Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Abstract

Background: Myocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis. Although many studies having confirmed that helminthderived proteins have strong immunomodulatory functions and could treat inflammatory diseases, there is no report on the therapeutic effect of Schistosoma japonicum-produced cystatin (Sj-Cys) on sepsis-induced cardiac dysfunction. Methods: A model of sepsis-induced myocardial injury was established by cecal ligation and puncture (CLP) in mice. Upon CLP operation, each mouse was intraperitoneally treated with 10 µg of recombinant Sj-Cys (rSj-Cys). Twelve hours after CLP, the systolic and diastolic functions of the left ventricular were examined by echocardiography. The levels of myoglobin (Mb), cardiac troponin I (cTnI), N-terminal pro-Brain Natriuretic peptide (NT-proBNP) in sera, and the activity of myeloperoxidase (MPO) in cardiac tissues were examined as biomarkers for heart injury. The heart tissue was collected for checking pathological changes, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of rSj-Cys, myeloid differentiation factor 88 (MyD88) was determined in heart tissue of mice with sepsis and LPS-stimulated H9C2 cardiomyocytes. In addition, the therapeutic effects of rSj-Cys on LPS-induced cardiomyocyte apoptosis were also detected. The levels of M1 biomarker iNOS and M2 biomarker Arg-1 were detected in heart tissue. The pro-inflammatory cytokines TNF-α and IL-6, and regulatory cytokines IL-10 and TGF-β were measured in sera and their mRNA levels in heart tissue of rSj-Cys-treated mice. Results: After rSj-Cys treatment, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were significantly alleviated, characterized as significantly decreased infiltration of inflammatory cells in cardiac tissues and fiber swelling, reduced levels of Mb, cTnI and NT-proBNP in sera, and MPO activity in heart tissue. The therapeutic efficacy of rSj-Cys is associated with downregulated pro-inflammatory cytokines (TNF-α and IL-6) and upregulated regulatory inflammatory cytokines (IL-10 and TGF-β), possibly through inhibiting the LPS-MyD88 signal pathway. Conclusions: RSj-Cys significantly reduced sepsis-induced cardiomyopathy and could be considered as a potential therapeutic agent for the prevention and treatment of sepsis associated cardiac dysfunction.

Therapeutic Efficacy of Excretory-Secretory Products of Trichinella spiralis Adult Worms on Sepsis-Induced Acute Lung Injury in a Mouse Model

“…After being treated with Ts -AES, protein expression levels and the mRNA expression levels of HMGB1, TLR2 and MyD88 in lung tissues were significantly decreased. Our results further confirm that severe infection of bacteria in sepsis stimulates inflammatory immune responses through HMGB1/TLR2/MyD88 activation signal pathway as shown for other helminth-derived proteins ( Li et al., 2017 ; Ilic et al., 2018 ; Gao et al., 2020 ).…”

Schistosome Infection and Schistosome-Derived Products as Modulators for the Prevention and Alleviation of Immunological Disorders

“…The same team showed that in a murine model of LPS-induced sepsis, intraperitoneal administration of rSj-Cys significantly alleviated LPS-induced organ pathologies, reduced the levels of liver and renal functional indexes and pro-inflammatory cytokines, and increased the serum level of IL-10 ( 55 ). The same group showed that rSj-Cys significantly reduced sepsis-induced cardiomyopathy in mice and suggested this molecule should be considered as a potential therapeutic for preventing and treating sepsis-associated cardiac dysfunction ( 117 ).…”

Schistosoma japonicum Cystatin Alleviates Sepsis Through Activating Regulatory Macrophages

“…Our previous studies have identified that treatment with Sj -Cys significantly reduced the pathology caused by LPS-induced ( Wan et al., 2018 ) or bacterial infestation-induced ( Li et al., 2017 ) sepsis in mice with less inflammation and tissue damage through stimulating anti-inflammatory cytokines and inhibiting Th1 pro-inflammatory cytokines. In particular, treatment with Sj -Cys significantly reduced sepsis-induced cardiomyopathy ( Gao et al., 2020 ). However, the immunological mechanism and targeted immune cells underlying the immunomodulation and therapeutic effect of Sj -Cys on sepsis remains unknown.…”