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Deficiency in DDR1 Induces Pulmonary Hypertension and Impaired Alveolar Development

Quinn A Bonafiglia1,2, Yu-Qing Zhou2, Guangpei Hou1,2

  • 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

American Journal of Respiratory Cell and Molecular Biology
|August 4, 2022
PubMed

Insights

Discoidin domain receptor 1 (DDR1) is crucial for lung development and alveolarization. DDR1 deficiency in mice leads to pulmonary hypertension and bronchopulmonary dysplasia, highlighting its role in preventing these conditions.

Area of Science:

  • Cell biology
  • Developmental biology
  • Pulmonary medicine

Background:

  • Pulmonary hypertension (PH) is a severe condition often linked to right ventricular failure.
  • Bronchopulmonary dysplasia (BPD) in infants can cause secondary PH and high mortality.
  • The role of discoidin domain receptor 1 (DDR1) in lung development and PH is not understood.

Purpose of the Study:

  • To investigate the function of DDR1 in lung development.
  • To determine if DDR1 deficiency contributes to pulmonary hypertension and BPD pathogenesis.
  • To explore the mechanisms by which DDR1 influences alveolar epithelial cells.

Main Methods:

  • Utilized a mouse model with DDR1 deletion (Ddr1 mice).
  • Conducted pathological analysis of lung tissue for alveolar development and vascular changes.
  • Performed gene expression analysis to assess alveologenesis and epithelial-to-mesenchymal transition (EMT) markers.
  • Conducted in vitro mechanistic studies on alveolar epithelial cells.

Main Results:

  • DDR1-deficient mice exhibited increased mortality (35%) between 1-4 months of age.
  • DDR1 deficiency led to reduced right ventricular contractility and distal pulmonary artery muscularization, indicative of PH.
  • Impaired alveolar development, characterized by enlarged alveolar spaces, was observed in Ddr1 mice.
  • Reduced expression of alveologenesis factors and EMT markers was found in Ddr1 mice.
  • In vitro studies confirmed DDR1's role in mediating EMT, migration, and growth of alveolar epithelial cells.

Conclusions:

  • DDR1 plays a critical role in mediating alveolarization during lung development.
  • DDR1 deficiency results in a novel mouse model of spontaneous PH and BPD.
  • Targeting DDR1 may offer therapeutic potential for lung development disorders and PH.

Keywords:
bronchopulmonary dysplasiadiscoidin domain receptorsechocardiographymouse modelpulmonary hypertension

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