Protective effect of Ulinastatin against murine models of sepsis: Inhibition of TNF-α and IL-6 and augmentation of IL-10 and IL-13
Introduction
To our knowledge, sepsis is an enormously complex clinical syndrome and a considerable health problem, which arises from the activation of an innate host response to danger (Dellinger et al., 2004). Despite rapid progress in health care over the past decades, sepsis continues as a leading cause of death in many intensive care units. During 1979–2000, the total sepsis-related mortality rose from 22 to 44 per 100,000 population (Martin et al., 2003), accounting for 9% of the overall annual mortality in the United States alone (Angus et al., 2001, Sands et al., 1997). Current knowledge implies that sepsis represents a state of inflammatory mediators’ over-expression, after various noxious insults, especially bacterial infections (Bone, 1996). Enhanced pro-inflammatory cytokine and inhibited anti-inflammatory cytokine concentrations are considered as an important component of the patho-physiology of sepsis.
Cytokines, a group of endogenous inflammatory and immunomodulating proteins, primarily mediate the patho-physiology of the sepsis (Parrillo et al., 1990, Pinsky et al., 1993). The production of both pro- and anti-inflammatory cytokines in sepsis has widely been studied. Proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1α and IL-1β, IL-6, IL-12, and interferon (IFN)-γ, are necessary for initiating an effective inflammatory process against infection, whereas their excess production has been associated with multiple organ-system dysfunction and mortality (Blackwell and Christman, 1996, Gardlund et al., 1995, Friedman et al., 1997). In contrast, anti-inflammatory cytokines, such as IL-10, IL-13, IL-4, or transforming growth factor (TGF)-β, seem to be prerequisite for controlling and down-regulating the inflammatory response leading to a depression of the immune system of patients (Van Zee et al., 1992, Pruitt et al., 1996). It has been demonstrated that non-survival from sepsis is mainly associated with increasing levels of pro-inflammatory cytokines and decreasing levels of anti-inflammatory cytokines (Waage et al., 1987). A wealth of data in the literature on the correlation of serum and plasma levels of various cytokines and disease severity also indicated that it is the balance between pro- and anti-inflammatory cytokines that determines the severity of infection (Girardin et al., 1988, Damas et al., 1992).
Ulinastatin (UTI), a human protease inhibitor, inhibits polymorphonuclear granulocyte elastase (PMNE), which is involved in the development of several pathologic inflammatory processes (Nishiyama and Hirasaki, 1994). PMNE released into the circulation is bound by α1-antitrypsin, resulting in PMNE–α1-antitrypsin complex. UTI has been used clinically for the prevention of multiple organ failure (Inoue et al., 2005). UTI suppresses the activity of PMNE in vitro, and decreases PMNE release from granulocyte stimulated by multiple injury (Ogawa et al., 1987). However, whether UTI could cause protective effects on sepsis is largely unknown.
On the basis aforementioned, we investigated, in the present study, the effects of UTI on the intestinal concentrations of the main pro- and anti-inflammatory cytokines, such as TNF-α, IL-6, IL-10 and IL-13 in cecal ligation and puncture (CLP)-induced sepsis, in order to find out possible mechanism of UTI on inflammatory responses.
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Animals
Sixty male Wistar rats, weighing 180–200 g, were purchased from the Laboratory Animal Center of Third Military Medical University, and housed in a temperature-controlled environment on a 12 h light:12 h darkness cycle. Rats were initially housed three to a cage and given access to food and drink free for 5 days to allow for acclimatization. During the experiments, the environmental temperature was maintained between 23 °C and 25 °C. The experimental protocol was approved by the local animal care and
Intestinal concentrations of pro-inflammatory cytokines in different groups
The intestinal concentrations of TNF-α and IL-6 were determined by ELISA. The contents of TNF-α and IL-6 in the intestine of rats were increased, which were induced by CLP operation, and their levels reached the maximum at 8 h following the operation (p < 0.001) (Fig. 1, Fig. 2). The effects of UTI on TNF-α and IL-6 were also examined at this time point. UTI at the doses of 5000 U/kg and above dramatically suppressed the elevation of TNF-α following CLP operation (p < 0.001). Accordingly, at the
Discussion
Many previous literatures in the field of sepsis have a uniform agreement that it is an enormously complex clinical syndrome that arises from the activation of an innate host response to danger, causing cell injury and organ dysfunction (Levy et al., 2003, Hotchkiss and Karl, 2003, Glueck and Opal, 2004). It is believed that the intestine may not only a major target organ which is passively injured, but also a “motor” responsible for multiple organ failure (MOF) during this disease process (Yu
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The authors contribute equally to this paper.