The WNT signaling pathways are major regulators of organ development. Ample research over the past few decades revealed that these pathways are critically involved in adult tissue homeostasis and ...stem cell function as well as the development of chronic diseases, such as cancer and fibrosis. In this review, we will describe the different WNT signal pathways, summarize the current evidence of WNT signal involvement in wound healing and fibrosis, and highlight potential novel therapeutic options for fibrotic disorders targeting WNT signaling pathways.
•WNT, beyond its role in development, is a critical mediator in human fibrosis development and progression across organs.•Interference with active WNT signaling leads to attenuation of several experimental fibrosis models in vivo•WNT/β-catenin dependent and independent pathways contribute to cellular phenotypes triggering and facilitating fibrosis•WNT signaling represents promising therapeutic targets with growing number of compounds and drugs in (pre)clinical trials
Lipids are major actors and regulators of physiological processes within the lung. Initial research has described their critical role in tissue homeostasis and in orchestrating cellular communication ...to allow respiration. Over the past decades, a growing body of research has also emphasized how lipids and their metabolism may be altered, contributing to the development and progression of chronic lung diseases such as pulmonary fibrosis. In this review, we first describe the current working model of the mechanisms of lung fibrogenesis before introducing lipids and their cellular metabolism. We then summarize the evidence of altered lipid homeostasis during pulmonary fibrosis, focusing on their extracellular forms. Finally, we highlight how lipid targeting may open avenues to develop therapeutic options for patients with lung fibrosis.
Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis. The STAT3 signaling pathway has shown a pivotal role ...in cancer cell migration, invasion, metastasis and drug resistance of TNBC cells. IL-6 is a main upstream activator of the JAK2/STAT3 pathway. In the present study we examined the impact of the NO-donor glyceryl trinitrate (GTN) on the activation of the JAK2/STAT3 signaling pathway and subsequent migration, invasion and metastasis ability of TNBC cells through in vitro and in vivo experiments. We used a subtoxic dose of carboplatin and/or recombinant IL-6 to activate the JAK2/STAT3 signaling pathway and its functional outcomes. We found an inhibitory effect of GTN on the activation of the JAK2/STAT3 signaling, migration and invasion of TNBC cells. We discovered that GTN inhibits the activation of JAK2, the upstream activator of STAT3, and mediates the S-nitrosylation of JAK2. Finally, the effect of GTN (Nitronal) on lung metastasis was investigated to assess its antitumor activity in vivo.
Idiopathic pulmonary fibrosis is a chronic, progressive and lethal disease of unknown etiology that ranks among the most frequent interstitial lung diseases. Idiopathic pulmonary fibrosis is ...characterized by dysregulated healing mechanisms that lead to the accumulation of large amounts of collagen in the lung tissue that disrupts the alveolar architecture. The two currently available treatments, nintedanib and pirfenidone, are only able to slow down the disease without being curative. We demonstrated in the past that HSPB5, a low molecular weight heat shock protein, was involved in the development of fibrosis and therefore was a potential therapeutic target. Here, we have explored whether NCI-41356, a chemical inhibitor of HSPB5, can limit the development of pulmonary fibrosis. In vivo, we used a mouse model in which fibrosis was induced by intratracheal injection of bleomycin. Mice were treated with NaCl or NCI-41356 (six times intravenously or three times intratracheally). Fibrosis was evaluated by collagen quantification, immunofluorescence and TGF-β gene expression. In vitro, we studied the specific role of NCI-41356 on the chaperone function of HSPB5 and the inhibitory properties of NCI-41356 on HSPB5 interaction with its partner SMAD4 during fibrosis. TGF-β1 signaling was evaluated by immunofluorescence and Western Blot in epithelial cells treated with TGF-β1 with or without NCI-41356. In vivo, NCI-41356 reduced the accumulation of collagen, the expression of TGF-β1 and pro-fibrotic markers (PAI-1, α-SMA). In vitro, NCI-41356 decreased the interaction between HSPB5 and SMAD4 and thus modulated the SMAD4 canonical nuclear translocation involved in TGF-β1 signaling, which may explain NCI-41356 anti-fibrotic properties. In this study, we determined that inhibition of HSPB5 by NCI-41356 could limit pulmonary fibrosis in mice by limiting the synthesis of collagen and pro-fibrotic markers. At the molecular level, this outcome may be explained by the effect of NCI-41356 inhibiting HSPB5/SMAD4 interaction, thus modulating SMAD4 and TGF-β1 signaling. Further investigations are needed to determine whether these results can be transposed to humans.
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