Abnormal ADAM17 expression causes airway fibrosis in chronic obstructive asthma

Biomed Pharmacother. 2021 Aug:140:111701. doi: 10.1016/j.biopha.2021.111701. Epub 2021 May 27.

Abstract

Patients with chronic obstructive asthma (COA) develop airflow obstruction caused by subepithelial fibrosis. Although a disintegrin and metalloproteinase 17 (ADAM17) has been implicated in lung inflammation and tissue fibrosis, its role in airway fibrosis in COA has not been explored. Here, we found marked overexpression of ADAM17, phosphorylated ADAM17, and connective tissue growth factor (CTGF) in human airway fibroblasts from COA patients, compared with those of normal subjects. Similarly, levels of ADAM17, CTGF, α-smooth muscle actin (α-SMA), and collagen were increased in endobronchial biopsies from COA patients, but not in controls. In an ovalbumin-challenge asthma model, airway fibrosis was inhibited in ADAM17f/f/Cre+ mice compared to control mice. TGF-β- and thrombin-induced fibrotic protein expression was reduced by ADAM17 small interfering (si)RNA, TAPI-0 (an ADAM17 inhibitor), and EGFR siRNA. In addition, exogenous HB-EGF reversed fibrotic response in ADAM17 knockdown human lung fibroblasts. ADAM17 causes subepithelial fibrosis through regulation of enhanced extracellular matrix production and fibroblast differentiation and is the common pathway for airway fibrosis mediated by TGF-β and thrombin through an aberrant ADAM17/EGFR signalling pathway.

Keywords: ADAM17; Airway fibrosis; Chronic obstructive asthma; EGFR; Human lung fibroblasts.

MeSH terms

  • ADAM17 Protein / genetics*
  • ADAM17 Protein / metabolism
  • Adult
  • Allergens
  • Animals
  • Asthma / genetics
  • Asthma / metabolism
  • Asthma / pathology*
  • Bronchi / metabolism
  • Bronchi / pathology*
  • Cells, Cultured
  • Chronic Disease
  • ErbB Receptors / genetics
  • Female
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Male
  • Mice, Transgenic
  • Middle Aged
  • Ovalbumin
  • Thrombin / pharmacology
  • Transforming Growth Factor beta / pharmacology

Substances

  • Allergens
  • Transforming Growth Factor beta
  • Ovalbumin
  • EGFR protein, mouse
  • ErbB Receptors
  • Thrombin
  • ADAM17 Protein
  • Adam17 protein, mouse