Ulinastatin ameliorates acute kidney injury induced by crush syndrome inflammation by modulating Th17/Treg cells

• Published in: International immunopharmacology Vol. 81; p. 106265
• Main Authors: Yang, Xin-Yue, Song, Jie, Hou, Shi-Ke, Fan, Hao-Jun, Lv, Qi, Liu, Zi-Quan, Ding, Hui, Zhang, Yong-Zhong, Liu, Jin-Yang, Dong, Wen-Long, Wang, Xue
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2020; Elsevier BV
• Subjects: Acute kidney injury; Acute Kidney Injury - drug therapy; Addition polymerization; Animal models; Animals; Anti-Inflammatory Agents - therapeutic use; CD25 antigen; CD4 antigen; Crush syndrome; Crush Syndrome - drug therapy; Crushing; Cytokines; Cytokines - blood; Disease Models, Animal; Edema; Enzyme-linked immunosorbent assay; Extrusion; Flow cytometry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene Expression Regulation; Glycoproteins - therapeutic use; Helper cells; Humans; Inflammation; Inflammation - drug therapy; Inflammatory response; Injuries; Innate immunity; Interleukin 17; Kidneys; Lethality; Lymphocytes; Lymphocytes T; Male; Muscles; Myoglobins; Peripheral blood; Polymerase chain reaction; Protease inhibitors; Proteinase inhibitors; Rats; Rats, Wistar; Sepsis; Serine; Serine proteinase; Staining; T-Lymphocytes, Regulatory - immunology; Th17 cells; Th17 Cells - immunology; Tissues; Transcription factors; Treg cells; Ulinastatin; Treg cells; Crush syndrome; Ulinastatin; Acute kidney injury; Th17 cells
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.106265

•Crush syndrome usually occurs in natural disasters or man-made accidents.•Acute kidney injury (AKI) is a common severe comorbidity of crush syndrome, and it can be life-threatening.•The imbalance of Th17/Treg cells is involved in the progression of acute kidney injury induced by crush syndrome.•The therapeutic effect of UTI may be mediated by restoring the balance between Th17/Treg cells. Acute kidney injury (AKI) is the main complication of crush syndrome (CS), and it is also a cause of lethality in CS. However, effective treatments for AKI are still lacking. Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor extracted from human urine that reportedly modulates innate immunity and pro-inflammatory responses in sepsis. Here, we explored the effect and the potential mechanism of ulinastatin on crush syndrome-induced acute kidney injury (CSAKI). A CSAKI rat model was established by using a digital crush injury device platform. Forty-six male Wistar rats were randomly divided into five groups: the normal control (n = 6), CSAKI model (n = 10), CSAKI plus UTI1 (50,000 U/kg) (n = 10), CSAKI plus UTI2 (100,000 U/kg) (n = 10) and CSAKI plus UTI3 (200,000 U/kg) (n = 10) groups. Hematoxylin-eosin (HE) staining was used to investigate the reliability of the CSAKI model. The percentage of Th17/Treg lymphocytes in peripheral blood was measured by flow cytometry, and the expression of transcription factors associated with Th17/Treg cells was evaluated by quantitative real-time polymerase chain reaction (PCR). In addition, specific cytokines released by Th17/Treg cells in serum and kidney tissues were detected by enzyme-linked immunosorbent assay (ELISA). Treatment with ulinastatin could significantly decrease serum BUN, CK, Scr, Mb and K+ levels compared with CSAKI group. HE staining results showed that ulinastatin could inhibit inflammatory cells infiltration, decrease sarcomere rupture in muscle tissues induced by extrusion, and alleviate the glomerular congestion and edema, as well as decrease myoglobin cast in kidney tissues. The proportion of CD4+CD25+Foxp3+ regulatory T (Treg) cells and Foxp3 expression levels were decreased in the CSAKI animals, while IL-17 expression levels were significantly increased, compared with those of the normal control group. Treatment with ulinastatin upregulated the proportion of Treg cells in CD4+ T cells and downregulated the expression of IL-17 compared with those of the CSAKI group. The findings of our study indicate that UTI attenuates CS-induced AKI and alleviate the inflammatory response during the early stage. The mechanism of UTI may be due to regulating the balance between Th17/Treg cells. Our study provides a new mechanism for the beneficial effect of ulinastatin on CSAKI.