Loss of JCAD/KIAA1462 Protects the Lung from Acute and Chronic Consequences of Chronic Obstructive Pulmonary Disease

Int J Mol Sci. 2024 Aug 31;25(17):9492. doi: 10.3390/ijms25179492.

Abstract

Even with recent advances in pathobiology and treatment options, chronic obstructive pulmonary disease (COPD) remains a major contributor to morbidity and mortality. To develop new ways of combating this disease, breakthroughs in our understanding of its mechanisms are sorely needed. Investigating the involvement of underanalyzed lung cell types, such as endothelial cells (ECs), is one way to further our understanding of COPD. JCAD is a junctional protein in endothelial cells (ECs) arising from the KIAA1462 gene, and a mutation in this gene has been implicated in the risk of developing COPD. In our study, we induced inflammation and emphysema in mice via the global knockout of KIAA1462/JCAD (JCAD-KO) and confirmed it in HPMECs and A549 to examine how the loss of JCAD could affect COPD development. We found that KIAA1462/JCAD loss reduced acute lung inflammation after elastase treatment. Even after 3 weeks of elastase, JCAD-KO mice demonstrated a preserved lung parenchymal structure and vasculature. In vitro, after KIAA1462 expression is silenced, both endothelial and epithelial cells showed alterations in pro-inflammatory gene expression after TNF-α treatment. We concluded that JCAD loss could ameliorate COPD through its anti-inflammatory and anti-angiogenic effects, and that KIAA1462/JCAD could be a novel target for COPD therapy.

Keywords: JCAD; angiogenesis; chronic obstructive pulmonary disease; emphysema; inflammation.

MeSH terms

  • A549 Cells
  • Animals
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Disease Models, Animal
  • Endothelial Cells* / metabolism
  • Humans
  • Lung* / metabolism
  • Lung* / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Pulmonary Disease, Chronic Obstructive* / etiology
  • Pulmonary Disease, Chronic Obstructive* / genetics
  • Pulmonary Disease, Chronic Obstructive* / metabolism
  • Pulmonary Disease, Chronic Obstructive* / pathology

Substances

  • JCAD protein, mouse
  • Cell Adhesion Molecules