Pharmacometabolic response to pirfenidone in pulmonary fibrosis detected by MALDI-FTICR-MSI

Sun, Na; Fernandez, Isis E.; Wei, Mian; Witting, Michael; Aichler, Michaela; Feuchtinger, Annette; Burgstaller, Gerald; Verleden, Stijn E.; Schmitt‐Kopplin, Philippe; Eickelberg, Oliver; Walch, Axel

doi:10.1183/13993003.02314-2017

Cited by 32 publications

(20 citation statements)

References 44 publications

(49 reference statements)

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“…Recent study have focused on metabolic changes in bleomycin-treated mouse lung and IPF patient lung, proteomic analysis was performed on these lung tissues. They observed reduced glycolysis/gluconeogenesis and enhanced ascorbate and aldarate metabolism, and the imbalanced metabolism can be restored by pirfenidone [16]. Proteomic analysis also have been applied to identify serum biomarkers for IPF, they found that 97 out of total 394 proteins were associated with IPF, C-reactive protein (CRP), fibrinogen- α chain, haptoglobin, and kininogen-1 were useful candidate biomarkers for IPF [17].…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomic characterization of lung tissue in idiopathic pulmonary fibrosis

Tian

Gao

et al. 2019

Clin Proteom

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, eventually fatal disease. IPF is characterized by excessive accumulation of the extracellular matrix (ECM) in the alveolar parenchyma and progressive lung scarring. The pathogenesis of IPF and whether the ECM involved in the process remain unknown.MethodsTo identify potential treatment target and ECM associated proteins that may be involved in the development of IPF, we employed isobaric tag for relative and absolute quantitation (iTRAQ) combined liquid chromatography–tandem mass spectrometry (LC–MS/MS) approach to examine protein expression in lung tissues from IPF patients.ResultsA total of 662 proteins with altered expression (455 upregulated proteins and 207 downregulated proteins) were identified in lung tissue of IPF patients compared with control. KEGG pathway enrichment analysis showed that the altered proteins in lung tissue mainly belonged to the PI3K-Akt signaling, focal adhesion, ECM-receptor interaction, and carbon metabolism pathways. According to the bioinformatic definition of the matrisome, 229 matrisome proteins were identified in lung tissue. These proteins comprised the ECM of lung, of which 104 were core matrisome proteins, and 125 were matrisome-associated proteins. Of the 229 ECM quantified proteins, 56 significantly differentially expressed proteins (19 upregulated proteins and 37 downregulated proteins) were detected in IPF lung tissue samples. In addition to proteins with well-known functions such as COL1A1, SCGB1A1, TAGLN, PSEN2, TSPAN1, CTSB, AGR2, CSPG2, and SERPINB3, we identified several novel ECM proteins with unknown function deposited in IPF lung tissue including LGALS7, ASPN, HSP90AA1 and HSP90AB1. Some of these differentially expressed proteins were further verified using Western blot analysis and immunohistochemical staining.ConclusionsThis study provides a list of proteomes that were detected in IPF lung tissue by iTRAQ technology combined with LC–MS/MS. The findings of this study will contribute better understanding to the pathogenesis of IPF and facilitate the development of therapeutic targets.Electronic supplementary materialThe online version of this article (10.1186/s12014-019-9226-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Quantitative proteomic characterization of lung tissue in idiopathic pulmonary fibrosis

Tian

Gao

et al. 2019

Clin Proteom

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“…FG4592 administration. Increased ascorbate and aldarate metabolism was previously observed in both mice and humans with pulmonary fibrosis (39). Moreover, ascorbate and its analogs are reported to stimulate collagen synthesis and accumulation in cultured human skin fibroblasts (24,25).…”

Section: Hif-1 Is Activated In Uir Mice Kidney and Human Fibrotic Kidneysmentioning

confidence: 89%

Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability

Chen

Miao

et al. 2021

Clinical Science

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Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG-4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG-4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.

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“…Tissue preparation steps for MALDI imaging mass spectrometry (MALDI-MSI) analysis was performed as previously described 49,50 . Frozen tissues were cryo sectioned at 10 µm from the same tissue block as used for spatial transcriptomics and thaw mounted onto indium-tin-oxide coated conductive slides (Bruker Daltonik, Bremen, Germany).…”

Section: Methodsmentioning

confidence: 99%

Spatiotemporal heterogeneity of glioblastoma is dictated by microenvironmental interference

Ravi

Will

Kueckelhaus

et al. 2021

Preprint

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Glioblastomas are highly malignant tumors of the central nervous system. Evidence suggests that these tumors display large intra- and inter-patient heterogeneity hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. However, the source for dynamic reorganization of cellular states within their spatial context remains elusive. Here, we in-depth characterized glioblastomas by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering exclusive and shared transcriptional programs across patients, we inferred that glioblastomas develop along defined neural lineages and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Metabolic profiling and imaging mass cytometry supported the assumption that tumor heterogeneity is dictated by microenvironmental alterations. Analysis of copy number variation (CNV) revealed a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. Deconvolution of age-dependent transcriptional programs in malignant and non-malignant specimens identified the aging environment as the major driver of inflammatory transformation in GBM, suggesting that tumor cells adopt transcriptional programs similar to inflammatory transformation in astrocytes. Glioblastoma stem cells implanted into human neocortical slices of varying age levels, independently confirmed that the ageing environment dynamically shapes the intratumoral heterogeneity towards reactive transcriptional programs. Our findings provide insights into the spatial architecture of glioblastoma, suggesting that both locally inherent tumor as well as global alterations of the tumor microenvironment shape its transcriptional heterogeneity. Global age-related inflammation in the human brain is driving distinct transcriptional transformation in glioblastomas, which requires an adjustment of the currently prevailing glioma models.

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Pharmacometabolic response to pirfenidone in pulmonary fibrosis detected by MALDI-FTICR-MSI

Cited by 32 publications

References 44 publications

Quantitative proteomic characterization of lung tissue in idiopathic pulmonary fibrosis

Quantitative proteomic characterization of lung tissue in idiopathic pulmonary fibrosis

Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability

Spatiotemporal heterogeneity of glioblastoma is dictated by microenvironmental interference

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