**2. Cytokine storm in the course of sepsis**

Cytokine storm is frequently described as an extremely dangerous immune response, being a positive feedback loop between cytokines and immune system cells [2]. That immune reaction provokes releasing of circulating proinflammatory cytokines, causing a direct threat to life. At the same time an increased activation occurs of the immune system cells as a result of, among other factors, action of various pathogens, autoimmune disorders, monogenic diseases or malignancies.

Proinflammatory cytokines, at the time of the beginning of the fight against pathogens by the immune system, send a signal to the lymphocytes and macrophages to start their transfer to the inflammation site. Cytokines activate also the cells to produce effector cytokines. All that cascade of interrelations frequently falls outside control, leading to hyperactivation of immune cells at a given site, damaging the organ involved in the inflammation. Remote organs also suffer damages but in the mechanism of cytokine release into the circulation, activating other immune system cells. Moreover, according to the literature data, it is believed that some inflammation mediators can be helpful for the monitoring of the inflammatory condition but also can be harmful for patient's organism [2]. That depends on the patient's health condition when the inflammation mediators are secreted into the bloodstream - whether the patient is in a physiological good condition or in a dysfunction state i.e. with upset immune system.

The course of cytokine storm itself can prognosticate the events being a consequence of the inflammatory condition but also suggests possible effects after administration of an appropriate treatment. Cytokine storm includes a number of immune system disorders with characteristic systemic signs of inflammation and multiple organ dysfunction, leading to damage in case of inadequate therapy. A plethora of factors are directly or indirectly involved in cytokine storm. The key factors include: interferon γ, interleukin-1, −6, −18, TNF-α and NFκB, but the transcription factor NFκB emerges to the foreground in view of its ability to induce expression of proinflammatory genes. NFκB and its protein inhibitor (IκB) are located in the cell cytoplasm. NFκB activation can occur due to the effect of many stimulators, such as: bacterial pathogens recognised by Toll-like receptor 4 (TLR-4) or proinflammatory cytokines recognised by their specific membrane receptors (e.g. TNF receptor) [3].

The inhibitor protein closely related to NFκB, being a heterodimer built from two subunits: p50 and p65, undergoes phosphorylation. The phosphorylation

*Organ Damage in Sepsis: Molecular Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.98302*

#### **Figure 1.** *NFκB activation pathway.*

process is preceded by TLR-4 receptor activation by a lipopolysaccharide (LPS) complex with binding protein (LPS/LBP), leading to activation of redoxdependent kinases. Then, after ubiquitination, a degradation of the inhibitor occurs in proteasomes, as shown in **Figure 1**. At the same time, the p50:p65 dimer is released from its bond with IκB and transferred to the cell nucleus, where it regulates the expression of the genes of the proinflammatory molecules: TNFα, IL-1β, IL-6, MCP-1 (monocytic chemoattractant protein 1). The NFκB factor can also activate the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Such intensity of NFκB participation in immune system response, as well as in inflammatory reaction gives a possibility to consider that factor a candidate in the strategy of therapeutic management of multiple organ damage in sepsis [4].
