Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis
Open accessAbstract
IL-4 and IL-13 are major T-helper cell (Th) 2 cytokines implicated in the pathogenesis of several lung diseases, including pulmonary fibrosis. In this study, using a novel repetitive intradermal bleomycin model in which mice develop extensive lung fibrosis and a progressive decline in lung function compared with saline-treated control mice, we investigated profibrotic functions of Th2 cytokines. To determine the role of IL-13 signaling in the pathogenesis of bleomycin-induced pulmonary fibrosis, wild-type, IL-13, and IL-4Rα-deficient mice were treated with bleomycin, and lungs were assessed for changes in lung function and pulmonary fibrosis. Histological staining and lung function measurements demonstrated that collagen deposition and lung function decline were attenuated in mice deficient in either IL-13 or IL-4Rα-driven signaling compared with wild-type mice treated with bleomycin. Furthermore, our results demonstrated that IL-13 and IL-4Rα-driven signaling are involved in excessive migration of macrophages and fibroblasts. Notably, our findings demonstrated that IL-13-driven migration involves increased phospho-focal adhesion kinase signaling and F-actin polymerization. Importantly, in vivo findings demonstrated that IL-13 augments matrix metalloproteinase (MMP)-2 and MMP9 activity that has also been shown to increase migration and invasiveness of fibroblasts in the lungs during bleomycin-induced pulmonary fibrosis. Together, our findings demonstrate a pathogenic role for Th2-cytokine signaling that includes excessive migration and protease activity involved in severe fibrotic lung disease.
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From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [151]
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Fibrosis: from mechanisms to medicines
Henderson, N. C., Rieder, F., & Wynn, T. A. (2020) · Nature · doi:10.1038/s41586-020-2938-9 · Cited by 1,868 · see citing works
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- Authors
- Singh, B., Kasam, R. K., Sontake, V., Wynn, T. A., & Madala, S. K.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- National Institute of Allergy and Infectious Diseases (US)
- Corresponding author
- Madala, Satish K.
- Venue
- American Journal of Physiology-Lung Cellular and Molecular Physiology
- Publisher
- American Physiological Society
- Published
- 2017-11-01
- Volume
- 313
- Issue
- 5
- Pages
- L796-L806
- ISSN
- 1040-0605 (ISSN-L)
- 1522-1504
- PMC
- PMC5792179
- OpenAlex
- W2744518245
- Cited by
- 48
- References
- 48
- Citations by year
- 2026: 8 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 5 · 2020: 4 · 2019: 8 · 2018: 4
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Lung Cellular and Molecular Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R21HL133539, R01HL134801)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R03AR062832)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- bleomycin-induced lung fibrosis, Th2 cytokines, IL-13, IL-4, IL-4 receptor alpha, macrophage migration, fibroblast migration, focal adhesion kinase signaling, F-actin polymerization, MMP-2, MMP-9, collagen deposition, lung function decline, mouse model
- MeSH terms
- Animals, Bleomycin, Disease Models, Animal, Fibroblasts, Lung, Mice, Inbred BALB C, Mice, Inbred C57BL, Pulmonary Fibrosis, Cytokines, Th2 Cells
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