Myeloid- and Epithelial-derived Heparin-Binding Epidermal Growth Factor-like Growth Factor Promotes Pulmonary Fibrosis.
Elissa M HultStephen J GurczynskiDavid N O'DwyerRachel L ZemansAndrew RaskyYizhuo WangSusan MurrayHoward C CrawfordBethany B MoorePublished in: American journal of respiratory cell and molecular biology (2022)
Idiopathic pulmonary fibrosis (IPF) is a poorly understood, progressive lethal lung disease with no known cure. In addition to alveolar epithelial cell (AEC) injury and excessive deposition of extracellular matrix proteins, chronic inflammation is a hallmark of IPF. Literature suggests that the persistent inflammation seen in IPF primarily consists of monocytes and macrophages. Recent work demonstrates that monocyte-derived alveolar macrophages (moAMs) drive lung fibrosis, but further characterization of critical moAM cell attributes is necessary. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an important epidermal growth factor receptor ligand that has essential roles in angiogenesis, wound healing, keratinocyte migration, and epithelial-mesenchymal transition. Our past work has shown HB-EGF is a primary marker of profibrotic M2 macrophages, and this study seeks to characterize myeloid-derived HB-EGF and its primary mechanism of action in bleomycin-induced lung fibrosis using Hbegf f/f ;Lyz2Cre + mice. Here, we show that patients with IPF and mice with pulmonary fibrosis have increased expression of HB-EGF and that lung macrophages and transitional AECs of mice with pulmonary fibrosis and humans all express HB-EGF. We also show that Hbegf f/f ;Lyz2Cre + mice are protected from bleomycin-induced fibrosis and that this protection is likely multifactorial, caused by decreased CCL2-dependent monocyte migration, decreased fibroblast migration, and decreased contribution of HB-EGF from AEC sources when HB-EGF is removed under the Lyz2Cre promoter.
Keyphrases
- growth factor
- pulmonary fibrosis
- idiopathic pulmonary fibrosis
- wound healing
- dendritic cells
- epidermal growth factor receptor
- high fat diet induced
- extracellular matrix
- epithelial mesenchymal transition
- interstitial lung disease
- endothelial cells
- oxidative stress
- high glucose
- tyrosine kinase
- systematic review
- liver fibrosis
- diabetic rats
- poor prognosis
- bone marrow
- advanced non small cell lung cancer
- peripheral blood
- transcription factor
- stem cells
- signaling pathway
- insulin resistance
- multiple sclerosis
- single cell
- dna binding
- type diabetes
- adipose tissue
- skeletal muscle
- long non coding rna
- liver injury