Abstract
Idiopathic Pulmonary fibrosis (IPF) is a catastrophic disease with poor outcomes and limited pharmacological approaches. Heat shock protein 90 (HSP90) has been recently involved in the wound-healing pathological response that leads to collagen deposition in patients with IPF and its inhibition represents an exciting drug target against the development of pulmonary fibrosis. Under physiological conditions, HSP90 guarantees proteostasis through the refolding of damaged proteins and the degradation of irreversibly damaged ones. Additionally, its inhibition, by specific HSP90 inhibitors (e.g., 17 AAG, 17 DAG, and AUY-922) has proven beneficial in different preclinical models of human disease. HSP90 inhibition modulates a complex subset of kinases and interferes with intracellular signaling pathways and proteome regulation. In this review, we evaluated the current evidence and rationale for the use of HSP90 inhibitors in the treatment of pulmonary fibrosis, discussed the intracellular pathways involved, described the limitations of the current understanding and provided insights for future research.
Highlights
Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease, characterized by the progressive substitution of the lung parenchyma with a fibrotic scar
IPF is a disease characterized by unbalance of the proteome
Heat shock protein 90 (HSP90) plays an important role in the pathogenesis of the fibrotic process in the lung
Summary
Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease, characterized by the progressive substitution of the lung parenchyma with a fibrotic scar. It is associated with poor prognosis and an estimated mean survival of 2–5 years from the time of diagnosis [1]. HSP90 is one of the most expressed heat shock proteins, found in both bacteria and eukaryotes [23] It plays an important role in the stress response to environmental insults (heat, hypoxia, and oxidative stress) as it mediates the correct folding and stabilization of several proteins, guaranteeing their function and promoting cell survival. It is important to note that the C-terminal domain of HSP90 presents an alternative ATP-binding pocket, which guarantees a minimal chaperone activity when the N-terminal binding pocket is occupied or inhibited [35]
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