# Inflammation: What's There and What's New?
## 2 Inflammatory Mechanisms  
### Initiation of the Inflammatory Response  
#### 2.1.1 Vasodilatation, Fluid Exudation, and Leukocyte Migration  
Vasodilatation is a typical characteristic of acute inflammation that is manifested at the injury site by redness associated with a warming of the site. The vasodil response promotes the local delivery of soluble mediators and inflammatory cells, usually vasodilating prostaglandandins and nitric oxide (NO). Upon exposure to microbial agents or pro-inflammatory cytokines, the activated leukocytes develop nitric oxide synthase (NOS) enzymes derived from L-arginine. There are three known isoforms of NOS: neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3), which are formed constitutively. Through cyclic guanosine monophosphate (cGMP)-dependent pathways, the formed NO induces subsequent smooth muscle relaxation [1]. Prostacycline (PGI2), PGD2, PGE2, and PGF2a are the main vasodilatory prostaglandandins [1] formed by the activities of phospholipase and cyclooxygenase from arachid acid [5]. Vasodilatation caused by inflammation first requires arterioles accompanied by the formation of new micro-vascular beds. Highly spread vasodilatation can induce systemic hypotension, as well as shock, in cases of severe systemic inflammation, such as sepsis. Such physiological modifications are potentiated by myocardial depression caused by the sepsis stage, a condition triggered by the activities of nitric oxide and pro-inflammatory cytokines, namely tumor necrosis factor-a (TNF-a) [6]. Another indication of inflammation is edema formation; the trans-vascular movement from the intravascular compartment into the interstitium of protein-rich fluid is caused by the activities of histamine, bradykinin, leukotrienes, complement elements, substance P, and platelet-activating factor (PAF). The mentioned processes significantly affect the membrane activity of small blood vessels and improve the permeability of both water and protein capillaries and venules [7]. Capillary hydrostatic pressure at the injury site also increases earlier during damage caused by inflammatory processes, triggered by local vasodilation. The spillage of fluids rich in proteins induces erythrocyte aggregation in small vessels and increases blood viscosity. This flow of trans-vascular fluid gradually returns to normal intravascular pressure at the inflammation site. At the same time, plasma protein loss reduces oncotic pressure intravascularly [1]. The increase in vascular permeability, the increase in the capillary hydrostatic pressure, and the decrease in plasma oncotic pressure work together to cause trans-vascular fluid and protein to flow into the interstitium with inflammation. The main purpose of these actions is to facilitate the release of antibodies, for example, to the injury site. However, extreme systemic inflammation can lead to intense vascular permeability, which can contribute to the development of edema in the lungs and extremities. In critically ill patients, the fluid that accumulates in the lungs causes serious respiratory distress syndrome, which can lead to morbidity and death [8]. Vasodilation and fluid exudation occur during leukocyte adhesion and migration. In an infection or inflammatory site, neutrophils are the first and most abundant leukocytes to emerge. The migration of neutrophils from the intravascular space to the inflamed interstitium takes place primarily in the systemic circulation of postcapillary venules and in the pulmonary capillaries of the lung. Transmigration can be divided into many phases, including imagination, turning, membership, diapedesis, and chemotaxis [9]. The process of neutrophil migration from the main bloodstream to the vessel's periphery is named marginalization; this process is facilitated by stasis after fluid exudation and contact established by erythrocytes and neutrophils.