Caffeine inhibits TGFβ activation in epithelial cells, interrupts fibroblast responses to TGFβ, and reduces established fibrosis inex vivoprecision-cut lung slices

Abstract

Caffeine is a commonly used food additive found naturally in many products. In addition to potently stimulating the central nervous system caffeine is able to affect various systems within the body including the cardiovascular and respiratory systems. Importantly, caffeine is used clinically to treat apnoea and bronchopulmonary dysplasia in premature babies. Recently, caffeine has been shown to exhibit antifibrotic effects in the liver in part through reducing collagen expression and deposition, and reducing expression of the profibrotic cytokine TGFβ. The potential antifibrotic effects of caffeine in the lung have not previously been investigated. Using a combined in vitro and ex vivo approach we have demonstrated that caffeine can act as an antifibrotic agent in the lung by acting on two distinct cell types, namely epithelial cells and fibroblasts. Caffeine inhibited TGFβ activation by lung epithelial cells in a concentration-dependent manner but had no effect on TGFβ activation in fibroblasts. Importantly, however, caffeine abrogated profibrotic responses to TGFβ in lung fibroblasts. It inhibited basal expression of the α-smooth muscle actin gene and reduced TGFβ-induced increases in profibrotic genes. Finally, caffeine reduced established bleomycin-induced fibrosis after 5 days treatment in an ex vivo precision-cut lung slice model. Together, these findings suggest that there is merit in further investigating the potential use of caffeine, or its analogues, as antifibrotic agents in the lung.

Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Etiology of Exfoliation Syndrome

“…[91][92][93][94][95] Moreover, coffee and caffeine inhibit collagen expression and deposition, and have anti-fibrotic effects by blocking expressions and/or by modulating effects of profibrotic factors. [96][97][98][99] Our results that show enrichment in crosslinking of collagen fibrils, a crucial constituent of connective tissues, and endosomal-vacuolar Reactome pathways, in our associated genes further confirm the importance of connective tissues in the etiology of XFS. In addition, there may be anomalies in an endosomal-vacuolar pathway shown to be involved in the accumulation of other aberrant proteins, including: Aβ peptides, 100 prion 101 , and Huntingtin 102 in neurons, and implicated in neurodegeneration.…”

Caffeine inhibits hypoxia-induced renal fibroblast activation by antioxidant mechanism

“…In a model of alcoholinduced liver fibrosis, activation of hepatic stellate cells via cAMP/PKA/CREB pathway was inhibited by caffeine treatment [14]. In addition, caffeine could inhibit TGF-βinduced epithelial cell and fibroblast activation in vitro and could also reduce collagen production in established fibrosis of lung tissue ex vivo [16]. However, the role of caffeine in renal fibrosis remained unclear.…”

Effects of Systemic and Local Caffeine on Vessel Diameter, Anastomosis Patency, and Intimal Hyperplasia in the Rat

“…In experimental studies, caffeine is shown to have antifibrotic features. Such an effect was demonstrated in the studies of liver fibrosis prevention 31,32 and pulmonary fibroblast response reduction. 33 Although this study was not designed to investigate this property, to our surprise, the tissue dissection at 3 weeks was much easier in group 5 with significantly less scar tissue that in fact resembled a virginal wound bed (►Fig.…”