**3. Systemic inflammatory response**

The Systemic Inflammatory Response Syndrome (SIRS) is a complex plurifactorial syndrome often associated with the ECC. The SIRS to ECC is initiated by many aggressive factors including surgical trauma, blood contact with nonendothelial sufaces, cardioplegia, ischemia-reperfusion injury (Raja & Berg, 2007; Larmann & Theilmerr, 2004; Royston, 1997). Several blood elements such as neutrophils, monocytes, endothelial cells, platelets and complement proteins are involved in the SIRS. These blood components when activates, release of cytotoxic and vasoactive substances, produce inflammatory and inhibitory cytokine, express cell receptors interacting with specific cellular substance (Royston 1997). Therefore when SIRS is initiated, several inflammatory mediators, including antiinflammatory and pro-inflammatory cytokines could be associated with a worse postoperative course.

Miniaturized Extracorporeal Circulation 139

renal function and lung function (Royston 1997). Cytokines are strongly involved in myocardial stunning process and in multiorgan failure syndrome (Larmann & Theilmeier 2004) Important cytokines involved in the SIRS are the interleukin 1β (IL-1β), the interleukin

IL-1β is produced mainly by monocytes. This cytokine derives from IL-1 by the action of the IL-1β converting enzyme. An increase of IL-1β was found after ECC with a peak

IL-6 is produced and released by the monocytes and endothelial cells following a stimulus by the IL-1 and TNF-α The IL-6 has the peak concentration few hours after the end of ECC and gradual decrease within the following 24 hours (Beghi et al 2006; Whipperman et al 2005; Fromes et al 2002). The IL-6 concentration increase also after major noncardiac

TNF-α is a cytokine produced by neutrophils and monocytes. This cytokine stimulates the surrounding stromal and parenchymal cells to produce more cytokines and chemokines. A significant increase of TNF-α was shown after removal of the cross-clamp and a peak concentration is reached after 24 hours the end of ECC. The TNF-α has an inotropic negative

sCD40L is produced by activated platelets and upregulates the expression of inflammatory adhesion receptors including E-selectin, VCAM-1, tissue factor and matrix mettalloproteinases (Nannizzi-Alaimo et al 2002). Furthermore, sCD40L was described has a major mediator of vascular inflammation (Antoniades et al 2009a). Plasma levels of CD40L increase within 1 hour on ECC and increased further to almost 4 fold hours after 2 hours. (Nannizzi-Alaimo et al 2002). High preoperative level of CD40L were associated with an high risk of postoperative atrial fibrillation in patients underwent off-pump myocardial

Chemotactic proteins play an important role in inflammatory response to ECC. Monocyte chemotactic protein 1 (MCP-1) is implicated in transendothelian monocyte recruitment to inflammatory site (Luster 1998). Various stimuli in the heart cause the production and releasing of MCP-1, leading to recruitment of monocytes that causes a stress response in the heart. There is strong evidence that MCP-1 plays a role in atherosclerosis, myocarditis,

Metalloproteinases are proteolityc enzymes that have a role in degradation of proteins and collagens of extracellular matrix and vascular basement membrane. MMP-8 and MMP-13 increase at the end of ECC and 30 minutes later (Joffs et al. 2001). MMP-9 increases after the

Oxidative stress describes an increased bioactivity of reactive oxidant substances (ROS) that can participate to endothelial and myocardial damage. The ROS are produced and released by neutrophils, monocytes and macrophages when they are activated. The ROS are a potent arsenal of cytotoxic mediators of acute inflammation response (Babior 2000). There are four enzymes that generate a various amount of ROS. They are represented by nicotamide

removal of aortic cross-clamp and the reaches the peak concentration after 24 hours

6 (IL-6), the tumor necrosis factor α (TNF-α), soluble CD 40 ligand (sCD40L).

operation and the peak concentration occur after 6-24 hours the end of operation.

effect and the myocardium is a major source after ischemia reperfusion injury.

concentration after 24 hours (Fromes et al 2002).

revascularization (Antoniades et al 2009b)

ischemia/reperfusion injury and transplant rejection.

**3.2.2 Chemotactic proteins** 

**3.2.3 Mettalloproteinases** 

**3.2.4 Oxidative stress** 

#### **3.1 Activated blood cells 3.1.1 Neutrophils**

Neutrophils are strongly activated during ECC. When activated, the neutrophils are recruited to inflammation site by inflammatory cytokines (IL-1β, TNF-α, IL-8), complement proteins and adhesion molecules (Royston 1997). The activated neutrophils can contribute to myocardial damage by infiltrating the myocardium and worsening the mechanism of ischemiareperfusion damage that initiates after aortic cross clamp removal (Paparella et al 2002). Moreover the neutrophils can infiltrate not only the myocardium but also the lungs and the brain (Lagan et al. 2008). Usually the neutrophils blood count and the total white blood cell count increase during ECC and over the first 48 hours after the operation (Fromes et al 2002)
