Hypoxia-inducible factor-1α regulates epithelial-to-mesenchymal transition in paraquat-induced pulmonary fibrosis by activating lysyl oxidase

Abstract

Pulmonary fibrosis (PF) is one of the most prevalent causes of death following paraquat (PQ) poisoning. As demonstrated in previous studies by the present authors, epithelial-to-mesenchymal transition (EMT) is associated with PQ-induced PF. In addition, hypoxia-inducible factor-1α (HIF-1α) and lysyl oxidase (LOX) promote EMT following PQ poisoning. However, the association between HIF-1α- and LOX-mediated regulation of EMT remains unclear. The present study investigated the association between HIF-1α and LOX with regard to PQ-induced EMT. A549 and RLE-6TN cells were treated with PQ, and HIF-1α and LOX expression was silenced with short interfering RNAs. Changes in the expression of HIF-1α, LOX, β-catenin and EMT-related makers were detected using real-time quantitative polymerase chain reaction, immunofluorescence, and western blotting. HIF-1α and LOX were associated with PQ-induced EMT, and their expression levels were significantly increased (P<0.05). LOX expression was significantly decreased following PQ poisoning when HIF-1α expression was inhibited (P<0.05). However, the level of HIF-1α did not change significantly when LOX was silenced. The expression level of β-catenin and the degree of EMT were significantly decreased following HIF-1α and LOX silencing in both cell lines (P<0.05). The association between HIF-1α and LOX in regulating EMT during PQ-induced PF may be unidirectional. HIF-1α may regulate PQ-induced EMT through the LOX/β-catenin pathway.

Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases

“…Numerous studies on bleomycin-induced lung fibrosis have confirmed the induction of LOX expression and the amelioration of fibrosis by the pan-lysyl oxidase inhibitor β-aminopropionitrile (BAPN) ( Table 1 ) [ 35 , 36 , 37 , 86 ]. Elevated activity of LOX has been confirmed for other models of IPF, for example in paraquat-induced fibrosis [ 39 , 40 ] ( Table 1 ). Elevated levels of LOXL2 also play important roles in IPF with links to disease progression risk [ 38 ], increased fibroblast-to-myofibroblast transition (FMT) [ 41 ] and increased collagen fibril thickness [ 43 ].…”

Role of epithelial-to-mesenchymal transition in the pulmonary fibrosis induced by paraquat in rats

“…The TGF-β1-β-catenin signaling pathway might join in the early PF process in PQ-poisoned rats. [14] Moreover, the lysyl oxidase (LOX) [21] or Wnt1 [29,30] could regulate the PQ-induced EMT by activating β-catenin that participated in the development of PF process in cell models. Our study showed that the mRNA expression of Wnt2 and β-catenin in rat lung dramatically increased with a peak on day 21 after PQ injection.…”

“…The epithelial cells gradually obtained the features of mesenchymal phenotype, e.g., signifi cantly enhancing expression of α-smooth muscle actin (α-SMA) protein and fibroblast specific protein-1 (FSP-1) as the markers of mesenchymal cells. [17] In vitro studies [18][19][20][21][22] showed that the EMT process in PQ-induced PF was mediated by the transforming growth factor-β1 (TGF-β1), Smad, mitogen-activated protein kinase (MAPK), and β-catenin. However, few studies [14,23] focused on the mechanism of EMT with PQ-induced animal models.…”

Influence of strengthened hemoperfusion combined with continuous venovenous hemofiltration on prognosis of patients with acute paraquat poisoning: SHP + CVVH improve prognosis of acute PQ patients

“…The mechanism of lung injury caused by acute paraquat poisoning was not fully clear. Previous studies revealed that it may be related to oxidation-reduction system disorder caused by oxygenfree radicals, HO-1 and other genetic expression changes, cell apoptosis, increased inflammatory factors and other multiple factors [15][16][17][18]. Respiratory failure is one of the most common clinical manifestations at the time of acute lung injury.…”