**2. Inflammation and edema: influence in the vascular permeability**

Inflammation is a natural defense mechanism to Pathogen-associated molecular pattern (PAMPs) or Damage-associated molecular pattern (DAMPs) involving cells and blood vessels. In this process, local and immune cells (macrophages, neutrophils, and lymphocytes) promote the release of pro-inflammatory mediators, such as those mentioned earlier. Although the inflammatory response is a natural mechanism, this process may become harmful to tissues and organs when persistently stimulated [17, 18]. The inflammation course and edema formation are linked because edema is one of inflammation cardinal signs [2].

After a trauma or injury, intracellular components are released, modifying the inflammatory site characteristics (**Figure 1**). Migrant and local cells, such as mast cells and basophils, release vasoactive amines, serotonin, and histamine. These molecules initially cause increase in blood vessel permeability and vasodilation [19–21]. Thus, these vascular changes cause liquid leakage from the vascular environment. Plasma protein, such as albumin, in the extravascular medium may modulate the vascular pressures. The press alteration favors the fluid and electrolyte passage to interstitial space generating swelling [3, 22].

Coagulation factor activation, such as the Hangeman factor, induces bradykinin and proteases synthesis stimulation. Bradykinin is a kinin involved in vascular permeability and other vascular mechanisms [23–25]. Additionally, the complement system fragments exhibit a crucial role in the immunity and vascular processes. The anaphylatoxins, such as C3a, C4a, and C5a, act on leukocyte recruitment and also in bradykinin signaling [23, 26–29].

The pro-inflammatory cytokines participate in pain mechanisms and also promotes increase in vascular permeability [23]. Stamacovic [30] described cytokines participating in the central nervous system inflammation and Blood–brain barrier

**Figure 1.**

*Inflammatory mediators are acting on vascular permeability.*

*Inflammatory Mediators Leading to Edema Formation through Plasma Membrane Receptors DOI: http://dx.doi.org/10.5772/intechopen.99230*

permeability. The increase in IL-1β, IL-6, and TNF-α may cooperate for brain edema emergence. Martin et al. [31] showed vascular increase induced by IL-1 and IFN-y in Wistar rats. IL-1β is very approached in a mechanism involving nociception and sensibility to pain, as well as bradykinin [32, 33]. Furthermore, increase of IL-1β and TNF-α induct arachidonic acid metabolites [34]. Arachidonic acid metabolites like prostaglandins, leukotrienes, prostacyclin, and thromboxane also mediate vascular changes [35]. Prostaglandins is directly involved in the modulation of pain mechanisms [9, 36].

IL-18 is another IL-1 family member involved in pain mechanisms. The IL-1β and IL-18 synthesis possess similarities in their signaling [37]. Pilat and colleagues' study involving the IL-18 inhibition [38] showed nociception reduction in a neuropathic pain model. Besides, IL-18 is also notorious as the IFN-y-inducing factor [37, 39].

Additionally, inflammatory mediators modulate inflammatory diseases, and some data confirms this actuation in organ pathophysiology such as lung, liver, heart, and others [40–43]. Thus, vital organ disturbs promote vascular fluids imbalance. Additional data about cytokines modulation at vascular mechanisms can be found in the following works [23, 44, 45].
