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A2216 - Characterization of Shared Molecular Pathways in Idiopathic Pulmonary Fibrosis and Depression
Author Block: S. E. Smith1, S. Kanekar2, J. Lee1, A. Plante1, P. Renshaw2, M. Scholand1; 1Department of Internal Medicine, Pulmonary Division, University of Utah, Salt Lake CIty, UT, United States, 2Department of Psychiatry, University of Utah, Salt Lake CIty, UT, United States.
Rationale:
A majority of patients affected by interstitial lung disease (ILD), and especially idiopathic pulmonary fibrosis (IPF), also suffer from depressive symptoms. While depression in chronic diseases is not uncommon, studies show that chronic respiratory and cardiovascular diseases linked to hypoxia have higher comorbidity for depression than those which are not associated with hypoxia, such as diabetes or osteoporosis. In IPF patients, an astounding 25-50% exhibit depressive symptoms, a comorbidity that further perpetuates disability in this patient population. Given the co-occurrence of IPF and depression, we aimed to determine whether the molecular pathways underlying IPF involve key depression biomarkers.
Methods:
Using Ingenuity® Pathway Analysis, we mined over a dozen of peer-reviewed databases (including Ensembl, GenBank, and Human Metabolome Database) to identify key IPF-related molecules, and generated a graphical representation of only direct relationships among these molecules. We subsequently added 30 well-recognized depression-linked biomarkers for inflammation, immune response, or oxidative stress and computed a composite pathway analysis to identify shared pathways and key molecules in both IPF and depression.
Results:
Our analyses show that several IPF hub molecules also play a key role in depression pathways: Signal Transducer and Activator of Transcription 3 (STAT3), Glucocorticoid Receptor (NR3C1), Nuclear Factor Kappa B Subunit 1 (NFKB1), and Catenin Beta 1 (CTNNB1). These hub molecules regulate several key depression cytokines, including interleukin (IL)6, IL1B, IL10, and Leptin (LEP), as well as the enzyme Prostaglandin-Endoperoxide Synthase 2 (PTGS2) and the Transmembrane Receptor TNF Receptor Superfamily Member 1A (TNFRSF1A). Of note, the IL6 /STAT3 /NFKB1 positive feedback loop, implicated in depression, is also involved in IPF. We further identified the following top transcriptional regulators: IL1B, P38 Mitogen-Activated Protein Kinase (P38 MAPK), Complement 3 (C3), and Transforming Growth Factor Beta 1 (TGF1B), which are implicated in lung inflammation and fibrosis, and Tumor Necrosis Factor (TNF), which is linked to IPF exacerbations and aberrant wound healing responses. These pro-inflammatory and pro-fibrotic cytokines are also implicated in depression.
Conclusion:
This study offers a graphical overview of the molecular pathways in IPF and depression, and illustrates that while pro-fibrotic processes have a predominant role in IPF pathogenesis, pro-inflammatory markers play a role in both diseases. Identification of shared molecular pathways in IPF and depression can lead to the implementation of targeted preventive measures to ameliorate patients’ quality of life.