Dataset Information

Proteomic changes to immune and inflammatory processes underlie lung preservation using ex vivo cytokine adsorption

ABSTRACT: The field of graft preservation has made considerable strides in recent years improving outcomes related to solid organ restoration and regeneration. In lungs, the use of ex vivo lung perfusion (EVLP) in line with devices and treatments has shown promising results within preclinical and clinical studies with the potential to improve graft quality. The benefit of the therapy would be to render marginal and declined donor lungs suitable for transplantation, ultimately increasing the donor pool available for transplantation. Additionally, such therapies used in machine perfusion could also increase preservation time, facilitating logistical planning. Cytokine adsorption has been demonstrated as a potentially safe and effective therapy when applied to the EVLP circuit and post transplantation. The mechanism by which this treatment improves the donor lung on a molecular basis is not yet fully elucidated. We hypothesized that there were characteristic inflammatory and immunomodulatory differences between lungs treated with and without cytokine adsorption, reflecting in proteomic changes in gene ontology pathways and across inflammation-related proteins. In the current study we investigate the molecular mechanisms and signaling pathways of how cytokine adsorption impacts the lung function when used during EVLP and when used post transplantation as hemoperfusion in a porcine model. Lung tissue from EVLP and post lung transplantation were analyzed for their proteomic profile using mass spectrometry. The inflammatory and immune processes were compared between the treated and the non-treated groups to show the differences occurring between the forms of graft preservation.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Sus Scrofa Domesticus (domestic Pig)

TISSUE(S): Lung

SUBMITTER: Gabriel Hirdman

LAB HEAD: Sandra Lindstedt

PROVIDER: PXD044413 | Pride | 2023-10-24

REPOSITORIES: Pride

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Proteomic changes to immune and inflammatory processes underlie lung preservation using <i>ex vivo</i> cytokine adsorption.

Niroomand Anna A Hirdman Gabriel G Pierre Leif L Ghaidan Haider H Kjellström Sven S Stenlo Martin M Hyllén Snejana S Olm Franziska F Lindstedt Sandra S

Frontiers in cardiovascular medicine 20231002

<h4>Introduction</h4>In recent years, the field of graft preservation has made considerable strides in improving outcomes related to solid organ restoration and regeneration. Ex vivo lung perfusion (EVLP) in line with the related devices and treatments has yielded promising results within preclinical and clinical studies, with the potential to improve graft quality. Its main benefit is to render marginal and declined donor lungs suitable for transplantation, ultimately increasing the donor pool ...[more]

PMID: 37849943

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Project description:Background: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have revealed major differences between HFpEF, HF with reduced EF (HFrEF), and controls. How this translates at the protein level is currently unknown. Methods: Myocardial tissue from patients with HFpEF and non-failing donor controls was analyzed by data-dependent (DDA, n=10 HFpEF, n=9 controls) and data-independent (DIA, n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Previously reported myocardial proteomic data from end-stage HFrEF and controls were also used. Differential protein expression analysis, machine learning and pathway enrichment were integrated with clinical characteristics and myocardial transcriptomics. Results: DDA-MS proteomics identified 88 significantly upregulated and 248 down-regulated proteins in HFpEF vs controls, out of 1996 identified proteins. Principal component analysis of DDA-MS proteomics found HFpEF was separated into 2 sub-groups: one being similar to controls the other quite disparate. Top proteins contributing to the separation of HFpEF subgroups were enriched in actin/myosin binding, regulation of DNA replication/repair, transcription, and translation. Downregulated proteins in HFpEF vs controls were enriched in pathways related to ribosome structure, transmembrane transporters, metabolic enzymes, and oxidative phosphorylation (OxPhos) proteins. Enriched pathways for proteins upregulated in HFpEF related to actin and phospholipid binding, growth factor signaling, kinase regulation, and glycolysis. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. OxPhos gene (increased) versus protein (decreased) expression was discordant in HFpEF. The second DIA proteomic analysis also yielded two HFpEF sub-groups; the one most different from controls also having reduced OxPhos and protein translation pathways. A higher proportion of these patients also had severe obesity. Conclusions: Integrative proteomics, transcriptomics, and pathway analysis supports a translational defect particularly involving mitochondrial, ribosomal and protein translation proteins in HFpEF. Patients with more distinct proteomic signatures from control were more often very obese. The results support therapeutic efforts targeting metabolism, mitochondrial function, and protein translation in this subgroup.

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Dataset Information

Proteomic changes to immune and inflammatory processes underlie lung preservation using ex vivo cytokine adsorption

Publications

Proteomic changes to immune and inflammatory processes underlie lung preservation using <i>ex vivo</i> cytokine adsorption.

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