Abstract
BackgroundMyocardial 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 helminth-derived 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.MethodsA 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.ResultsAfter 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.ConclusionsRSj-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.
Highlights
Myocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis
We explore the therapeutic effect of rSjCys on sepsis-triggered cardiac dysfunction and we found that treatment with recombinant Sj-Cys (rSj-Cys) significantly reduced the sepsis-induced cardiomyopathy and heart injury in a mouse model, providing an alternative approach to control sepsis-induced heart failure and death
The results showed that sepsis mice displayed a significant decline in E/A ratio values compared to sham control mice (ANOVA: F(3, 23) = 10.99, P < 0.0002) (Fig. 1b, d)
Summary
Myocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis. Studies have suggested that sepsis-induced cardiac dysfunction, the major cause of sepsis mortality (70–90%) [6], is caused by myocardial apoptosis mediated by the MyD88 signal pathway that activates and over-expresses a variety of pro-inflammatory cytokines, including TNF-α and IL-6 [7]. The most commonly used drugs for the treatment of sepsis-induced cardiac dysfunction are glucocorticoid, norepinephrine, low molecular weight heparin and antibiotics. These drugs are capable of preventing the development of inflammation, activating the anticoagulation system, enhancing anti-inflammatory function, or suppressing the bacterial proliferation, there is still a proportion of patients who cannot survive from severe sepsis. Other alternative approaches to better control sepsis and reduce sepsis-related myocardial dysfunction is greatly needed
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