Extracellular Heat Shock Proteins as Therapeutic Targets and Biomarkers in Fibrosing Interstitial Lung Diseases

Abstract

Interstitial lung diseases (ILDs) include a large number of diseases and causes with variable outcomes often associated with progressive fibrosis. Although each of the individual fibrosing ILDs are rare, collectively, they affect a considerable number of patients, representing a significant burden of disease. Idiopathic pulmonary fibrosis (IPF) is the typical chronic fibrosing ILD associated with progressive decline in lung. Other fibrosing ILDs are often associated with connective tissues diseases, including rheumatoid arthritis-ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD), or environmental/drug exposure. Given the vast number of progressive fibrosing ILDs and the disparities in clinical patterns and disease features, the course of these diseases is heterogeneous and cannot accurately be predicted for an individual patient. As a consequence, the discovery of novel biomarkers for these types of diseases is a major clinical challenge. Heat shock proteins (HSPs) are molecular chaperons that have been extensively described to be involved in fibrogenesis. Their extracellular forms (eHSPs) have been recently and successfully used as therapeutic targets or circulating biomarkers in cancer. The current review will describe the role of eHSPs in fibrosing ILDs, highlighting the importance of these particular stress proteins to develop new therapeutic strategies and discover potential biomarkers in these diseases.

Novel Biomarkers, Diagnostic and Therapeutic Approach in Rheumatoid Arthritis Interstitial Lung Disease—A Narrative Review

“…IFN- γ was not discovered in the PBMC of patients with other connective tissue diseases (CTD)-ILD. This is due to the fact that IFN- γ production is increased by cit-Hsp90 T lymphocytes specific for RA-ILD [ 19 , 27 , 28 ].…”

The role of heat shock proteins in metastatic colorectal cancer: A review

“…The overexpression of αB-crystalline in epithelial cells and fibroblasts increases the nuclear localization of Smad4 by antagonizing its mono-ubiquitination and subsequent nuclear export, thereby promoting the activation of TGF-β downstream target genes. 133 These studies suggest that to facilitate tumor progression, αB-crystallin regulates core components of the EMT program.…”

Extracellular HSPs: The Potential Target for Human Disease Therapy

“…Subsequently, several teams have provided reliable evidence showing that eHSP70 was actually able to activate the immune cells, such as macrophages and monocytes [ 31 , 32 ]. Nowadays, growing evidence has shown that HSPs could be released by various types of cells in several ways, passively or actively, and therefore, the scientific community has fully accepted this phenomenon and more attention has been given to the function of eHSPs in many human diseases [ 19 , 20 , 21 , 33 , 34 ].…”

“…For the last 20 years, HSPs have been considered to be typical intracellular proteins since the report of the heat shock response and characterization of the 70 kD heat shock proteins. However, growing evidence suggests that HSPs can be released into the extracellular space and blood and that they play essential roles in many human diseases through the modulation of inflammation and immune responses [ 18 , 19 , 20 , 21 , 22 ]. In this review, first, we describe the types of eHSPs, and then discuss the mechanisms of eHSP secretion.…”