**3. Microcirculation and endothelial dysfunction in sepsis**

Vascular endothelial cells constitute a dynamic vascular homeostasis regulator. They play not only the role of a barrier limiting the transportation of water, gases, proteins and cells between the intravascular and interstitial compartments, but also actively produce and release mediators, which regulate a wide range of physiological and pathological processes, including: vascular wall tension, angiogenesis, inflammatory condition and coagulation process. The activation and dysfunction of the endothelium are important elements of sepsis, and seem to play the key role in the sepsis phenotype as presented in **Figure 2**. During sepsis, endothelial cells become activated and dysfunctional, leading to haemostasis disturbances, increased migration of leucocytes, enhanced inflammatory condition, altered vascular wall tension and loss of the barrier function [5, 6]. The disturbed endothelial cell function can play a decisive role in microcirculation dysfunction. Microcirculatory changes in sepsis are characterised by heterogeneous perfusion of tissues due to absent or intermittent perfusion of the capillary vessels. Microcirculation heterogeneity in sepsis can disturb tissue oxygenation and lead to insufficient oxygen supply even in the presence of maintained total blood flow to organs. Such microcirculation disorders create favourable conditions for perfusion impairment, insufficient oxygen supply to tissues and then for organ failure.

#### **Figure 2.** *Pathophysiology of microcirculatory change in sepsis.*

Endothelial cells, receiving metabolic and physical signals regulate the microcirculatory flow through local releasing of vasodilating substances, particularly nitric oxide (NO), which modulate the tonus of vascular smooth muscles. NO is an activator of soluble guanylyl cyclase, the enzyme responsible for production of cGMP, a mediator of smooth muscle cell relaxation. For that reason, NO is considered the key factor of maintaining and autoregulation of homeostasis and microcirculation patency. During sepsis, the NO system is significantly disturbed – iNOS is nonhomogeneously expressed in various vascular spaces, what results in pathological blood flow in the microcirculation.

Endothelial cells usually promote antithrombotic properties and prevention of thrombocyte activation and aggregation. Endothelium also participates in the major pathogenetic pathways of diseases associated with a coagulopathy in sepsis, including, in the first place, in tissue factor (TF)-mediated generation of thrombin, and in dysfunctional and impaired fibrinolysis. A natural antithrombotic protein – protein C is activated on endothelial cell surface, while thrombin binds to thrombomodulin (TM) – a transmembrane glycoprotein. In sepsis, the C protein system is weakened, possibly due to reduced synthesis and increased protein C consumption and reduced protein C activation as a consequence of reduced endothelial expression of thrombomodulin. In sepsis, an internalisation and degradation of TM occurs, leading to formation of inactive soluble fragments as illustrated in **Figure 3**. Under these

**Figure 3.** *Change of endothelial cell properties after thrombin receptor stimulation.*

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

conditions the interaction between thrombin and thrombin receptor leads to a change of endothelial phenotype from antithrombotic to a prothrombotic phenotype.

In sepsis, the tissue factor can be released not only by monocytes and macrophages but also by endothelial cells. The TF pathway inhibitor, mainly expressed by endothelial cells, is functionally inhibited by reduced synthesis of glycosaminoglycans on endothelial surfaces. Furthermore, platelets, the aggregation of which leads to the development of thrombocytic thrombi, are a strong amplifier of the coagulation cascade. Thrombus formation can be additionally facilitated by the factors released from neutrophils undergoing apoptosis. The formation of microvascular thrombi can cause tissue ischaemia and multiple organ failure.

#### **4. Renin-angiotensin system in sepsis**

The renin-angiotensin system (RAS) is one of the most important hormonal mechanisms controlling haemodynamic stability through regulation of blood pressure, fluid volume and sodium-potassium balance as shown in **Figure 4**. Changes in the concentrations of molecules which form RAS contribute to arterial hypertension development. Renin is synthesised in the kidneys as inactive form and released into the bloodstream, where pro-renin is proteolytically transformed into its active form. Active renin catalyses angiotensinogen breakdown, generating angiotensin I (Ang I). Ang I is decomposed through angiotensin-converting enzyme (ACE) to angiotensin II (Ang II), the main effector in RAS (**Figure 4**). Ang I is also transformed through neutral endopeptidase (NEP) into angiotensin (1–7), another active peptide, which remains in opposition to Ang II (**Figure 4**). Angiotensin (1–7) can be also produced by Ang II splitting by angiotensin-converting enzyme 2 (ACE2), reducing thus Ang II concentration [7].

The mechanisms of RAS effect on sepsis development is presented in **Figure 5**. RAS participates in the pathogenesis of sepsis through equilibration of the modulation of the inflammation-related pathways. Through binding to AT1R, Ang II can increase the abundance of inflammatory mediators, increase vascular permeability and stimulate the expression of chemoattractants and adhesive molecules and also lead to recruitment of inflammatory cells. Moreover, the activation of the ERK 1/2, JNK, p38MAPK and NF-κB pathways is also involved in the intensification of inflammatory reaction by Ang II.

**Figure 4.** *Renin-angiotensin system.*

**Figure 5.** *The mechanisms of RAS effect on sepsis development, blue line - promote; red line - inhibit.*

Ang (1–7) can inhibit the activity of these signalling pathways and thus can inhibit the inflammatory reaction in sepsis. Many studies have provided evidence that RAS interventions can alleviate sepsis and associated organ function disorders through inhibition of the above mentioned inflammation-related pathways. ACE2 exerts a protective effect against acute respiratory distress syndrome (ARDS) caused by sepsis, through inhibition of TLR4, ERK1/2, JNK and NF-κB pathways. Ang (1–7) inhibited the p38MAPK pathway in order to protect mice against sepsisinduced skeletal muscle atrophy and liver damage. AT1R blockade can exert a protective effect against sepsis-induced multiple organ damage (SIMD) through inhibition of the MAPK and NF-κB pathways. Moreover, angiotensin I-converting enzyme inhibitors (ACEIs) and sartans (angiotensin receptor blockers, ARBs) decrease the release of proinflammatory cytokines, pro-oxidants and proapoptotic factors and thus alleviate the damages caused by sepsis.
