Acute inflammatory response constitute the first line of defense against infection pathogenesis and how immune system works as well as the initial stage in restoring injured tissue to normalcy. Acute inflammation is recognized by redness, swelling, heat and pain in the affected area. These symptoms stem from a multitude of events taking place within the inflamed site. The humoral arm of the immune response, including circulating antibodies and the complement system, is activated.
Leukocytes which normally travel within the bloodstream recognize signs of tissue in distress, adhere to and traverse the blood vessel wall and migrate toward the source of irritation. The permeability of small venules increases, leading to edema formation, and furthermore the blood flow through inflamed tissue is altered as a result of modification of arteriolar tone. Additionally, a multitude of cell types are activated to liberate various inflammatory mediators, including cytokines arachidonic acid metabolites, which in turn can affect every aspect of inflammation mentioned above. The intricacy and complexity of the acute inflammatory reactions cannot be underestimated and the detrimental impact of these events on normal function is often massive.
Cause of Acute Inflammation
While a classical immune response can elicit acute inflammation, both through antibody—antigen complex formation and through activation by cytokines secreted by T cell epitopes activated macrophages, the focus of this entry will be on effector cells such as neutrophils and endothelial cells. Signs of acute inflammation are seen in connection with infection by various pathogens types, but tissue injury induced by physical, chemical or thermal means, without infection of foreign bodies per Se, will also induce an acute inflammatory response.
A particularly important clinical problem is the inflammatory response followed by tissue injury which is associated with ischemial/reperfusion situations such as myocardial infarction, stroke or transplantation of organs. Another example of an inflammatory response gone awry is the systemic inflammatory response syndrome (SIRS) sometimes seen in connection with systemic infection, extensive burns, ischemia, trauma or hemorrhagic shock. These conditions highlight the importance of understanding the acute inflammatory reactions for the purpose of adequate clinical intervention.
The Neutrophil Granulocyte: Mechanisms of Neutrophil Infiltration
The first leukocytes to infiltrate a site of inflammation are neutrophil granulocytes, which some times begin to accumulate within minutes of induction of inflammation. A host of adhesion molecules essential for neutrophil recruitment have been identified. During its journey through the vasculature, the neutrophil makes transient contact with the vascular wall of postcapillary venules, which gives the cell a rolling motion across the endothelium.
This phenomenon is dependent on L-selectin (CD6ZL), present on the neutrophil surface, which recognizes and binds carbohydrates on the luminal surface of the vascular endothelium. Near an inflammatory site, however, the neutrophil becomes activated, the L-selectin is shed from the surface, and now the CDI lb/CDI8 adhesion complex, part of the integrin family, comes into play as the neutrophil adheres firmly to the vascular wall. Next, the neutrophil migrates our of the vessel through the junction between adjacent endothelial cells, and continues to move through the tissue toward the inflamed area, guided by inflammatory mediators which Form a chemoractic gradient.
Other selectins, P- and E- selectin (CD62P and CD62E. respectively), can be found on the endothelial surface after stimulation with certain inflammatory mediators. P-selectin appears within minutes, whereas E- selectin is first found some hours after stimulation. Both P.- and E-selectin can support neutrophil rolling along the endothelium together with neutrophil L-selectin.
An interesting exception to this scenario is seen in the lung. The low pressure in the pulmonary circulation combined with the narrow dimensions of lung capillaries leads to occasional trapping of neutrophil in these vessels, a phenomenon referred to as plugging’. When activated, neutrophil become stiffer as a result of intracellular actin polymerization, facilitating capillary trapping which may take place independently of the above-mentioned adhesion proteins. The cells may then migrate from the capillaries, which appear to be the main site for neutrophil extravasation in the lung. Plugging is also seen in some ischemia/reperfusion models, and has been suggested to account for hv no-reflow phenomenon after severe ischemia, although this remains controversial.
Tissue injury by neutrophils
The neutrophil contains a formidable arsenal of proteinases, lysozyme and oxygen radical-forming enzymes in its granules, usually employed to kill microorganisms ingested by the neutrophil. Occasionally, however, these injurious products may be released to the extracellular space and cause tissue damage, for example if the perceived foreign body is too large for ingestion. In addition, anti proteinases normally present in the interstitial fluids can he inactivated by neutrophil-derived oxygen radicals, thereby enhancing the damage inflicted by neutrophil proteinases such as elastase, gelatinase and collagenase. Experimental proof for neutrophil -inflicted tissue injury is found in models of immune complex-induced dysfunction of various organs such as the Arthus reaction and nephrotoxic nephritis acute, among others.
Vascular leakage
Tissue swelling is one of the most obvious signs of inflammation. It is generated by an increase in vascular permeability to plasma proteins and fluid. Under normal conditions the endothelial layer lining blood vessel walls is relatively nonpermeable to proteins and other molecules above 30 A, and the small exchange between the intravascular and extravascular compartments occurs by transport through the endothelial cell bodies as well as through junctions between adjacent endothelial cells. During allergic inflammation the endothelial cells in small venules retract from each other after cell junctions, in the form of cadherins, break apart. This results in large pore formation and massive exudation of plasma proteins. Many inflammatory mediators, including histamine, bradykinin, certain complement factors and serotonin can act directly on the endothelial cells to cause retraction, although the exact underlying mechanism is yet to he described. This is partly due to the difficulty in studying these events in in vitro cell culture.
