Acute inflammation may progress to chronic
Microbes, necrotic cells and injurious stimuli elicit a response, called “inflammation”. Inflammation is the body’s reaction against injurious stimuli and products of cell injury to repair the cell. It can be acute or chronic.
Acute inflammation is an immediate reaction to cell injury or injurious stimuli by the release of leukocytes and plasma proteins. Redness, swelling, heat, pain, and loss of function are signs we should be vigilant of in acute inflammation.
The causes of acute inflammation include: microbial infection, autoimmunity, tissue necrosis, tampon, hypoxia. In microbial infections, Toll-like receptors sense the presence of microbes. Tissue hypoxia causes affected cells to produce HIF-alpha, which then activates VEGF for vascular permeability.
Mechanism of acute inflammation include the following:
- Nitric oxide-induced vasodilation on vascular smooth muscle wall
- Increased blood flow resulting in heat & redness
- Leakage of fluid and proteins in the extravascular space
- Decreased blood flow leading to vascular congestion
- Neutrophil adhesion to endothelium and migration to extravascular space.
It is important to distinguish between exudate from transudate which is a product of acute inflammation. An exudate is a protein rich fluid with blood cells, and cell debris. Transudate fluid contains little to no protein or cell debris as a result of hydrostatic and colloid osmotic pressure imbalance.
Process of microbial product and necrotic tissue degradation:
Cytokines (TNF, IL-I) produced by macrophages, cause leukocyte transmigration in the post-capillary venule. Transmigration of leukocytes occur by margination, rolling, and adhesion.
TNF & IL-1 enable expression of adhesion molecules (selectins, integrins, ICAM-1) to enable adhesion. Chemokines (histamines) enable movement across endothelium into the interstitial space. For identification of microbes and necrotic tissues for phagocytosis, leukocytes have TLR and opsonin receptors(Fc, C3, Lenin). Lysosomal enzymes and reactive oxygen species destroy phagocytic vacuole through phagocyte oxidase.
Examples of leukocyte defects include:
- Inherited leukocyte adhesion deficiency type 1 & 2 due to defective adhesion molecules. This causes recurrent bacterial infection.
- Inherited Chediak-Higashi syndrome due to defective lysosomal mobilization to phagosome. Causes neutropenia, recurrent bacterial infection.
- Inherited impairment in microbicidal function due to phagocyte oxidase defect. This often leads to granuloma.
- Acquired Leukocyte deficiency from cancer therapy and leukemia. This leads to neutropenic sepsis.
Neutrophils die by apoptosis after their activities to ensure regulation of inflammation. Other cells (e.g. macrophages) produce anti-inflammatory cytokines e.g. IL -10 AND TGB-β to stop inflammation for tissue repair.
The mediators of inflammation:
Cyclo-oxygenase 1&2 enzymes produce prostaglandins. Under normal resting circumstances, there is an expression of Cox-1 in the platelets and all kinds of tissues. Expression of COX-2 by many tissues including endothelium, usually occurs when there is an inflammatory reaction. Prostaglandin D2 & E2 cause vasodilation & increase permeability in post-capillary venules.
Platelets produce thromboxane (TxA2), which is a vasoconstrictor & platelet aggregator. Endothelium Produces prostacyclin (PGI2) for vasodilation & inhibition of platelet aggregation. PGE2 is responsible for pain & fever during inflammation. PGF2 mediates uterine and bronchial smooth muscle contraction. It also contracts the arteriole.
Leukocytes produce leukotrienes and lipoxins by the actions of lipoxygenase enzymes on arachidonic acid. Examples are LTB4 & LTC4. LTB4 attracts neutrophils, while LTC4 induction is in asthmatic conditions. Lipoxins mainly acts as anti-inflammatory.
Histamine and serotonin are vasoactive amines. Mast cells, basophils, and platelets produce histamines. The making of serotonin takes place in platelets and neuroendocrine cells e.g. G.I tract. They both cause arteriole vasodilation and venule permeability. H1 receptor in endothelium binds histamine which influences its activities.
Cytochines and Chemokines are important mediators of inflammation in different ways. Llymphocytes and macrophages produce cytokines that stimulate other cells. In contrast, Chemokines are smaller molecules that attract specific leukocytes. E.g. cytokines (IL-1, IL-6, IL-17, TNF); chemokines (IL-8, eotaxin).
PlateletS and other cells make the Platelet Activating Factor (PAF). It causes platelet aggregation, vasoconstriction & bronchoconstriction in lungs, and vasodilation & permeability in vessels.
Lysosomal enzymes from neutrophils and monocytes destroy extracellular matrix and microbes, and also cleave complement proteins. E.g. elastase, lysozyme, collagenase. Release of reactive oxygen species in the extracellular matrix also promotes signaling and inflammation.
Nitric oxide is a vasodilator and an inhibitor of inflammation. Substance P released from sensory nerves, transmit pain signals, and venule permeability.
Inflammation and coagulation:
There is a connection between inflammation and coagulation such that, one influences another. The endothelial basement membrane & collagen activate factor XII to XIIa in the intrinsic pathway. This in turn activates thrombin that forms fibrin from fibrinogen. Thrombin is also pro-inflammatory.
Bradykinin is a vasoactive substance that causes smooth muscle contraction, vasodilation, pain & venule permeability. Kallikerein cleaves kininogen to produce bradykinin. Plasminogen activator (from endothelium) & kallikrein activate plasmin from plasminogen to cleave fibrins.
The liver is the source of the complement system, which is a number of inactive plasma proteins C1-C9. When activated in blood plasma, they cause vascular permeability, chemotaxis & promote phagocytosis.
In the activation of the complement system, C1 first binds antigen bound IgG/IgM, leading to C1 activation. C1 activation results in C3 convertase formation. C3 convertase cleaves C3 into C3b + C3a. C3b + C3 convertase form the C5 convertase.
C5 convertase cleaves C5 into C5b + C5a. C5b binds with C6-C8, & multiple C9 molecules to form the membrane attack complex (MAC) which are deposited on microbial surface.
The cleavage products of the related complement proteins, C3a & C5a are anaphylatoxins that cause mast cell degranulation. MAC causes cell lysis by making microbial cell surface water permeable.
The outcomes of acute inflammation are: resolution; organization; & progression to chronic inflammation. The neutralization of the offending agent is the end and begining of inflammation. In some cases, it heals by fibrin replacement in lungs. When offending agent is severe, it may result in chronic inflammation.
The structural and microscopic patterns of acute inflammation:
Serous inflammation: This is the leakage of plasma fluid into the extracellular space. This can occur during skin burns or viral infections.
Fibrinoid inflammation: Excess fibrin-mixed exudate forms in the extracellular matrix. E.g. fibrinous pleuritis; fibrinous peritonitis; fibrinous meningitis.
Ulcers: Occurs when there is a shedding of necrotic tissues. E.g. Peptic ulcer, mouth ulcers.
Purulent inflammation & Abscess: Bacterial infection causes the formation of thick-white exudates mixed with neutrophils & necrotic tissues to form pus. Abscess is the local accumulation of pus itself. E.g. acute pancreatitis, complicated peritonitis.