Effect of decreased expression of latent TGF-β binding proteins 4 on the pathogenesis of emphysema as an age-related disease

Abstract

Purpose

Latent TGF-β binding protein 4 (LTBP4) is involved in the production of elastin fibers and has been implicated in LTBP4-related cutis laxa and its complication, emphysema-like changes. Various factors have been implicated in the pathogenesis of emphysema, including elastic degeneration, inflammation, cellular senescence, mitochondrial dysfunction, and decreased angiogenesis in the lungs. We investigated the association between LTBP4 and emphysema using human lung fibroblasts with silenced LTBP4 genes.

Methods

Cell contraction, elastin expression, cellular senescence, inflammation, anti-inflammatory factors, and mitochondrial function were compared between the LTBP4 small interfering RNA (siRNA) and control siRNA.

Results

Under the suppression of LTBP4, significant changes were observed in the following: decreased cell contractility, decreased elastin expression, increased expression of the p16 gene involved in cellular senescence, increased TNFα, decreased GSTM3 and SOD, decreased mitochondrial membrane potential, and decreased VEGF expression. Furthermore, the decreased cell contractility and increased GSTM3 expression observed under LTBP4 suppression were restored by the addition of N-acetyl-L-cysteine or recombinant LTBP4.

Conclusion

The decreased elastin expression, cellular senescence, inflammation, decreased antioxidant activity, mitochondrial dysfunction, and decreased VEGF expression under reduced LTBP4 expression may all be involved in the destruction of the alveolar wall in emphysema. Smoking is the most common cause of emphysema; however, genetic factors related to LTBP4 expression and other factors may also contribute to its pathogenesis.