“…4 ). Notably, pro-survival pathways up-regulated in TGFβ-treated and glaucomatous LC (such as JAK-STAT, PAK, JNK and AKT), are highly associated with pro-fibrotic processes orchestrated by TGFβ, 31,32 further supporting the idea that TGFβ induced fibrogenesis is an integral part of the POAG development. Figure 4.…”
While primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, it still does not have a clear mechanism that can explain all clinical cases of the disease. Elevated IOP is associated with increased accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) that prevents normal outflow of aqueous humor (AH) and has damaging effects on the fine mesh-like lamina cribrosa (LC) through which the optic nerve fibers pass. Applying a pathway analysis algorithm, we discovered that an elevated level of TGFβ observed in glaucoma-affected tissues could lead to pro-fibrotic pathway activation in TM and in LC. In turn, activated pro-fibrotic pathways lead to ECM remodeling in TM and LC, making TM less efficient in AH drainage and making LC more susceptible to damage from elevated IOP via ECM transformation in LC. We propose pathway targets for potential therapeutic interventions to delay or avoid fibrosis initiation in TM and LC tissues.
“…4 ). Notably, pro-survival pathways up-regulated in TGFβ-treated and glaucomatous LC (such as JAK-STAT, PAK, JNK and AKT), are highly associated with pro-fibrotic processes orchestrated by TGFβ, 31,32 further supporting the idea that TGFβ induced fibrogenesis is an integral part of the POAG development. Figure 4.…”
While primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, it still does not have a clear mechanism that can explain all clinical cases of the disease. Elevated IOP is associated with increased accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) that prevents normal outflow of aqueous humor (AH) and has damaging effects on the fine mesh-like lamina cribrosa (LC) through which the optic nerve fibers pass. Applying a pathway analysis algorithm, we discovered that an elevated level of TGFβ observed in glaucoma-affected tissues could lead to pro-fibrotic pathway activation in TM and in LC. In turn, activated pro-fibrotic pathways lead to ECM remodeling in TM and LC, making TM less efficient in AH drainage and making LC more susceptible to damage from elevated IOP via ECM transformation in LC. We propose pathway targets for potential therapeutic interventions to delay or avoid fibrosis initiation in TM and LC tissues.
“…TIMPs are natural endogenous inhibitors of MMPs, and TGF‐β‐induced TIMP‐3 is one of the primary antagonists of MMP activity in cartilage. Smad2/3 is the canonical intracellular mediators of TGF‐β signalling; activated Smad2/3 is involved in TGF‐β‐induced cell proliferation, differentiation and target gene expression . It has been shown that Smad2/3 siRNA blocks TGF‐β signalling and maintains TIMP‐1 expression in endothelial cells .…”
This study investigated the roles of ERK1 and ERK2 in transforming growth factor‐β1 (TGF‐β1)‐induced tissue inhibitor of metalloproteinases‐3 (TIMP‐3) expression in rat chondrocytes, and the specific roles of ERK1 and ERK2 in crosstalk with Smad2/3 were investigated to demonstrate the molecular mechanism of ERK1/2 regulation of TGF‐β1 signalling. To examine the interaction of specific isoforms of ERK and the Smad2/3 signalling pathway, chondrocytes were infected with LV expressing either ERK1 or ERK2 siRNA and stimulated with or without TGF‐β1. At indicated time‐points, TIMP‐3 expression was determined by real‐time PCR and Western blotting; p‐Smad3, nuclear p‐Smad3, Smad2/3, p‐ERK1/2 and ERK1/2 levels were assessed. And then, aggrecan, type II collagen and the intensity of matrix were examined. TGF‐β1‐induced TIMP‐3 expression was significantly inhibited by ERK1 knock‐down, and the decrease in TIMP‐3 expression was accompanied by a reduction of p‐Smad3 in ERK1 knock‐down cells. Knock‐down of ERK2 had no effect on neither TGF‐β1‐induced TIMP‐3 expression nor the quantity of p‐Smad3. Moreover, aggrecan, type II collagen expression and the intensity of matrix were significantly suppressed by ERK1 knock‐down instead of ERK2 knock‐down. Taken together, ERK1 and ERK2 have different roles in TGF‐β1‐induced TIMP‐3 expression in rat chondrocytes. ERK1 instead of ERK2 can regulate TGF‐β/Smad signalling, which may be the mechanism through which ERK1 regulates TGF‐β1‐induced TIMP‐3 expression.
“…It has been demonstrated that the TGF-β1/Smad pathway is activated in myofibroblast differentiation, and inhibiting its phosphorylation may attenuate myofibroblast differentiation and the fibrogenic response. Dong et al ( 28 ) demonstrated that interleukin-27 inhibited the proliferation, differentiation and collagen synthesis of lung fibroblasts by reducing the activation of the TGF-β1/Smad signaling pathways. In cystic fibrosis lungs, TGF-β1 signaling was markedly increased, as observed by p-Smad2 expression, increased myofibroblast differentiation and tissue fibrosis ( 29 ).…”
The myofibroblast has been implicated to be an important pathogenic cell in all fibrotic diseases, through synthesis of excess extracellular matrix. Lung fibroblast migration, proliferation and differentiation into a myofibroblast-like cell type are regarded as important steps in the formation of lung fibrosis. In the present study, the effect of maresin 1 (MaR 1), a pro-resolving lipid mediator, on transforming growth factor (TGF)-β1-stimulated lung fibroblasts was investigated, and the underlying molecular mechanisms were examined. The results of the present study demonstrated that MaR 1 inhibited TGF-β1-induced proliferative and migratory ability, assessed using MTT and scratch wound healing assays. The TGF-β1-induced expression of α-smooth muscle actin (α-SMA) and collagen type I, the hallmarks of myofibroblast differentiation, was decreased by MaR 1 at the mRNA and protein levels, determined using the reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Immunofluorescence demonstrated that MaR 1 downregulated the TGF-β1-induced expression of α-SMA. In addition, phosphorylated mothers against decapentaplegic homolog 2/3 (Smad2/3) and extracellular signal-related kinases (ERK) 1/2 were upregulated in TGF-β1-induced lung fibroblasts, and these effects were attenuated by MaR 1 administration. In conclusion, the results of the present study demonstrated that MaR 1 inhibited the TGF-β1-induced proliferation, migration and differentiation of human lung fibroblasts. These observed effects may be mediated in part by decreased phosphorylation of Smad2/3 and ERK1/2 signaling pathways. Therefore, MaR 1 may be a potential therapeutic approach to lung fibrotic diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
