Micellar Hyaluronidase and Spiperone as a Potential Treatment for Pulmonary Fibrosis

Abstract

Concentration of hyaluronic acid (HA) in the lungs increases in idiopathic pulmonary fibrosis (IPF). HA is involved in the organization of fibrin, fibronectin, and collagen. HA has been proposed to be a biomarker of fibrosis and a potential target for antifibrotic therapy. Hyaluronidase (HD) breaks down HA into fragments, but is a subject of rapid hydrolysis. A conjugate of poloxamer hyaluronidase (pHD) was prepared using protein immobilization with ionizing radiation. In a model of bleomycin-induced pulmonary fibrosis, pHD decreased the level of tissue IL-1β and TGF-β, prevented the infiltration of the lung parenchyma by CD16+ cells, and reduced perivascular and peribronchial inflammation. Simultaneously, a decrease in the concentrations of HA, hydroxyproline, collagen 1, total soluble collagen, and the area of connective tissue in the lungs was observed. The effects of pHD were significantly stronger compared to native HD which can be attributed to the higher stability of pHD. Additional spiperone administration increased the anti-inflammatory and antifibrotic effects of pHD and accelerated the regeneration of the damaged lung. The potentiating effects of spiperone can be explained by the disruption of the dopamine-induced mobilization and migration of fibroblast progenitor cells into the lungs and differentiation of lung mesenchymal stem cells (MSC) into cells of stromal lines. Thus, a combination of pHD and spiperone may represent a promising approach for the treatment of IPF and lung regeneration.

Exploring therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis

“…Moreover, with the increasing understanding of the IPF mechanism, more and more potential therapeutic targets have been discovered, such as MMPs, 104 glycosaminoglycan, 105 non-coding RNA, 106 adenosine, 107 mechanosensitive MDM4, 108 micellar hyaluronidase, and spiperone. 109 So far, many researchers have focused on the downstream effectors of gene expression, such as cytokines and enzymes. The epigenetic modification also plays a vital role in IPF.…”

Effect of immobilized hyaluronidase and subtilisin enzymes on the ultrastructure of human conjunctival epithelial cells

“…Энзимотерапия при заболеваниях глаза описана в литературе, однако большого количества исследований и публикаций не наблюдается [16]. Применение иммобилизированных форм гиалуронидазы (ИГ) и субтилизина (ИС) для офтальмологической практики представляются весьма перспективным, поскольку их фармакологическое действие отслеживает многие патогенетические механизмы заболеваний глаза [17][18][19][20].…”

Anti-Inflammatory and Antifibrotic Potential of Longidaze in Bleomycin-Induced Pulmonary Fibrosis

“…The main enzyme that regulates HA metabolism is hyaluronidase (HD), which remodels the extracellular matrix by cleaving HA into fragments (glucosamines and glucuronic acid) [ 13 , 14 ]. Given the role of HA in the organization of fibrin, fibronectin, and collagen, it is considered one of the biomarkers of fibrosis and a potential target for antifibrotic therapy, in particular for drugs based on HD [ 15 ]. The pathogenesis of pulmonary fibrosis is complex and not fully understood, which hinders the development of specific therapies.…”

“…Previously, we investigated the effects of poloxamer hyaluronidase (pHD—a conjugate of Pluronic L31 and hyaluronidase) compared to native HD in a model of bleomycin-induced pulmonary fibrosis in C57BL/6 mice. It was shown that the administration of pHD reduced the content of connective tissue in the lung by more than twofold, and decreased the concentration of TGF-β, hydroxyproline, type 1 collagen, and total collagen in the lung homogenate [ 15 ].…”