BDNF/TrkB axis activation promotes epithelial–mesenchymal transition in idiopathic pulmonary fibrosis

Abstract

BackgroundNeurotrophins (NT) belongs to a family of growth factors which promotes neurons survival and differentiation. Increasing evidence show that NT and their receptor are expressed in lung tissues suggesting a possible role in lung health and disease. Here we investigated the expression and functional role of the TrkB/BDNF axis in idiopathic pulmonary fibrotic lung (myo)fibroblasts.MethodsLung fibroblast were isolated from IPF patients and characterized for the expression of mesenchymal markers in comparison to normal lung fibroblasts isolated from non-IPF controls.ResultsBDNF treatment promoted mesenchymal differentiation and this effect was counteracted by the TrkB inhibitor K252a. In this regard, we showed that K252a treatment was able to control the expression of transcription factors involved in epithelial to mesenchymal transition (EMT). Accordingly, K252a treatment reduced matrix metalloproteinase-9 enzyme activity and E-cadherin expression while increased cytoplasmic β-catenin expression.ConclusionsOur results suggest that BDNF/TrkB axis plays a role in EMT promoting the acquisition of (myo)fibroblast cell phenotype in IPF. Targeting BDNF/TrkB seems to represent a viable approach in order to prevent EMT dependent lung fibrosis.

Exercise training ameliorates bleomycin‐induced epithelial mesenchymal transition and lung fibrosis through restoration of H2S synthesis

“…Among the numerous cytokines that regulate EMT, TGF‐β1 represents a main inducer of EMT in multiple organ systems, since it can independently initiate and complete the entire course of EMT via activating the downstream Smad signalling pathway . Clinical and basic science studies have highlighted the role of TGF‐β1‐triggered EMT in the pathogenesis of lung fibrosis in both IPF patients and animal models treated with bleomycin . In addition, activation of developmental pathways, such as Wnt/LRP/β‐catenin pathway has been implicated in the pathogenesis of pulmonary fibrosis.…”

“…Myofibroblast accumulation may occur as a consequence of resident fibroblast to myofibroblast transition, epithelial‐mesenchymal transition (EMT) or by the recruitment of circulating fibroblastic stem cells . Recent studies have highlighted the role of EMT in the pathogenesis of IPF . Epithelial‐mesenchymal transition is controlled by a network of signalling and transcriptional events mediated in part by transforming growth factor (TGF)‐β/Smad signalling pathway .…”

The Influence of BuqiHuoxueTongluo Formula on Histopathology and Pulmonary Function Test in Bleomycin‐Induced Idiopathic Pulmonary Fibrosis in Rats

“…Transforming growth factor β 1 (TGF- β 1 ) was the most important starting factor of IPF [ 7 ]; it could accelerate the progress with which alveolar epithelial cell is transformed into mesenchymal myofibroblast, and then its specific marker α -smooth muscle actin ( α -SMA) was overexpressed [ 8 ]. During this course of epithelial-mesenchymal transition (EMT), the function of type II alveolar epithelial cell (AECII) such as secreting pulmonary surfactant (PS) would be influenced because of this transformation [ 9 ]. Lamellar body (LB) is an organelle of AECII, which could pack and secrete the pulmonary surfactant [ 10 ]; its ultrastructure could reflect the functional status of AECII.…”

The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases

“…In particular, it was noticed that BDNF/TrkB participated in the activities of fibroblasts. For example, Cherubini and colleagues found that TrkB was expressed in lung fibroblasts, and activation of BDNF/TrkB axis promoted the epithelial–mesenchymal transition in idiopathic pulmonary fibrosis [ 56 ]. Similarly, BDNF/TrkB was associated with pathologic changes of other types of fibroblasts such as airway [ 57 ] and human dermal fibroblast cells [ 58 ].…”

“…Helan et al reported that PAECs expressed and secreted BDNF in response to hypoxia via an HIF-1-regulated pathway [ 48 ]. Activation of the BDNF/TrkB axis accelerated epithelial–mesenchymal transition in idiopathic pulmonary fibrosis [ 56 ]. In addition, recent studies found that 7,8-DHF enhanced cholinergic contraction of rat gastric smooth muscle via upregulating muscarinic M 3 receptor expression [ 59 ].…”