**2. Sepsis**

#### **2.1 Pathogenesis of sepsis**

#### **2.1.1 Symptoms**

Sepsis is a systemic inflammatory state in the whole body by bacteria infection in the blood stream (i.e., systemic inflammatory response syndrome) (Bone RC et al, 1992). In systemic inflammatory response syndrome, the innate immune systems are overactivated. The systemic inflammatory response syndrome is characterized by the symptoms such as fever and hypotension in patients. In severe sepsis pathology, immunohistochemical studies using both of postmortem human and an animal model of sepsis in rodents reveal the brain ischemia (Sharshar T et al, 2004), edema (Pfister D et al, 2008), hemorrhage (Casanova E et al, 2001) after sepsis. On the other hand, following sepsis, several kinds of symptoms such as polyneuropathy are also observed. These symptoms enhance complexity of the septic pathophysiology (Bolton CF et al, 1993; Nauwynck M & Huyghens L, 1998). Hence, the septic conditions include neurological symptoms.

### **2.1.2 Molecular mechanisms**

Molecular mechanism of immunology for sepsis is investigated. When pathogen (bacteria etc.) is invaded into the blood stream, it is recognized to be pathogen-associated molecular pattern such as lipopolysaccaride, bacterial component in immunological dendritic cells and T cells. When the pathogen-associated molecular pattern binds to toll-like receptor, the tolllike receptor facilitates cytokine release (Kim KD et al, 2007). After the cytokine release, the septic condition triggers downstream signaling pathways. These pathways translocate and activate NF-kappa B in the nucleus through I-kappaB degradation and mitogen-activated protein kinase (MAPK) and JUN kinase activation. Finally, NF-kappaB drives transcription of interleukin family (interleukin -1, 2, 6, 8 and 12) and tumor necrosis factor-.

### **2.1.3 Cytokine storm**

These activations lead to be **cytokine storm** (Harrison C, 2010). In fact, 30% of septic patients have serious symptoms without bacteremia in their blood (Sprung CL et al, 1990). The result suggests that after removal of bacteria, cytokine storm is a major factor for the tissue injury after severe sepsis. What is a player for accelerating cytokine storm? Recent finding suggests that small protein 'complement' creates cytokine storm (Ward PA, 2010). The complement serves as a supportive factor to enhance the efficacy of antibodies in order to clear pathogen in the blood. The complement C5a has their receptors, C5aR and C5L2, in the pituitary and their receptors are up-regulated after sepsis. C5a is also performed as a central hub to activate various inflammatory responses including disseminated intravascular coagulation, systemic inflammatory response syndrome, lethal bacteremia, immunosuppression, septic shock and heart failure (Rittirsch D et al, 2008). Conversely, when the C5a is neutralized by specific antibody, blood brain barrier disruption and pituitary dysfunction in severe sepsis is alleviated in the rat (Flierl MA et al, 2009). Hence, C5a will be a hopeful target for cytokine storm regulation after sepsis.
