Extracellular vesicles transport heat shock proteins and exacerbate pulmonary fibrosis - 17/02/23

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease. Impaired cellular crosstalk between aberrantly activated lung (epithelium, (myo)fibroblasts and immune) cells is central in the disease. Heat Shock Proteins (HSPs) are secreted and have extracellular role during fibrosis. Extracellular vesicles (EVs) accumulate within the IPF lung and carry specific proteins. We explore whether HSPs are linked to EVs and how this contribute to pulmonary fibrosis.

EVs were isolated from broncho-alveolar lavage fluid (BALF) collected from mice with bleomycin-induced pulmonary fibrosis and from culture media of fibroblast by ultracentrifugation. These vesicles were analyzed by nanoparticle tracking analysis and western blotting. Functional properties of EVs have been tested using ex vivo lung tissue followed by transcriptomic and microscopic analyses.

BALF-EVs from mice with pulmonary fibrosis exhibited increased levels of HSP90 compared to control vesicles. In addition, these HSPs were found linked to EVs and not detected in the non-vesicular fraction. Functionally, levels of BALF-EVs correlated with mouse lung function. When applied to ex vivo cultured lung tissue, EVs from fibrotic mice or TGF-β1-activated fibroblasts increased the expression of the fibrosis-related genes Col1a1, Acta2, Fn1 as well as collagen deposition as observed by second harmonic generation.

During pulmonary fibrosis, the accumulation of EVs is correlated to aggravated lung function. Our data demonstrate that EVs isolated from a fibrotic model (mouse, fibroblast) is able to drive fibrogenesis. In parallel, EVs are also loaded with HSP. Whether HSPs play a role in the vesicle's activities remain to be elucidated.