Modulation of Bleomycin-Induced Lung Fibrosis by Pegylated Hyaluronidase and Dopamine Receptor Antagonist in Mice

Abstract

Hyaluronidases are groups of enzymes that degrade hyaluronic acid (HA). To stop enzymatic hydrolysis we modified testicular hyaluronidase (HYAL) by activated polyethylene oxide with the help of electron-beam synthesis. As a result we received pegylated hyaluronidase (pegHYAL). Spiperone is a selective D2 dopamine receptor antagonist. It was demonstrated on the model of a single bleomycin damage of alveolar epithelium that during the inflammatory phase monotherapy by pegHYAL or spiperone reduced the populations of hematopoietic stem /progenitor cells in the lung parenchyma. PegHYAL also reduced the levels of transforming growth factor (TGF)-β, interleukin (IL)-1β, tumor necrosis factor (TNF)-α in the serum and lungs, while spiperone reduced the level of the serum IL-1β. Polytherapy by spiperone and pegHYAL caused the increase of the quantity of hematopoietic stem/ progenitor cells in the lungs. Such an influx of blood cell precursors was observed on the background of considerable fall level of TGF-β and the increase level of TNF-α in the serum and lungs. These results show pegHYAL reduced the bleomycin-induced fibrosis reaction (production and accumulation of collagen) in the lung parenchyma. This effect was observed at a single and repetitive bleomycin damage of alveolar epithelium, the antifibrotic activity of pegHYAL surpassing the activity of testicular HYAL. The antifibrotic effect of pegHYAL is enhanced by an additional instillation of spiperone. Therapy by pegHYAL causes the flow of CD31‒CD34‒CD45‒CD44+CD73+CD90+CD106+-cells into the fibrous lungs. These cells are incapable of differentiating into fibroblast cells. Spiperone instillation separately or together with pegHYAL reduced the MSC-like cells considerably. These data enable us to assume, that pegHYAL is a new and promising instrument both for preventive and therapy of toxic pneumofibrosis. The blockage of D2 dopamine receptors with the following change of hyaluronan matrix can be considered as a new strategy in treatment of pneumofibrosis.

HYAL1 Is Downregulated in Idiopathic Pulmonary Fibrosis and Inhibits HFL-1 Fibroblast Proliferation When Upregulated

“…Consistent with our previous study [27], no sample type preference was identified. HYAL1 was one of the top 25 genes that was significantly downregulated in IPF lung tissues, which supports the reported antifibrotic effect of hyaluronidases in lung fibrosis [34,36]. Our observation of reduced HYAL1 expression in IPF lung tissue was consistent with reports of the absence of HYAL1 mRNA in lung carcinoma cell lines [12] and reduced HYAL1 protein levels in endometrial carcinomas [13].…”

“…The role of hyaluronidases in lung fibrosis is evident from the noted therapeutic applications [33] and antifibrotic effects in bleomycin-induced lung fibrosis in mice [34]. In addition, HYAL2 was found to regulate the splicing of CD44 pre-mRNA, which determines the antifibrotic phenotype [35].…”

Hyaluronan as a therapeutic target in human diseases

“…Hyaluronidase-loaded PLGA microparticles reduced neutrophil recruitment and collagen deposition after bleomycin treatment [177]. Intranasal therapy with immobilized and testicular hyaluronidases prevented the deposition of collagen in the parenchyma of bleomycin-treated lungs [178]. Hyaluronidase attenuation of bleomycin-induced lung fibrosis might be due to promoting a population of mesenchymal stem cell-like cells in the bleomycin injured lung [178].…”

“…Intranasal therapy with immobilized and testicular hyaluronidases prevented the deposition of collagen in the parenchyma of bleomycin-treated lungs [178]. Hyaluronidase attenuation of bleomycin-induced lung fibrosis might be due to promoting a population of mesenchymal stem cell-like cells in the bleomycin injured lung [178]. Further study is needed to dissect the role of hyaluronidase in pulmonary fibrosis and the potential molecular mechanisms.…”

“…Recently, immobilized hyaluronidases have been investigated. Pegylated hyaluronidase reduced bleomycin-induced lung fibrosis in mice [178]. Hyaluronidase-loaded poly(D,L-lactide-co-glycolide) (PLGA) microparticles reduced neutrophil recruitment and collagen deposition after bleomycin treatment in mice [177].…”