Recombinant hirudin attenuates pulmonary hypertension and thrombosis in acute pulmonary embolism rat model

Xiang Wei; Yanfen Zou; Shunli Dong; Yi Chen; Guoping Li; Bin Wang

doi:10.7717/peerj.17039

Recombinant hirudin attenuates pulmonary hypertension and thrombosis in acute pulmonary embolism rat model

PeerJ. 2024 Apr 5:12:e17039. doi: 10.7717/peerj.17039. eCollection 2024.

Authors

Xiang Wei^#^{1

2}, Yanfen Zou^#³, Shunli Dong^{1

2}, Yi Chen^{1

2}, Guoping Li^{1

2}, Bin Wang^{1

2}

Affiliations

¹ Department of Respiratory Medicine, Huzhou Central Hospital, Huzhou, Zhejiang Province, China.
² Huzhou Key Laboratory of Precision Diagnosis and Treatment in Respiratory Diseases, Huzhou, Zhejiang Province, China.
³ Departments of Obstetrics and Gynecology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shangdong Province, China.

^# Contributed equally.

Abstract

Background: Acute pulmonary embolism (APE) is classified as a subset of diseases that are characterized by lung obstruction due to various types of emboli. Current clinical APE treatment using anticoagulants is frequently accompanied by high risk of bleeding complications. Recombinant hirudin (R-hirudin) has been found to have antithrombotic properties. However, the specific impact of R-hirudin on APE remains unknown.

Methods: Sprague-Dawley (SD) rats were randomly assigned to five groups, with thrombi injections to establish APE models. Control and APE group rats were subcutaneously injected with equal amounts of dimethyl sulfoxide (DMSO). The APE+R-hirudin low-dose, middle-dose, and high-dose groups received subcutaneous injections of hirudin at doses of 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg, respectively. Each group was subdivided into time points of 2 h, 6 h, 1 d, and 4 d, with five animals per point. Subsequently, all rats were euthanized, and serum and lung tissues were collected. Following the assessment of right ventricular pressure (RVP) and mean pulmonary artery pressure (mPAP), blood gas analysis, enzyme-linked immunosorbnent assay (ELISA), pulmonary artery vascular testing, hematoxylin-eosin (HE) staining, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, immunohistochemistry, and Western blot experiments were conducted.

Results: R-hirudin treatment caused a significant reduction of mPAP, RVP, and Malondialdehyde (MDA) content, as well as H₂O₂ and myeloperoxidase (MPO) activity, while increasing pressure of oxygen (PaO₂) and Superoxide Dismutase (SOD) activity. R-hirudin also decreased wall area ratio and wall thickness to diameter ratio in APE rat pulmonary arteries. Serum levels of endothelin-1 (ET-1) and thromboxaneB2 (TXB2) decreased, while prostaglandin (6-K-PGF1α) and NO levels increased. Moreover, R-hirudin ameliorated histopathological injuries and reduced apoptotic cells and Matrix metalloproteinase-9 (MMP9), vascular cell adhesion molecule-1 (VCAM-1), p-Extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P65/P65 expression in lung tissues.

Conclusion: R-hirudin attenuated pulmonary hypertension and thrombosis in APE rats, suggesting its potential as a novel treatment strategy for APE.

Keywords: Acute pulmonary embolism; Recombinant hirudin; p-ERK1/2/ERK1/2; p-P65/P65.

MeSH terms

Animals
Hirudins / pharmacology
Hominidae*
Hydrogen Peroxide / therapeutic use
Hypertension, Pulmonary* / drug therapy
Pulmonary Embolism* / complications
Rats
Rats, Sprague-Dawley
Thrombosis* / drug therapy

Substances

Hirudins
Hydrogen Peroxide

Grants and funding

This study was supported by The Public Technology Applied Research Program of Huzhou City (Program no. 2022GY05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.