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Molecular Mechanisms Underlying Systemic Sclerosis–Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: an Update

  • Role of Metabolism in Fibrosis: Translational Implications (K Saag, Section Editor)
  • Published:
Current Treatment Options in Rheumatology Aims and scope Submit manuscript

Abstract

Purpose of review

Systemic sclerosis–associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF) are fatal fibrotic lung disorders characterized by progressive fibrosis, immune dysregulation, vascular damage, fibroblast activation, and myofibroblast differentiation. In this review, we will briefly update all the above-mentioned mechanisms, cell-type involvement from single cell-RNA sequencing, and the differences with emerging common biomarkers and available treatment options.

Recent findings

In the IPF, tissue injury and lung fibrosis are thought to be initiated by injury of the alveolar epithelium and activation of alveolar epithelial cells (AECs) that release cytokines to activate the fibroblasts. By contrast, vascular damage is an early event in the pathogenesis of SSc-ILD and several diverse cells, such as myofibroblasts, fibroblasts, and endothelial cells, participate in inflammatory activation. Recent findings from single-cell RNA-seq suggested the presence of different subsets of innate and adaptive immune cells and differentiation of myofibroblasts from distinct sources, which complicates the understanding of the disease landscape. Fibroblast activation and myofibroblast accumulation are the final common pathways of lung fibrosis in both SSc-associated ILD and IPF.

Summary

Fibrosis in IPF appears to be related to aberrant repair following injury, but whether this also holds for SSc-ILD is less evident. Additionally, compared to IPF, immune dysregulation appears to contribute more to profibrotic responses in SSc-ILD. Nevertheless, persistent myofibroblast activity leads to progressive tissue fibrosis leading to organ failure and death. Few FDA-approved drugs (nintedanib, tocilizumab, and pirfenidone) are available for the treatment of fibrotic lung disease. Prospective high-throughput strategy-based approaches are required to understand the complexity of the diseases and develop specific therapeutic targets as part of precision medicine.

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Acknowledgements

We thank Kris Shah for editing.

Funding

This study was supported by grants from the National Institutes of Health, National Institute of Arthritis, and Musculoskeletal and Skin Diseases (NIAMS AR074997) and the National Scleroderma Foundation.

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  1. Division of Rheumatology, Department of Internal Medicine, Michigan Scleroderma Program, University of Michigan, Ann Arbor, MI, USA

    Priyanka Verma ph.D, Swarna Bale ph.D, John Varga MD & Swati Bhattacharyya ph.D

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PV and SB wrote the review; SBa and JV reviewed and edited.

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Correspondence to Swati Bhattacharyya ph.D.

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Verma, P., Bale, S., Varga, J. et al. Molecular Mechanisms Underlying Systemic Sclerosis–Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: an Update. Curr Treat Options in Rheum 9, 221–235 (2023). https://doi.org/10.1007/s40674-023-00213-z

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