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.
Highlights
Pneumofibrosis includes a heterogeneous group of lung disorders, characterized by a progressing and irreversible destruction of alveolar epithelium architecture, caused by scar-forming, which leads to the failure of gases interchange, and, to death from respiratory failure [1]
The concentrations of IL-1β, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β in lung parenchyma and serum were determined by ELISA according to manufacturer instructions (BD Biosciences)
Macrophages, neutrophils [85] and T-helper cells [86,87,88] produce TGF-β, IL-1β and TNF-α. These results demonstrate that the decrease in the TGF-β and IL-1β levels in the serum of animals with pneumofibrosis can be caused be the inhibiting action of spiperone, conditioned by D2 dopamine receptors
Summary
Pneumofibrosis includes a heterogeneous group of lung disorders, characterized by a progressing and irreversible destruction of alveolar epithelium architecture, caused by scar-forming, which leads to the failure of gases interchange, and, to death from respiratory failure [1]. Idiopathic pulmonary fibrosis (IPF) is the most serious form of pneumofibrosis with unknown etiology. IPF of lungs can grow as a complication after virus infections, radiotherapy and chemical therapy, after adverse effects of environmental spray toxins [10,11,12,13]. The existing set of treatment procedures for IPF is limited and ineffective. The clinical practice is focused mainly on treatment of complications and supporting therapy [16, 17]
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