Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis
Abstract Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating...
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| Format: | Article |
| Language: | English |
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BMC
2021-10-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-021-01860-3 |
| _version_ | 1818732551514095616 |
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| author | Pitchumani Sivakumar Ron Ammar John Ryan Thompson Yi Luo Denis Streltsov Mary Porteous Carly McCoubrey Edward Cantu Michael F. Beers Gabor Jarai Jason D. Christie |
| author_facet | Pitchumani Sivakumar Ron Ammar John Ryan Thompson Yi Luo Denis Streltsov Mary Porteous Carly McCoubrey Edward Cantu Michael F. Beers Gabor Jarai Jason D. Christie |
| author_sort | Pitchumani Sivakumar |
| collection | DOAJ |
| description | Abstract Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating biomarkers of IPF are limited and none are in clinical use. Methods We previously reported dysregulated pathways and new disease biomarkers in advanced IPF through RNA sequencing of lung tissues from a cohort of transplant-stage IPF patients (n = 36) in comparison to normal healthy donors (n = 19) and patients with acute lung injury (n = 11). Here we performed proteomic profiling of matching plasma samples from these cohorts through the Somascan-1300 SomaLogics platform. Results Comparative analyses of lung transcriptomic and plasma proteomic signatures identified a set of 34 differentially expressed analytes (fold change (FC) ≥ ± 1.5, false discovery ratio (FDR) ≤ 0.1) in IPF samples compared to healthy controls. IPF samples showed strong enrichment of chemotaxis, tumor infiltration and mast cell migration pathways and downregulated extracellular matrix (ECM) degradation. Mucosal (CCL25 and CCL28) and Th2 (CCL17 and CCL22) chemokines were markedly upregulated in IPF and highly correlated within the subjects. The mast cell maturation chemokine, CXCL12, was also upregulated in IPF plasma (fold change 1.92, FDR 0.006) and significantly correlated (Pearson r = − 0.38, p = 0.022) to lung function (%predicted FVC), with a concomitant increase in the mast cell Tryptase, TPSB2. Markers of collagen III and VI degradation (C3M and C6M) were significantly downregulated (C3M p < 0.001 and C6M p < 0.0001 IPF vs control) and correlated, Pearson r = 0.77) in advanced IPF consistent with altered ECM homeostasis. Conclusions Our study identifies a panel of tissue and circulating biomarkers with clinical utility in IPF that can be validated in future studies across larger cohorts. |
| first_indexed | 2024-12-17T23:35:22Z |
| format | Article |
| id | doaj.art-e669f581a774421099ad94ddbc23a0a9 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-12-17T23:35:22Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-e669f581a774421099ad94ddbc23a0a92022-12-21T21:28:34ZengBMCRespiratory Research1465-993X2021-10-0122111310.1186/s12931-021-01860-3Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosisPitchumani Sivakumar0Ron Ammar1John Ryan Thompson2Yi Luo3Denis Streltsov4Mary Porteous5Carly McCoubrey6Edward Cantu7Michael F. Beers8Gabor Jarai9Jason D. Christie10Translational Early Development, Bristol-Myers Squibb Research and DevelopmentInformatics and Predictive Sciences, Bristol-Myers Squibb Research and DevelopmentInformatics and Predictive Sciences, Bristol-Myers Squibb Research and DevelopmentTranslational Medicine, Bristol-Myers Squibb Research and DevelopmentFibrosis Discovery Biology, Bristol-Myers Squibb Research and DevelopmentPulmonary and Critical Care Medicine, University of PennsylvaniaPulmonary and Critical Care Medicine, University of PennsylvaniaDepartment of Surgery, Division of Cardiovascular Surgery, University of PennsylvaniaPulmonary and Critical Care Medicine, University of PennsylvaniaFibrosis Discovery Biology, Bristol-Myers Squibb Research and DevelopmentPulmonary and Critical Care Medicine, University of PennsylvaniaAbstract Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating biomarkers of IPF are limited and none are in clinical use. Methods We previously reported dysregulated pathways and new disease biomarkers in advanced IPF through RNA sequencing of lung tissues from a cohort of transplant-stage IPF patients (n = 36) in comparison to normal healthy donors (n = 19) and patients with acute lung injury (n = 11). Here we performed proteomic profiling of matching plasma samples from these cohorts through the Somascan-1300 SomaLogics platform. Results Comparative analyses of lung transcriptomic and plasma proteomic signatures identified a set of 34 differentially expressed analytes (fold change (FC) ≥ ± 1.5, false discovery ratio (FDR) ≤ 0.1) in IPF samples compared to healthy controls. IPF samples showed strong enrichment of chemotaxis, tumor infiltration and mast cell migration pathways and downregulated extracellular matrix (ECM) degradation. Mucosal (CCL25 and CCL28) and Th2 (CCL17 and CCL22) chemokines were markedly upregulated in IPF and highly correlated within the subjects. The mast cell maturation chemokine, CXCL12, was also upregulated in IPF plasma (fold change 1.92, FDR 0.006) and significantly correlated (Pearson r = − 0.38, p = 0.022) to lung function (%predicted FVC), with a concomitant increase in the mast cell Tryptase, TPSB2. Markers of collagen III and VI degradation (C3M and C6M) were significantly downregulated (C3M p < 0.001 and C6M p < 0.0001 IPF vs control) and correlated, Pearson r = 0.77) in advanced IPF consistent with altered ECM homeostasis. Conclusions Our study identifies a panel of tissue and circulating biomarkers with clinical utility in IPF that can be validated in future studies across larger cohorts.https://doi.org/10.1186/s12931-021-01860-3Idiopathic pulmonary fibrosisBiomarkersChemokinesMast cellsExtracellular matrix |
| spellingShingle | Pitchumani Sivakumar Ron Ammar John Ryan Thompson Yi Luo Denis Streltsov Mary Porteous Carly McCoubrey Edward Cantu Michael F. Beers Gabor Jarai Jason D. Christie Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis Respiratory Research Idiopathic pulmonary fibrosis Biomarkers Chemokines Mast cells Extracellular matrix |
| title | Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis |
| title_full | Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis |
| title_fullStr | Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis |
| title_full_unstemmed | Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis |
| title_short | Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis |
| title_sort | integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis |
| topic | Idiopathic pulmonary fibrosis Biomarkers Chemokines Mast cells Extracellular matrix |
| url | https://doi.org/10.1186/s12931-021-01860-3 |
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