Acute Inflammation

-  Acute inflammation is an immediate and early response to an injurious agent and it is relatively of short duration, lasting for minutes, several hours or few days.

-  It is characterized by exudation of fluids and plasma proteins and the emigration of predominantly neutrophilic leucocytes to the site of injury.

 The five cardinal signs of acute inflammation are

 -  Redness (rubor) which is due to dilation of small blood vessels within damaged tissue as it occurs in cellulitis.

-  Heat (calor) which results from increased blood flow (hyperemia) due to regional vascular dilation 

-  Swelling (tumor) which is due to accumulation of fluid in the extravascular space which, in turn, is due to increased vascular permeability.

-  Pain (dolor), which partly results from the stretching & destruction of tissues due to

inflammatory edema and in part from pus under pressure in as abscess cavity.

Some chemicals of acute inflammation, including bradykinins, prostaglandins and serotonin are also known to induce pain.

-  Loss of function: The inflammed area is inhibited by pain while severe swelling may also physically immobilize the tissue.

Events of acute inflammation:

Acute inflammation is categorized into an early vascular and a late cellular responses.

1) The Vascular response has the following steps:

 a)  Immediate (momentary) vasoconstriction in seconds due to neurogenic or chemical stimuli.

b)  Vasodilatation of arterioles and venules resulting in increased blood flow.

c)  After the phase of increased blood flow there is a slowing of blood flow & stasis due to increased vascular permeability that is most remarkably seen in the post-capillary venules. The increased vascular permeability oozes protein-rich fluid into extra-vascular tissues. Due to this, the already dilated blood vessels are now packed with red blood cells resulting in stasis. The protein-rich fluid which is now found in the extravascular space is called exudate.  The presence of the exudates clinically appears as swelling. Chemical mediators mediate the vascular events of acute inflammation. 

2) Cellular response

The cellular response has the following stages:

A.  Migration, rolling, pavementing, & adhesion of leukocytes

B.  Transmigration of leukocytes

C. Chemotaxis

D. Phagocytosis

-   Normally blood cells particularly erythrocytes in venules are confined to the central (axial) zone and plasma assumes the peripheral zone. As a result of increased vascular permeability (See vascular events above), more and more neutrophils accumulate along the endothelial surfaces (peripheral zone). 

A) Migration, rolling, pavementing, and adhesion of leukocytes

-  Margination is a peripheral positioning of white cells along the endothelial cells.

-  Subsequently, rows of leukocytes tumble slowly along the endothelium in a process known as rolling

-  In time, the endothelium can be virtually lined by white cells. This  appearance is called pavementing 

-  Thereafter, the binding of leukocytes with endothelial cells is facilitated by cell adhesion molecules such as selectins, immunoglobulins, integrins, etc which result in adhesion of leukocytes with the endothelium.

 B). Transmigration of leukocytes

-  Leukocytes escape from venules and small veins but only occasionally from capillaries.  The movement of leukocytes by extending pseudopodia through the vascular wall occurs by a process called diapedesis.

-   The most important mechanism of leukocyte emigration is via widening of inter-endothelial junctions after endothelial cells contractions. The basement membrane is disrupted and resealed thereafter immediately.

 C). Chemotaxis: 

-  A unidirectional attraction of leukocytes from vascular channels towards the site of inflammation within the tissue space guided by chemical gradients (including bacteria and cellular debris) is called chemotaxis. 

-  The most important chemotactic factors for neutrophils are components of the complement system (C5a), bacterial  and mitochondrial products of arachidonic acid metabolism such as leukotriene B4 and cytokines (IL-8). All granulocytes, monocytes and to lesser extent lymphocytes respond to chemotactic stimuli.

-  How do leukocytes "see" or "smell" the chemotactic agent? This is because receptors on cell membrane of the leukocytes react with the chemoattractants resulting in the activation of phospholipase C that ultimately leads to release of cytocolic calcium ions and these ions trigger cell movement towards the stimulus.

D)  Phagocytosis

-  Phagocytosis is the process of engulfment and internalization by specialized cells of particulate material, which includes invading microorganisms, damaged cells, and tissue debris. 

-  These phagocytic cells include polymorphonuclear leukocytes (particularly neutrophiles), monocytes and tissue macrophages.

Phagocytosis involves three distinct but interrelated steps.

 1).  Recognition and attachment of the particle to be ingested by the leukocytes: Phagocytosis is enhanced if the material to be phagocytosed is coated with certain plasma proteins called opsonins. These opsonins promote the adhesion between the particulate material and the phagocyte’s cell membrane. The three major opsonins are: the Fc fragment of the immunoglobulin, components of the complement system C3b and C3bi, and the carbohydrate-binding proteins – lectins.  Thus, IgG binds to receptors for the Fc piece of the immunoglobulin (FcR) whereas 3cb and 3bi are ligands for complement receptors CR1 and CR2 respectively. 

2). Engulfment: During engulfment, extension of the cytoplasm (pseudopods) flow around the object to be engulfed, eventually resulting in complete enclosure of the particle within the phagosome created by the cytoplasmic membrane of the phagocytic cell. As a result of fusion between the phagosome and lysosome, a phagolysosome is formed and the engulfed particle is exposed to the degradative lysosomal enzymes.

3) Killing or degradation

The ultimate step in phagocytosis of bacteria is killing and degradation. There are two forms of bacterial killing

a). Oxygen-independent mechanism: 

-  This is mediate by some of the constituents of the primary and secondary granules of polymorphonuclear leukocytes. These include:  Bactericidal permeability increasing protein (BPI)

Lysozymes

Lactoferrin

Major basic protein

Defenses

-  It is probable that bacterial killing by lysosomal enzymes is inefficient and relatively unimportant compared with the oxygen dependent mechanisms. The lysosomal enzymes are, however, essential for the degradation of dead organisms within phagosomes.

b) Oxygen-dependent mechanism:  

 There are two types of oxygen- dependent killing mechanisms

 i) Non-myeloperoxidase dependent

 -  The oxygen - dependent killing of microorganisms is due to formation of reactive oxygen species such as hydrogen peroxide (H₂O₂), super oxide (O₂) and hydroxyl ion (HO-) and possibly single oxygen (1O₂). These species have single unpaired electrons in their outer orbits that react with molecules in cell membrane or nucleus to cause damages. The destructive effects of H₂O₂ in the body are gauged by the action of the glutathione peroxidase and catalase. 

 ii) Myloperoxidase–dependent

-  The bactericidal activity of  H₂O₂ involves the lysosomal enzyme myeloperoxidase, which in the presence of halide ions converts H₂O₂ to hypochlorous acid (HOCI).  This  H₂O₂ – halide - myecloperoxidease system is the most efficient bactericidal system in neutrophils. A similar mechanism is also effective against fungi, viruses, protozoa and helminths. 

 Like the vascular events, the cellular events (i.e. the adhesion, the transmigration, the chemotaxis, & the phagocytosis) are initiated or activated by chemical mediators.

References

Bezabeh ,M. ; Tesfaye,A.; Ergicho, B.; Erke, M.; Mengistu, S. and Bedane,A.; Desta, A.(2004). General Pathology. Jimma University, Gondar University Haramaya University, Dedub University.