Micellar Hyaluronidase and Spiperone as a Potential Treatment for Pulmonary Fibrosis.

Evgenii Skurikhin,Mariia Zhukova,Darius Widera,Pavel Madonov,Natalia Ermakova,Edgar Pan,Lubov Sandrikina,Andrey Artamonov,Alexander Dygai,Olga Pershina,Angelina Pakhomova

doi:10.3390/ijms22115599

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.

Highlights

Hyaluronic acid (HA) is of great interest to the scientific and clinical community [1,2].HA is present in body fluids, tissues, and in the extracellular matrix [3]
We have studied the conjugate of Pluronic L31 and hyaluronidase 1 as a potential therapeutic agent for the treatment of pulmonary fibrosis
Our study showed that poloxamer-hyaluronidase, created using electron beam synthesis, has anti-inflammatory and antifibrotic effects in animals with pulmonary fibrosis

Summary

Introduction

Hyaluronic acid (HA) is of great interest to the scientific and clinical community [1,2].HA is present in body fluids, tissues, and in the extracellular matrix [3]. Hyaluronic acid performs a structural function by binding to cells and other components of the extracellular matrix through specific and nonspecific interactions. Interacting with proteoglycans, such as aggrecan and versican, HA participates in the organization of fibrin, fibronectin, and collagen [3], and is involved in the regulation of cell adhesion, migration, and proliferation [1,3,4,5]. Which is explained by tissue damage (destruction of epithelial cells) and inflammation [8,9]. Hyaluronic acid can act as a marker of fibrotic changes in the lungs. HA is a convenient target for drug therapy

Objectives

Methods

Results

Discussion

Conclusion