2.3 Anti-fibrotic effects
There is growing evidence that transforming growth factor‐β(TGFβ), connective tissue growth factor(CTGF), and transgelin, play an important role in the pathogenesis of BPD in rodent models. Tatler et al. showed for the first time that caffeine exerted antifibrotic effects in a concentration-dependent manner in lung epithelial cells and fibroblasts63. Caffeine directly inhibited TGFβ activation in lung epithelial cells, whereas in lung fibroblasts, it suppressed the basal expression of α-smooth muscle actin genes and reduced the TGFβ-induced increase in pro-fibrotic genes via a pro-fibrotic response to TGFβ63. In a vitroprecision-cut lung section model, caffeine was shown to reduce bleomycin-induced fibrosis63.
CTGF is a downstream regulator of TGF-β that is responsible for abnormal extracellular matrix(ECM) deposition and tissue fibrosis. Transgelin is a cytoskeleton binding and stabilizing protein. Both of these factors are regulated by TGF-β1 and play an important role in airway remodeling. The increased conditional expression of CTGF in alveolar type II epithelial cells was shown to disrupt alveolarization and vascular development, induce vascular remodeling, and led to pulmonary hypertension, a pathological feature of severe BPD64. Transgelin is an important target of TGFβ-regulated type II alveolar epithelial cell fibrosis. Increase dexpression of transgelinin ATII cells may lead to TGF-dependent alveolar type II (ATII) cell injury, along with repair and migration in pulmonary fibrosis65.Caffeine antagonizes the TGF-β1-induced upregulation of CTGF and transgelin, and plays a role in airway remodeling in BPD66. Caffeine treatment has also been shown to attenuate glucocorticoid-induced CTGF expression and thus promote the restoration of intrapulmonary homeostasis67. Interestingly, recent studies have found that the stereological analysis of lung structure after caffeine administration found no effects of caffeine on alveolar simplification in lungs exposed to hyperoxia68. Caffeine was also found to enhance the ability of TGF-β to drive CTGF gene expression in type II alveolar epithelial cells and fibroblasts68. Therefore, the mechanism by which caffeine can exert regulatory effects on TGFβ, CTGF, and transgelin, still requires further research.