One of the common consequences of the inflammatory response is the development of edema. Although some of the pathophysiological events that lead to its formation are similar to those described for hemodynamic derangements, there are numerous events that are unique to inflammation. One of the hallmarks of the inflammatory response is the production and secretion of various proinflammatory cytokines and vasogenic mediators. Among the proinflammatory mediators and cytokines produced during inflammation, it is mainly histamine, bradykinin, platelet-activating factor, interleukin (IL)-1, and tumor necrosis factor (TNF) that are involved in the pathogenesis of inflammation-mediated edema . The magnitude of their action is largely dependent on the etiology of the inflammatory response and length of exposure to offending stimuli. Furthermore, the dominance of each of these agents also depends on the offending stimuli leading to endothelial injury. For example, following minor stimuli IL-1 and TNF secretion provide cellular and tissue protection through upregulation of certain anti-inflammatory cytokines (i.e., IL-6, IL-8). In contrast, IL-1 and TNF have a cardinal role in the endothelial damage associated with sepsis and endotoxemia. Most cases of sepsis are caused by endotoxin-producing Gram-negative bacilli. Endotoxins are bacterial lipopolysaccharides (LPS) released by degradation of the cell wall. LPS binds to LPS binding proteins, and this complex binds to specific receptors (CD14) on monocytes, macrophages, and neutrophils. Exposure to high levels of LPS induces the inflammatory response of primarily mononuclear phagocytes, leading to the production and secretion of TNF, which in turn activates IL-1 synthesis. Both cytokines act on the endothelial cells to produce other cytokines and endothelial effectors. Some of these effectors such as nitric oxide, platelet-activating factors, and other eicosanoids may mediate the release of proteolytic enzymes by neutrophils that can damage the endothelium itself and surrounding tissues. Thus, the pathogenesis of edema formation during inflammation is complex and may involve the combination of multiple mechanisms.
The main events that participate in the pathogenesis of inflammatory edema are therefore, alterations in vascular hemodynamics and an increase in vascular permeability (Figure 1B).
During inflammation there is a sequence of events in the microvasculature that leads to the formation of edema. Initially, there is transient vasoconstriction mediated by the secretion of various vasoconstricting mediators. This, in turn, is rapidly followed by vasodilatation of arterioles and expansion of microvascular beds in the involved region. Hence, the increase in the hydraulic pressure secondary to this vasodilatation results in transudation of protein-poor fluid to the extracellular compartment. At the same time, another edema-forming mechanism is activated. This mechanism, which is the hallmark of inflammatory edema, involves the induction and development of increased microvascular permeability.
Increased vascular permeability during inflammation occurs mainly at the microcirculatory level, involving the arterioles, capillaries, and venules. Unlike the forms of edema described earlier, here there is loss of protein-rich fluid (exudate) from the intravascular compartment to the interstitial space. Thus, a decrease in the intravascular oncotic pressure accompanied by an increase in the interstitial osmotic pressure result in marked movement of fluids to the interstitium and impairment of venous return.
Under normal conditions, the microvascular endothelium is composed of a thin, continuous layer of squamous epithelium with closely apposed intercellular junctions. Thus, bidirectional movement of water and small solutes is permitted between the intravascular compartment and the interstitial compartment, but larger particles, such as albumin and other plasma proteins, cannot cross freely. At the capillary level there is somewhat freer movement of proteins owing to the presence of micropinocytotic vesicles (25 nm). Despite its simple structure, the endothelium is actually metabolically active and is capable of secreting various proteins, including prostaglandins, cytokines, and collagen.
The primary factor leading to increased vascular permeability during inflammation is an injury to the endothelium. Acute inflammation may induce vascular leakiness of endothelial monolayers through a response elicited by a number of pathophysiological mechanisms. Arterioles, capillaries, and venules may be affected differently, depending on the severity of the inflammatory response and the pathways involved. These mechanisms may present distinctively or, more commonly, they tend to overlap each other. The first and most common response is observed immediately following injury and is of very short duration. This response, also known as the immediate transit response, occurs distinctively at small and medium-sized postcapillary venules. This type of response is reversible and results from the activation of histamine, bradykinin, and leukotrienes. The primary effect of these mediators is a significant contraction of the endothelial cells, leading to the formation of large intercellular gaps and escape of exudate to the interstitial space. Vascular permeability may also be increased by structural changes in the endothelial cytoskeleton. This pathway, which is mediated by the action of the proinflammatory cytokines IL-1 and TNF, is of longer duration (up to 24 hours). Here, vascular leakage results from endothelial cell retraction (not contraction) and disruption of the intercellular junctions.
Another mechanism that may lead to a massive and sustained increase in vascular permeability is severe endothe-lial injury that results in endothelial cell necrosis. Various insults such as severe burn injuries, sepsis, and endotoxemia are usually associated with this pathway. Cell necrosis may be the result of direct injury or may occur secondary to outpouring of noxious cellular mediators including oxygen radicals and proteolytic enzymes. These factors are mainly derived from recruited leukocytes. Because leukocytes need to adhere to become effective, this type of injury is commonly seen in venules or pulmonary capillaries. Here, vascular leakage also begins immediately, and this reaction will be sustained until the endothelium is repaired or the blood vessel is occluded by a thrombus. Another variant of this type of response is of delayed onset but again may be of long duration. It is commonly seen following thermal injury, exposure to various toxins, and irradiation. In this setting, the increase in vascular permeability occurs mainly at the capillary level. The exact mechanism leading to the delayed onset is unknown, but the possible role of some cytokines and apoptosis were recently suggested.
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