylene guanidine phosphate (PHMG) [ 1 , 2 ], well known to induce lung fibrosis and inflammation in the rodent model [ 4 – 9 ]. However, previous rodent model PHMG experiments were for less than 10 weeks after PHMG exposure and the authors mainly focused on acute lung disease.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the long-term effect of polyhexamethylene guanidine phosphate in a rat lung model using conventional chest computed tomography with histopathologic analysis

et al. 2021

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There have been no studies on the effects of polyhexamethylene guanidine phosphate (PHMG) after a long period of exposure in the rodent model. We aimed to evaluate long-term lung damage after PHMG exposure using conventional chest computed tomography (CT) and histopathologic analysis in a rat model. A PHMG solution was intratracheally administrated to 24 male rats. At 8, 26, and 52 weeks after PHMG instillation, conventional chest CT was performed in all rats and both lungs were extracted for histopathologic evaluation. At 52 weeks after PHMG instillation, four carcinomas had developed in three of the eight rats (37.5%). Bronchiolo-alveolar hyperplasia and adenoma were found in rats at 8, 26, and 52 weeks post-instillation. The number of bronchiolo-alveolar hyperplasia significantly increased over time (P-value for trend< 0.001). The severity of lung fibrosis and fibrosis scores significantly increased over time (P-values for trend = 0.002 and 0.023, respectively). Conventional chest CT analysis showed that bronchiectasis and linear density scores suggestive of fibrosis significantly increased over time (P-value for trend < 0.001). Our study revealed that one instillation of PHMG in a rat model resulted in lung carcinomas and progressive and irreversible fibrosis one year later based on conventional chest CT and histopathologic analysis. PHMG may be a lung carcinogen in the rat model.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of the long-term effect of polyhexamethylene guanidine phosphate in a rat lung model using conventional chest computed tomography with histopathologic analysis

et al. 2021

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“…For the metabolomics study using plasma samples from study subjects, profiling analyses of fatty acids (FAs), organic acids (OAs) and AAs were performed by GC-MS/MS as tert -butyldimethylsilyl (TBDMS)-, methoxime (MO)-TBDMS-, and ethoxylcarbonyl (EOC)-TBDMS derivatives, respectively, as previously described [24, 25]. Profiling analyses of kynurenine pathway metabolites, nucleosides, and AAs were performed by LC-MS/MS using our platforms as detailed previously [24]. F urther detailed descriptions of each analysis, sample preparation, and data processing are also available in the supplementary material.…”

Section: Methodsmentioning

confidence: 99%

Plasma metabolomics profiling and machining learning-driven prediction of nonalcoholic steatohepatitis

Choi

et al. 2021

Preprint

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Rationale: We performed targeted metabolomics with machine learning (ML)-based interpretation to identify metabolites that distinguish the progression of nonalcoholic fatty liver disease (NAFLD) in a cohort. Methods: We conducted plasma metabolomics analysis in healthy control subjects (n=25) and patients with NAFL (n=42) and nonalcoholic steatohepatitis (NASH, n=19) by gas chromatography-tandem mass spectrometry (MS/MS) and liquid chromatography-MS/MS as well as RNA sequencing (RNA-seq) analyses on liver tissues from patients with varying stages of NAFLD (n=12). The resulting metabolomic data were subjected to routine statistical and ML-based analyses and multiomics interpretation with RNA-seq data. Results: We found six metabolites that were significantly altered in NAFLD among 79 detected metabolites. Random-forest and multinomial logistic regression analyses showed that eight metabolites (glutamic acid, cis-aconitic acid, aspartic acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, myristoleic acid, and tyrosine) could distinguish the three groups. Then, the recursive partitioning and regression tree algorithm selected three metabolites (glutamic acid, isocitric acid, and aspartic acid) from these eight metabolites. With these three metabolites, we formulated an equation, the MetaNASH score that distinguished NASH with excellent performance. Finally, metabolic map construction and correlation assays integrating metabolomics data into the transcriptome datasets of the liver showed correlations between the concentration of plasma metabolites and the expression of enzymes governing metabolism and specific alterations of these correlations in NASH. Conclusions: We found several metabolites that distinguish NASH from non-NASH via metabolomics analysis and ML approaches, developed the MetaNASH score, and suggested the pathophysiologic implications of metabolite profiles in relation to NAFLD progression.

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“…Reduced sphingolipid and ceramide metabolism suggested gross structural remodeling of fibrotic lungs (Zhao et al, 2017). Similarly, metabolomic profiling of Bleomycin-treated mouse lungs identified increases in collagen synthesis and protein degradation (Milara et al, 2015;Seo et al, 2019), as well as increased energy production (Aichler et al, 2018;Seo et al, 2019;Sun et al, 2018). In addition, oxidative stress and glutathione metabolism were also increased (Milara et al, 2015;Seo et al, 2019).…”

Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptmentioning

confidence: 99%

“…Similarly, metabolomic profiling of bleomycin-treated mouse lungs identified increases in collagen synthesis and protein degradation ( Milara et al, 2015 ; Seo et al, 2019 ), as well as increased energy production ( Aichler et al, 2018 ; Seo et al, 2019 ; Sun et al, 2018 ). In addition, oxidative stress and glutathione metabolism were shown to be increased ( Milara et al, 2015 ; Seo et al, 2019 ). Although the inflammatory response was mostly upregulated upon bleomycin challenge, one study found a decrease in prostaglandins ( Milara et al, 2015 ; Sun et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Mapping the metabolomic and lipidomic changes in the bleomycin model of pulmonary fibrosis in young and aged mice

Weckerle

Picart‐Armada

Klee

et al. 2022

Disease Models &Amp; Mechanisms

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Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic targets. However, knowledge of metabolic and lipid regulation in fibrotic lungs is limited. To comprehensively characterize metabolic perturbations in the Bleomycin mouse model of IPF we analyzed the metabolome and lipidome by mass spectrometry. We identified increased tissue turnover and repair, evident by enhanced breakdown of proteins, nucleic acids, lipids and ECM turnover. Energy production was upregulated, including glycolysis, tricarboxylic acid (TCA) cycle, glutaminolysis, lactate production and increased fatty acid oxidation. Higher eicosanoid synthesis indicated inflammatory processes. Since the risk of IPF increases with age, we investigated how age influences metabolomic and lipidomic changes in the Bleomycin-induced pulmonary fibrosis model. Surprisingly, except cytidine, we did not detect any significantly differential metabolites or lipids between old and young Bleomycin-treated lungs. Together, we identified metabolomic and lipidomic changes in fibrosis that reflect higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation that might serve for improving diagnostic and therapeutic options for fibrotic lung diseases in the future.

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Metabolomic study on bleomycin and polyhexamethylene guanidine phosphate-induced pulmonary fibrosis mice models

Cited by 22 publications

References 43 publications

Evaluation of the long-term effect of polyhexamethylene guanidine phosphate in a rat lung model using conventional chest computed tomography with histopathologic analysis

Evaluation of the long-term effect of polyhexamethylene guanidine phosphate in a rat lung model using conventional chest computed tomography with histopathologic analysis

Plasma metabolomics profiling and machining learning-driven prediction of nonalcoholic steatohepatitis

Mapping the metabolomic and lipidomic changes in the bleomycin model of pulmonary fibrosis in young and aged mice

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