Abstract
Sepsis is one of the major causes of human morbidity and results in a considerable number of deaths each year. Lipopolysaccharide-induced sepsis has been associated with TLR4 signalling pathway which in collaboration with the JAK/STAT signalling regulate endotoxemia and inflammation. However, during sepsis our immune system cannot maintain a balance of cytokine levels and results in multiple organ damage and eventual death. Different opinions have been made in previous studies about the expression patterns and the role of proinflammatory cytokines in sepsis that attracted our attention towards qualitative properties of TLR4 and JAK/STAT signalling pathways using computer-aided studies. René Thomas’ formalism was used to model septic and non-septic dynamics of TLR4 and JAK/STAT signalling. Comparisons among dynamics were made by intervening or removing the specific interactions among entities. Among our predictions, recurrent induction of proinflammatory cytokines with subsequent downregulation was found as the basic characteristic of septic model. This characteristic was found in agreement with previous experimental studies, which implicate that inflammation is followed by immunomodulation in septic patients. Moreover, intervention in downregulation of proinflammatory cytokines by SOCS-1 was found desirable to boost the immune responses. On the other hand, interventions either in TLR4 or transcriptional elements such as NFκB and STAT were found effective in the downregulation of immune responses. Whereas, IFN-β and SOCS-1 mediated downregulation at different levels of signalling were found to be associated with variations in the levels of proinflammatory cytokines. However, these predictions need to be further validated using wet laboratory experimental studies to further explore the roles of inhibitors such as SOCS-1 and IFN-β, which may alter the levels of proinflammatory cytokines at different stages of sepsis.
Highlights
Sepsis is a serious medical condition associated with complications of an exacerbated human immune response against endotoxin/lipopolysaccharides (LPS) mediated severe infections [1]
Qualitative levels (0, 1 or 2) of TLR4, IFN-b, NFkB, Proinflammatory cytokines (PICyts) and suppressor of cytokine signalling-1 (SOCS-1) represent qualitative states, which are shown as nodes, whereas trajectories represent possible progress or evolution paths of entities depending upon the logical parameters and qualitative threshold levels (Figures 3–8)
Using computer-aided qualitative approach, we have tried to highlight these patterns of entities necessary to maintain a balance in a successful immune response
Summary
Sepsis is a serious medical condition associated with complications of an exacerbated human immune response against endotoxin/lipopolysaccharides (LPS) mediated severe infections [1]. The incidence of sepsis is growing regardless of advances in the therapeutic and supportive treatments [4,5]. In 1992, nearly 500,000 cases of sepsis were found in the United States among which 35% of the patients led to mortality [6]. In 2001, around 750,000 cases of sepsis with 28.6% mortality rate per annum was recorded [7]. In a trend analysis from 1993 to 2003, a significant increase in the cases of severe sepsis and hospitalization was reported [8], which is still rising [9]
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