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Macrophage-secreted TSLP and MMP9 promote bleomycin-induced pulmonary fibrosis

Guanqun Li1, Fuquan Jin1, Jiangxia Du1

  • 1Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Toxicology and Applied Pharmacology
|January 18, 2019
PubMed

Insights

Macrophages promote early pulmonary fibrosis by driving alveolar epithelial cells to undergo epithelial-mesenchymal transition and aiding fibroblast migration. Thymic stromal lymphopoietin and matrix metalloproteinase 9 are key mediators in this process.

Area of Science:

  • Pulmonary Medicine
  • Cell Biology
  • Immunology

Background:

  • Idiopathic pulmonary fibrosis (IPF) involves a faulty repair response to lung injury, impairing gas exchange.
  • Macrophages are implicated in IPF pathogenesis, but their precise role remains unclear.
  • Early macrophage aggregation precedes fibrosis development in experimental models.

Purpose of the Study:

  • To elucidate the mechanisms by which macrophages contribute to pulmonary fibrosis.
  • To identify specific molecular mediators involved in macrophage-driven fibrotic processes.

Main Methods:

  • Utilized mouse and rat models of pulmonary fibrosis.
  • Employed co-culture systems of macrophages with alveolar epithelial cells and fibroblasts.
  • Analyzed cytokine profiles using protein microarrays after bleomycin treatment.
  • Investigated the role of thymic stromal lymphopoietin (TSLP) and matrix metalloproteinase 9 (MMP9) using recombinant proteins and inhibitors.

Main Results:

  • Macrophage aggregation was observed prior to epithelial-mesenchymal transition (EMT) and fibrosis in experimental models.
  • Macrophages promoted EMT in alveolar epithelial cells and fibroblast migration in co-culture.
  • TSLP and MMP9 levels were significantly elevated post-bleomycin treatment.
  • TSLP mediated macrophage-induced alveolar epithelial cell EMT; MMP9 mediated macrophage-induced fibroblast migration.

Conclusions:

  • Macrophages play a critical role in the early stages of pulmonary fibrosis.
  • TSLP and MMP9 are key cytokines mediating macrophage-induced EMT and fibroblast migration, respectively.
  • These findings reveal underlying mechanisms of macrophage-promoted pulmonary fibrosis.
Keywords:
Epithelial-mesenchymal transitionFibroblast migrationMMP9MacrophagePulmonary fibrosisTSLP

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