Modulation of bleomycin-induced lung fibrosis by pegylated hyaluronidase and dopamine receptor antagonist in mice.
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.
Department of Pathophysiology and Regenerative Medicine, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk, Russia.
Evgenii Germanovich
EG
Skurikhin
Department of Pathophysiology and Regenerative Medicine, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk, Russia.
Olga Victorovna
OV
Pershina
Department of Pathophysiology and Regenerative Medicine, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk, Russia.
Alena Mikhaylovna
AM
Reztsova
Department of Pathophysiology and Regenerative Medicine, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk, Russia.
Natalia Nikolaevna
NN
Ermakova
Department of Pathophysiology and Regenerative Medicine, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk, Russia.
Ekaterina Sergeevna
ES
Khmelevskaya
Department of Pathophysiology and Regenerative Medicine, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk, Russia.
Vycheslav Andreevich
VA
Krupin
Department of Pathophysiology and Regenerative Medicine, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk, Russia.
Inna Ernestovna
IE
Stepanova
Limited Liability Company «Scientific Future Management», Novosibirsk, Russia.
Andrew Vladimirovich
AV
Artamonov
Limited Liability Company «Scientific Future Management», Novosibirsk, Russia.
Andrew Alexandrovich
AA
Bekarev
Limited Liability Company «Scientific Future Management», Novosibirsk, Russia.
Pavel Gennadjevich
PG
Madonov
Department of Pathophysiology and Regenerative Medicine, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk, Russia.
Alexander Mikhaylovich
AM
Dygai
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006821:Hyaluronoglucosaminidase / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy*; D013134:Spiperone / Q000627:therapeutic use
D018492:Dopamine Antagonists; D001761:Bleomycin; D013134:Spiperone; D006821:Hyaluronoglucosaminidase