Alvespimycin Exhibits Potential Anti-TGF-β Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and life-threatening lung disease of unknown cause, with limited treatment options currently available. One of the key drivers of pulmonary fibrosis (PF) is the transforming growth factor beta (TGF-β) signaling pathway, which orchestrates a series of molecular events leading to fibrosis. Recent studies have highlighted the enhancement of TGF-β receptor (TβR) signaling through the activation of HSP90, a molecular chaperone. HSP90 plays a crucial role in stabilizing and folding TGF-β receptors, thus regulating TGF-β1 signaling with remarkable precision. In this study, we explored the effects of alvespimycin, an HSP90 inhibitor, on TGF-β-mediated transcriptional responses, particularly focusing on its ability to destabilize TβRs. This destabilization is attributed to the direct interaction between TβR subtypes I and II and HSP90, which helps these receptors maintain their functional integrity within the cell.
A key aspect of TGF-β signal transduction termination is the regulation of the proteasome-dependent degradation of TβRs, which is a critical mechanism for the inactivation of TGF-β signaling. Oleuropein, the primary bioactive compound found in the olive tree (Olea europaea), has been identified as a potent proteasome activator, making it an ideal candidate to enhance proteasomal degradation processes. In this study, we investigated the therapeutic potential of combining oleuropein with alvespimycin for the treatment of PF. Using a rat model of PF induced by intratracheal bleomycin infusion, we administered this dual therapy to evaluate its effects on the progression of the disease.
The combination therapy demonstrated a significant reduction in the activation of TGF-β/SMAD2/3 signaling, a hallmark of fibrotic processes. Notably, this dual treatment improved both lung tissue structure and function, while effectively limiting the expression of key fibrosis markers, including PDGF-BB, TIMP-1, ACTA2, col1a1, and hydroxyproline. Mechanistically, our results indicated that the antifibrotic effects of the combined therapy were likely due to the enhanced degradation of both TβRI and TβRII, contributing to the inhibition of TGF-β signaling.
In conclusion, our findings suggest that the combination of proteasomal activators, such as oleuropein, with HSP90 inhibitors like alvespimycin represents a promising therapeutic strategy for managing PF. This approach not only addresses the dysregulated TGF-β signaling but also offers a novel pathway for targeting fibrosis at the molecular level, potentially leading to improved outcomes for patients suffering from this debilitating disease.