Role of microRNAs in sepsis.

INTRODUCTION: MicroRNAs have been found to be of high significance in the regulation of various genes and processes in the body. Sepsis is a serious clinical problem which arises due to the excessive host inflammatory response to infection. The non-specific clinical features and delayed diagnosis of sepsis has been a matter of concern for long time. FINDINGS: MicroRNAs could enable better diagnosis of sepsis and help in the identification of the various stages of sepsis. Improved diagnosis may enable quicker and more effective treatment measures. The initial acute and transient phase of sepsis involves excessive secretion of pro-inflammatory cytokines which causes severe damage. MicroRNAs negatively regulate the toll-like receptor signaling pathway and regulate the production of inflammatory cytokines during sepsis. Likewise, microRNAs have shown to regulate the vascular barrier and endothelial function in sepsis. They are also involved in the regulation of the apoptosis, immunosuppression, and organ dysfunction in later stages of sepsis. Their importance at various levels of the pathophysiology of sepsis has been discussed along with the challenges and future perspectives. CONCLUSION: MicroRNAs could be key players in the diagnosis and staging of sepsis. Their regulation at various stages of sepsis suggests that they may have an important role in altering the outcome associated with sepsis.

Differential Paradigms in Animal Models of Sepsis.

Sepsis is a serious clinical problem involving complex mechanisms which requires better understanding and insight. Animal models of sepsis have played a major role in providing insight into the complex pathophysiology of sepsis. There have been various animal models of sepsis with different paradigms. Endotoxin, bacterial infusion, cecal ligation and puncture, and colon ascendens stent peritonitis models are the commonly practiced methods at present. Each of these models has their own advantages and also confounding factors. We have discussed the underlying mechanisms regulating each of these models along with possible reasons why each model failed to translate into the clinic. In animal models, the timing of development of the hemodynamic phases and the varied cytokine patterns could not accurately resemble the progression of clinical sepsis. More often, the exuberant and transient pro-inflammatory cytokine response is only focused in most models. Immunosuppression and apoptosis in the later phase of sepsis have been found to cause more damage than the initial acute phase of sepsis. Likewise, better understanding of the existing models of sepsis could help us create a more relevant model which could provide solution to the currently failed clinical trials in sepsis.

Could stem cells be the future therapy for sepsis?

The severity and threat of sepsis is well known, and despite several decades of research, the mortality continues to be high. Stem cells have great potential to be used in various clinical disorders. The innate ability of stem cells such as pluripotency, self-renewal makes them potential agents for therapeutic intervention. The pathophysiology of sepsis is a plethora of complex mechanisms which include the initial microbial infection, followed by "cytokine storm," endothelial dysfunction, coagulation cascade, and the late phase of apoptosis and immune paralysis which ultimately results in multiple organ dysfunction. Stem cells could potentially alter each step of this complex pathophysiology of sepsis. Multiple organ dysfunction associated with sepsis most often leads to death and stem cells have shown their ability to prevent the organ damage and improve the organ function. The possible mechanisms of therapeutic potential of stem cells in sepsis have been discussed in detail. The route of administration, dose level, and timing also play vital role in the overall effect of stem cells in sepsis.