An Inhibitory Function of TRPA1 Channels in TGF-β1-driven Fibroblast to Myofibroblast Differentiation.
Fabienne GeigerSarah ZeitlmayrClaudia A Staab-WeijnitzSuhasini RajanAndreas BreitThomas GudermannAlexander DietrichPublished in: American journal of respiratory cell and molecular biology (2022)
Transient receptor potential ankyrin 1 (TRPA1) is a non-selective Ca2+ permeable cation channel, which was originally cloned from human lung fibroblasts (HLFs). TRPA1-mediated Ca2+ entry is evoked by exposure to several chemicals, including allyl isothiocyanate (AITC), and a protective effect of TRPA1 activation in the development of cardiac fibrosis has been proposed. Yet, the function of TRPA1 in transforming growth factor β1 (TGF-β1)-driven fibroblast to myofibroblast differentiation and the development of pulmonary fibrosis remains elusive. TRPA1 expression and function was analyzed in cultured primary HLFs, and mRNA levels were significantly reduced after adding TGF-β1. Expression of genes encoding fibrosis markers, e.g. alpha smooth muscle actin (ACTA2), plasminogen activator inhibitor 1 (SERPINE1), fibronectin (FN1) and type I collagen (COL1A1) was increased after siRNA-mediated down-regulation of TRPA1-mRNA in HLFs. Moreover, AITC-induced Ca2+ entry in HLFs was decreased after TGF-β1 treatment and by application of TRPA1 siRNAs, while AITC treatment alone did not reduce cell viability or enhanced apoptosis. Most interestingly, AITC-induced TRPA1 activation augmented ERK1/2 phosphorylation, which might inhibit TGF-β-receptor signaling. Our results suggest an inhibitory function of TRPA1 channels in TGF-β1-driven fibroblast to myofibroblast differentiation. Therefore, activation of TRPA1 channels might be protective during the development of pulmonary fibrosis in patients.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- pulmonary fibrosis
- smooth muscle
- binding protein
- signaling pathway
- oxidative stress
- high glucose
- newly diagnosed
- end stage renal disease
- chronic kidney disease
- cell proliferation
- endothelial cells
- heart failure
- dna methylation
- pi k akt
- transcription factor
- brain injury
- prognostic factors
- ionic liquid
- subarachnoid hemorrhage
- cell cycle arrest
- drug delivery
- hyaluronic acid
- patient reported outcomes
- stress induced
- cerebral ischemia