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  • Sepsis was defined as a systemic inflammatory response syndr


    Sepsis was defined as a systemic inflammatory response syndrome (SIRS) associated with severe infection in 1992 [9]. However, in the Third International Consensus Definitions for Sepsis and Septic Shock [10], it was redefined as life-threatening organ dysfunction provoked by a dysregulated host response to infection. This type of disease is sometimes observed in horses and has become one of the serious problems in equine medicine. In mature horses, SIRS is observed to be onset as a secondary condition to gastrointestinal diseases under certain circumstances. Moreover, in neonatal foals, sepsis is a sequela of failure of passive transfer and sometimes complicates bacteremia, pneumonia, enterocolitis, omphalophlebitis, meningoencephalitis, or arthritis [11]. Still, the exact mechanisms have been unclear, and the effective treatment has not yet been proposed. Recently, it was shown that the levels of HRG in the plasma was observed to be lowered in a mouse model of sepsis from cecal ligation and puncture [12]. Moreover, the administration of recombinant HRG to those septic mice decreased lethality through suppression of systemic inflammation and immune-thrombosis [12]. Although there is a possibility that administration of HRG could ameliorate the symptoms in horses with SIRS, studies on equine HRG are lacking. In this study, we first identified the equine HRG sequence from complementary DNA (cDNA) using liver samples from four Thoroughbred horses, proceeded to generate recombinant equine HRG using human embryonic kidney HEK293 cells, and detected serum HRG in healthy horses.
    Materials and Methods
    Discussion In this report, we first demonstrated the entire equine HRG sequence using cDNA isolated from the liver of Thoroughbred horses. A consensus amino Nicotinamide repeat observed in human and mouse HRG is GHHPH [1], while that of equine HRG is GPPPH. In addition, we identified undetermined sequences (135 bp), which is a part of the repeat sequence and corresponds to exons 7 and 8. We also displayed that equine HRG is smaller than human HRG in its molecular weight (approximately 70 kDa and 75 kDa, respectively). The estimated molecular weight from amino acid sequence of human HRG is 59.6 kDa and that of equine HRG is 56.7 kDa. However, the detected sizes of HRG from humans and horses were approximately 75 kDa and 70 kDa, respectively. Since HRG in peripheral blood is glycosylated, the molecular weight of HRG isolated from equine serum was larger than its estimated size [1]. HRG has various biological functions, such as interaction with plasminogen and fibrinogen in humans, binding activity to T cells in humans, and suppression of inflammation via neutrophil stabilization in humans and mice and heparin neutralization in humans [2], [3], [12], [16], [17], [18], [19]. Since we have detected equine HRG in blood, critical roles of HRG in physiological or pathologic condition of horses are suggested. Since HRG is a fusion protein with various structural domains [20], [21], unique characteristics of the equine HRG sequence suggest that the structure of equine HRG may be different from human or mouse HRG. The multifunctional activity of HRG is presumed to be supported by independent functions of each structural domain [20], [21], [22], [23], suggesting that the difference in structure may reflect the different functions of equine HRG. The recent studies using murine model for sepsis have revealed that decrease in blood HRG initiated formation of immuno-thrombosis and proceeded the process of sepsis [12]. In addition, the supplementation of HRG improved the survival rate. Thus, utilization of HRG for biomarker and treatment of SIRS is expecting. Although SIRS in horses is one of fulminant patterns, curative therapy more effective than antibiotics treatment has been unestablished. Therefore, research on kinetics of HRG may provide important information for veterinary diagnosis and treatment for horses.