Idiopathic pulmonary fibrosis (IPF) is a disease of unknown pathogenesis characterized by scarring of the lung and declining respiratory function. Originating from bone marrow, circulating monocytes can be recruited into the lung tissue and polarized toward the alternatively activated (M2) profibrotic macrophage phenotype. Recent literature has shown that cluster of differentiation 14 positive (CD14+) monocytes are more abundant in IPF patient blood and are associated with disease outcome and acute exacerbation. Additionally, a 52-gene risk profile from peripheral blood mononuclear cells for outcome prediction in IPF was recently published. Here, we began by characterizing macrophages in human IPF lung tissue. We then assembled a biobank and examined transcriptomic characteristics of blood-derived circulating monocytes from IPF patients.
Various histological assessments were completed on a tissue microarray including lung biopsies from 24 IPF patients and 17 controls, to characterize M2 macrophage expression in human tissue. Whole blood samples were collected from 50 IPF patients and 12 control subjects. CD14+ monocytes were isolated and mRNA was extracted for bulk RNA sequencing. Data were analyzed for differential expression (DE), and Gene Set Enrichment Analysis (GSEA) was performed to examine enrichment of the previously published 52-gene risk profile in our dataset.
We found that M2 macrophage expression was increased in IPF lung tissue compared to controls. CD14+ monocyte levels were significantly elevated in IPF patients in our cohort compared to control participants, and was negatively correlated with forced vital capacity (FVC). DE analysis comparing IPF and control monocytes yielded a 35-gene signature, with 16 up-regulated genes and 19 down-regulated genes. When comparing the signature related to long transplant-free survival from the published dataset to our data, GSEA demonstrated that this signature is enriched in donors from our dataset, supporting concurrence between the meanings of the two datasets. Overall, these results provide insight to identify targets to modulate monocyte/macrophage function in IPF and potentially affect progressive disease. / Thesis / Master of Science (MSc) / Idiopathic pulmonary fibrosis (IPF) is a disease of unknown cause that results in excessive scarring of the lungs and progressive impairment in lung function. We believe that white blood cells called monocytes and macrophages play a key role in the development and progression of this disease. Overall, it is thought that monocytes, which circulate in the blood, enter the lung tissue and become macrophages. These macrophages then lead to the formation of scar tissue, which is characteristic to IPF. In order to better understand how these cells contribute to IPF, we studied their properties in blood and lung biopsies from IPF patients. We found significant differences between monocytes/macrophages in IPF than those in healthy controls, that may help explain disease progression. We hope that these findings will provide insight into causes of the IPF, and potential avenues for therapeutic intervention.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25413 |
| Date | January 2020 |
| Creators | Vierhout, Megan |
| Contributors | Ask, Kjetil, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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