Preliminary reportLiu-Shen-Wan, a traditional Chinese medicine, improves survival in sepsis induced by cecal ligation and puncture via reducing TNF-α levels, MDA content and enhancing macrophage phagocytosis
Introduction
Sepsis describes a complex clinical syndrome that results from a harmful or damaging host response to infection. An overwhelming inflammatory response results in multiple organ damage, cardiovascular failure, disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS) and death. This systemic inflammatory response (SIRS) has been recognized as a prominent factor in sepsis-induced mortality [1], [2]. However, in spite of major advances in the understanding of the pathogenesis of sepsis, no satisfying therapy has emerged and treatment of this condition remains largely supportive [3]. Because of the high mortality of sepsis in the face of standard treatment, many efforts have been made to improve understanding of the dysregulation of the host response in sepsis. There has been evidence that sepsis impaired immune function by inducing defects in innate immunity and excessive lymphocyte apoptosis [4], [5], [6]. The resulting immunosuppression in late stage of sepsis has been suggested to be another contributing factor in sepsis-induced mortality [7], [8], [9]. Some studies have reported activation of macrophages with interferon in septic patients and blockade of complement-induced neutrophil dysfunction had beneficial effects [10], [11]. Accordingly, these findings demonstrate that both limiting systemic inflammatory response and improving host immunosuppression may represent a useful approach to the treatment of sepsis.
To find such an approach, in addition to very few compounds such as lysophosphatidylcholine (LPC) [12] and β-glucan [13], some researches have also been shift to effects of various traditional Chinese medicines, due to their advantages of regulating immunity dysfunction with apparent safety. Several traditional Chinese medicines have been evidenced to inhibit systemic inflammatory response and improve outcome of sepsis [14], [15], [16]. Liu-Shen-Wan (LSW), a well-known heat-clearing and detoxicating formula (a Chinese term meaning that it can reduce pathogenic fever and other inflammation resulting from some infections), is mainly composed of animal and mineral derived medicines including Musk (Moschus berezovskii Flerov), bezoar (Bos taurus domesticus Gmelin), toad venom (Bufo bufo gargarizans Cantor), borneol (Dryobalanops aromatica Gaertner. f.), pearl (Pteria martensii (Dunker) and realgar (Realgar). This ancient prescription has been believed to be effective in treating infectious inflammatory diseases such as diphtheria, scarlet fever, acute tonsillitis, purulent parotitis, encephalitis B, viral pneumonia and throat pain for more than 200 years [17], [18], and some pharmacological studies preliminarily showed that LSW had anti-inflammatory and anti-septic shock effects [19], [20], [21], [22]. In these reports, LSW protected mice from low blood pressure, disseminated intravascular coagulation (DIC) and death induced by lipopolysaccharides (LPS). Moreover, LSW and its constitute drugs exerted immunopotentiating and stimulatory effects in immune cells, including monocytes, macrophages and T lymphocytes [23], [24]. However, anti-infectious inflammatory and anti-sepsis effects of LSW have not been tested in a clinically relevant model characterized by true infection. Therefore, for the purpose of providing pharmacological evidence for its clinical use and further exploring new anti-sepsis drugs, the present study was designed to investigate potential anti-inflammatory and immunomodulating roles of LSW in a reliable model of sepsis represented by cecal ligation and puncture.
Section snippets
Animals
Male ICR mice weighing 18–22 g and male Sprague–Dawley rats weighing 250–300 g were obtained from the Experimental Animal House of China Pharmaceutical University (Nanjing, China). They were maintained with free access to pellet food (Jiangsu Cooperation Medical and Pharmaceutical Company, Nanjing, China) and water in plastic cages at 21 ± 2 °C and kept on a 12-h light/dark cycle. Animal welfare and experimental procedures were carried out in accordance with the guide for the care and use of
Effect of LSW on survival in CLP-induced mice sepsis
As shown in Fig. 1, mice survival in the CLP group, was 50% at 24 h after surgery and diminished progressively until the end of observation period, at which time only 7.14% were alive. The onset of death was markedly delayed in mice receiving LSW treatment. Indeed, at 72 h after CLP, the mortality rate in LSW groups was 36.36% and 45.45%, respectively.
Effect of LSW on pro-inflammatory cytokine levels in CLP-induced rat sepsis
CLP increased the levels of circulating pro-inflammatory cytokines in the early stage of sepsis resulted from peritoneal infection. In Fig. 2,
Discussion
The present study demonstrated that LSW effectively reduces the mortality of CLP-induced sepsis in mice. Further studies found that LSW reduces consequences of sepsis by limiting the inflammatory response in the systemic circulation and enhancing immunity function at primary infectious site.
Host responses to infectious challenge result in the overexpression of pro-inflammatory mediators, such as TNF-α and IL-1β. These cytokines are key mediators in the initiating of systemic inflammatory
Acknowledgements
This work was supported by a grant from Department of Education Administration, Jiangsu Province Government for Dr. Boyang Yu. We would like to thank Jianhong Zhang, Chunmei Zheng, Li Ma, Qiqiong Ran and Na Li for their assistance in experiments.
References (46)
- et al.
Protective effect of beta-glucan against oxidative organ injury in a rat model of sepsis
Int Immunopharmacol
(2005) - et al.
Enhancement by bufalin of retinoic acid-induced differentiation of acute promyelocytic leukemia cells in primary culture
Leuk Res
(1998) - et al.
Chemiluminescent detection of induced reactive oxygen metabolite production of human polymorphonuclear leucocytes by anthophyllite asbestos
Environ Res
(2002) - et al.
Correlation of plasma and tissue oxidative stresses in intra-abdominal sepsis
J Surg Res
(2004) - et al.
Selective macrophage suppression during sepsis
Cell Immunol
(2004) - et al.
Antimicrobial activity of the bufadienolides marinobufagin and telocinobufagin isolated as major components from skin secretion of the toad Bufo rubescens
Toxicon
(2005) - et al.
Effects of Chan Su, a traditional Chinese medicine, on the calcium transients of isolated cardiomyocytes: cardiotoxicity due to more than Na, K-ATPase blocking
Life Sci
(2002) - et al.
The international sepsis forum consensus conference on definitions of infection in the intensive care unit
Crit Care Med
(2005) - et al.
SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference
Crit Care Med
(2003) The immunopathogenesis of sepsis
Nature
(2002)
C5a receptor and thymocyte apoptosis in sepsis
FASEB J
Monocyte deactivation in septic patients: restoration by IFN-gamma treatment
Nat Med
Prevention of lymphocyte cell death in sepsis improves survival in mice
Proc Natl Acad Sci U S A
Sir Isaac Newton, sepsis, SIRS, and CARS
Crit Care Med
The pathophysiology and treatment of sepsis
N Engl J Med
Complement induced impairment of innate immunity during sepsis
J Immunol
Protective effects of C5a blockade in sepsis
Nat Med
Protective effects of anti-C5a peptide antibodies in experimental sepsis
FASEB J
Therapeutic effects of lysophosphatidylcholine in experimental sepsis
Nat Med
Effect of Dachengqi decoction on the cytoplasmic free calcium in peritoneal macrophage of mice of bacteria peritonitis
Chin J Integr Tradit West Med
Effect of Cistanche deserticola Y.C. Ma on acute lung injury in rats following septic shock
ACMP
Effects of Ginsenoside on cellular function and mortality infection in traumatized mice
Med J Chin PLA
Clinical applications of Liu-Shen-Wan
Chin J Ethnomed Ethnopharm
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