Inflammation Pathophysiology – Causes, Mechanisms, Mediators

Inflammation is a local response (reaction) of living vascularized tissues to endogenous and exogenous stimuli. The term is derived from the Latin “inflammable” meaning to burn. Inflammation is fundamentally destined to localize and eliminate the causative agent and to limit tissue injury.

Thus, inflammation is a physiologic (protective) response to injury, an observation made by Sir John Hunter in 1794 concluded: “inflammation is itself not to be considered as a disease but as a salutary operation consequent either to some violence or to some diseases”.

Causes

Causes of inflammation are apparently causes of diseases such as

• physical agents – mechanical injuries, alteration in temperatures and pressure, radiation injuries.
• chemical agents- including the ever-increasing lists of drugs and toxins.
• biologic agents (infectious)- bacteria, viruses, fungi, parasites
• immunologic disorders- hypersensitivity reactions, autoimmunity, immunodeficiency states, etc
• genetic/metabolic disorders- examples gout, diabetes mellitus, etc…
Acute & Chronic Inflammation - edulesson
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The nomenclatures of the inflammatory lesion are usually indicated by the suffix ‘itis’. Thus, inflammation of the appendix is called appendicitis and that of meninges as meningitis, etc.… However, like any rule, it has its own exceptions examples pneumonia, typhoid fever, etc….

 

How to Combat Chronic Inflammation | Inside Out Health & Wellness

 

Inflammation is classified crudely based on the duration of the lesion and histologic appearances into acute and chronic inflammation.
Acute Inflammation

Acute inflammation is an immediate and early response to an injurious agent and it is relatively short duration, lasting for minutes, several hours, or few days. It is characterized by the 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) 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) is due to the 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 inflamed area is inhibited by pain while severe swelling may also physically immobilize the tissue.
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Events of acute inflammation

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

1. The Vascular response has the following steps:

1. Immediate (momentary) vasoconstriction in seconds due to neurogenic or chemical stimuli.
2. Vasodilatation of arterioles and venules resulting in increased blood flow.
3. 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 extravascular 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 an 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:
1. Migration, rolling, pavements, & adhesion of leukocytes
2. Transmigration of leukocytes
3. Chemotaxis
4. 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).

1. Migration, rolling, pavements, and adhesion of leukocytes

• Margination is a peripheral positioning of white cells along with 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 pavements
• 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.

2. 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 interendothelial junctions after endothelial cell contractions. The basement membrane is disrupted and resealed thereafter immediately.

3. 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 the cell membrane of the leukocytes react with the chemoattractants resulting in the activation of phospholipase C that ultimately leads to the release of cytosolic 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 neutrophils), monocytes, and tissue macrophages.

 

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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, an extension of the cytoplasm (pseudopods) flow around the object to be engulfed, eventually resulting in the complete enclosure of the particle within the phagosome created by the cytoplasmic membrane of the phagocytic cell. As a result of the 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 mediated by some of the constituents of the primary and secondary granules of polymorphonuclear leukocytes. These include:
o Bactericidal permeability-increasing protein (BPI)
o Lysozymes
o Lactoferrin
o Major basic protein
o Defenses
o bacterial killing by lysosomal enzymes is probably 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
1. Non-myeloperoxidase dependent: The oxygen-dependent killing of microorganisms is due to the formation of reactive oxygen species such as hydrogen peroxide (H2O2), superoxide (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 the cell membrane or nucleus to cause damages. The destructive effects of H2O2 in the body are gauged by the action of glutathione peroxidase and catalase.
2. 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 – myeloperoxidase 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. Next, we will focus on the sources of these mediators.

Chemical mediators of inflammation

Chemical mediators account for the events of inflammation. Inflammation has the following sequence:
Cell injury → Chemical mediators → Acute inflammation (i.e. the vascular & cellular events).

 

Sources of mediators:

The chemical mediators of inflammation can be derived from plasma or cells.
a) Plasma-derived mediators:
• i) Complement activation
o increases vascular permeability (C3a, C5a)
o activates chemotaxis (C5a)
o opsoninization (C3b,C3bi)
• ii) Factor XII (Hageman factor) activation Its activation results in the recruitment of four systems: the kinin, the clotting, the fibrinolytic, and the compliment systems.
 
b) Cell-derived chemical mediators: Cell-derived chemical mediators include:
Cellular mediators Cells of origin Functions
histamine mast cell basophils vascular leakage
serotonin platelets vascular leakage
lysosomal enzymes neutrophiles Bacterial & tissue destruction
macrophages
prostaglandins all leukocytes Vasodilatation, pain, fever
leukotrienes all leukocytes
Chemoattractant LC4, LCD4, & LE4 Broncho and vasoconstriction
platelets activating factor all leukocytes Bronchoconstriction and WBC priming
activated oxygen species all leukocytes Endothelial and tissue damage
nitric oxide macrophages Leukocyte activation
 
cytokines lymphocytes, macrophages Leukocyte activation
• Most mediators perform their biologic activities by initially binding to specific receptors on target cells. Once activated and released from the cells, most of these mediators are short-lived. Most mediators have the potential to cause harmful effects.
Characteristically, the acute inflammatory response involves the production of exudates. An exudate is an edema fluid with high protein concentration, which frequently contains inflammatory cells. A transudate is simply non-inflammatory edema caused by cardiac, renal, undernutrition, & other disorders. The differences between exudate and a transudate are:
                                 Transudate                      Exudate
cause acute inflammation non-inflammatory disorders
appearance Colored, turbid, hem
hemorrhagic Clear, translucent or pale yellow
specific gravity Greater than or equal to 1.020 much less
Spontaneous coagulability yes no
Protein content: >3gm %
cells Abundant WBC, RBC, & Cell debris
usually, present Only a few mesothelial cells
bacteria present absent

 

There are different morphologic types of acute inflammation:

1. Serous inflammation
• This is characterized by an outpouring of a thin fluid that is derived from either the blood serum or secretion of mesothelial cells lining the peritoneal, pleural, and pericardial cavities.
• It resolves without reactions
2. Fibrinous inflammation
• More severe injuries result in greater vascular permeability that ultimately leads to the exudation of larger molecules such as fibrinogens through the vascular barrier.
• Fibrinous exudate is characteristic of inflammation in serous body cavities such as the pericardium (butter and bread appearance) and pleura.
The course of fibrinous inflammation include:
• Resolution by fibrinolysis
• Scar formation between parietal and visceral surfaces i.e. the exudates get organized
• Fibrous strand formation that bridges the pericardial space.
3. Suppurative (Purulent) inflammation
This type of inflammation is characterized by the production of a large amount of pus. Pus is a thick creamy liquid, yellowish or blood-stained in color and composed of
• A large number of living or dead leukocytes (pus cells)
• Necrotic tissue debris
• Living and dead bacteria
• Edema fluid

There are two types of suppurative inflammation:

1. Abscess formation: An abscess is a circumscribed accumulation of pus in living tissue. It is encapsulated by a so-called pyogenic membrane, which consists of layers of fibrin, inflammatory cells, and granulation tissue.
2. Acute diffuse (phlegmonous) inflammation:
This is characterized by the diffuse spread of the exudate through tissue spaces. It is caused by virulent bacteria (eg. streptococci) without either localization or marked pus formation. Example: Cellulitis (in palmar spaces).
4. Catarrhal inflammation
This is a mild and superficial inflammation of the mucous membrane. It is commonly seen in the upper respiratory tract following viral infections where mucous secreting glands are present in large numbers, eg. Rhinitis.
5. Pseudomembranous inflammation
The basic elements of pseudomembranous inflammation are extensive confluent necrosis of the surface epithelium of an inflamed mucosa and severe acute inflammation of the underlying tissues. The fibrinogens in the inflamed tissue coagulate within the necrotic epithelium. And the fibrinogen, the necrotic epithelium, the neutrophilic polymorphs, red blood cells, bacteria, and tissue debris from a false (pseudo) membrane forms a white or colored layer over the surface of inflamed mucosa. Pseudomembranous inflammation is exemplified by Dipthetric infection of the pharynx or larynx and Clostridium difficult infection in the large bowel following certain antibiotic use.

 

Effects of acute inflammation

A. Beneficial effects
• Dilution of toxins: The concentration of chemical and bacterial toxins at the site of inflammation is reduced by dilution in the exudate and its removal from the site by the flow of exudates from the venules through the tissue to the lymphatics.
• Protective antibodies: Exudation results in the presence of plasma proteins including antibodies at the site of inflammation. Thus, antibodies directed against the causative organisms will react and promote microbial destruction by phagocytosis or complement-mediated cell lysis.
• Fibrin formation: This prevents the bacterial spread and enhances phagocytosis by leukocytes.
• Plasma mediator systems provisions: The complement, coagulation, fibrinolytic, & kinin systems are provided to the area of injury by the process of inflammation.
• Cell nutrition: The flow of inflammatory exudates brings with it glucose, oxygen, and other nutrients to meet the metabolic requirements of the greatly increased number of cells. It also removes their solute waste products via lymphatic channels.
• Promotion of immunity: Micro-organisms and their toxins are carried by the exudates, either free or in phagocytes, along the lymphatics to local lymph nodes where they stimulate an immune response with the generation of antibodies and cellular immune mechanisms of defense.

B. Harmful effects

• Tissue destruction: Inflammation may result in tissue necrosis and the tissue necrosis may, in turn, incite inflammation.
• Swelling: The swelling caused by inflammation may have serious mechanical effects at certain locations. Examples include acute epiglottitis with interference in breathing; Acute meningitis and encephalitis with effects of increased intracranial pressure.
• Inappropriate response: The inflammatory seen in hypersensitivity reactions is inappropriate (i.e. exaggerated).
The course of acute inflammation
Acute inflammation may end up in:
• Resolution: i.e. complete restitution of normal structure and function of the tissue, eg. lobar pneumonia.
• Healing by fibrosis (scar formation).
• Abscess formation {Surgical law states -Thou shalt ( you should ) drain all abscesses.} However, if it is left untouched, it may result in
o -Sinus formation – when an abscess cavity makes contact with only one epithelial lining.
o -Fistula formation: when an abscess tract connects two epithelial surfaces. Or very rarely to septicemia or Pyemia with a subsequent metastatic abscess in heart, kidney, brain, etc.

 

CHRONIC INFLAMMATION

Definition: Chronic inflammation can be defined as a prolonged inflammatory process (weeks or months) where an active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously.

 

Causes of chronic inflammation

1. Persistent infections Certain microorganisms associated with intracellular infection such as tuberculosis, leprosy, certain fungi, etc characteristically cause chronic inflammation. These organisms are of low toxicity and evoke delayed hypersensitivity reactions.
2. Prolonged exposure to nondegradable but partially toxic substances either endogenous lipid components that result in atherosclerosis or exogenous substances such as silica, asbestos.
3. Progression from acute inflammation: Acute inflammation almost always progresses to chronic inflammation following a persistent suppuration as a result of uncollapsed abscess cavities, foreign body materials (dirt, cloth, wool, etc), sequestered in osteomyelitis, or a sinus/fistula from chronic abscesses.
4. Autoimmunity. Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are chronic inflammations from the outset.
Morphology

Cells of chronic inflammation

Monocytes and Macrophages are the prima Dona (primary cells) in chronic inflammation. Macrophages arise from the common precursor cells in the bone marrow, which give rise to blood monocytes. These cells are then diffusely scattered in various parts of the body, in the liver (Kupffer cells), spleen, lymph nodes (sinus histiocytes), lungs (alveolar
macrophages), bone marrow, brain (microglia), skin (Langerhan’s cells), etc…. These cells constitute the mononuclear- phagocytic system. Macrophages are scavenger cells of the body.
Other cells in chronic inflammation:
• T-Lymphocytes are primarily involved in cellular immunity with lymphokine production, and they are the key regulator and effector cells of the immune system.
• B-lymphocytes and Plasma cells produce antibodies directed either against a persistent antigen in the inflammatory site or against altered tissue components.
• Mast cells and eosinophils appear predominantly in response to parasitic infestations & allergic reactions.
Though neutrophils are hallmarks of acute inflammatory reactions, large numbers of neutrophils may be seen in some forms of chronic inflammation, notably chronic osteomyelitis, actinomycosis, & choric lung diseases induced by smoking and other stimuli. Thus, the overall differentiation points between acute and chronic inflammations include:
characteristics acute inflammation chronic inflammation
duration short relatively LNG
pattern stereotyped varied
predominant cell neutrophils lymphocytes macrophage, plasma cells
tissue destruction mild to moderate marked
fibrosis absent present
inflammatory reaction exudative productive

 

Classification of chronic inflammation

Chronic inflammation can be classified into the following two types based on histologic features:
1. Nonspecific chronic inflammation: – This involves a diffuse accumulation of macrophages and lymphocytes at the site of injury that is usually productive with new fibrous tissue formations. E.g. Chronic cholecystitis.
2. Specific inflammation (granulomatous inflammation)

Granulomatous inflammation is characterized by the presence of granuloma. A granuloma is a microscopic aggregate of epithelioid cells. The epithelioid cell is an activated macrophage, with a modified epithelial cell-like appearance (hence the name epithelioid). The epithelioid cells can fuse with each other & form multinucleated giant cells. So, even though, a granuloma is basically a collection of epithelioid cells, it also usually contains multinucleated giant cells & is usually surrounded by a cuff of lymphocytes and occasional plasma cells. There are two types of giant cells:

1. Foreign body-type giant cells that have irregularly scattered nuclei in presence of indigestible materials.
2. Langhans giant cells in which the nuclei are arranged peripherally in a horseshoe pattern which is seen typically in tuberculosis, sarcoidosis, etc… Giant cells are formed by the fusion of macrophages perhaps by a concerted attempt of two or more cells to engulf a single particle.

Pathogenesis

There are two types of granulomas, which differ in their pathogenesis.

1. Foreign body granuloma: These granulomas are initiated by inert foreign bodies such as talc, sutures (nonabsorbable), fibers, etc… that are large enough to preclude phagocytosis by a single macrophage and do not incite an immune response.
2. Immune granulomas: Antigen-presenting cells (macrophages) engulf a poorly soluble inciting agent. Then, the macrophage processes and presents part of the antigen (in association with MHC type2 molecules) to CD4+T helper 1 cells which become activated. The activated CD4+ T-cells produce cytokines (IL-2 and interferon-gamma). The IL-2 activates other CD4+T helper cells and perpetuates the response while IFN-γ is important in transforming macrophages into epitheloid cells and multinucleated giant cells. The cytokines have been implicated not only in the formation but also in the maintenance of granuloma. Macrophage inhibitory factor helps to localize activated macrophages and epitheloid cells.

 

Causes

Major causes of granulomatous inflammation include:
• Bacterial: Tuberculosis, Leprosy, Syphilis, Cat scratch disease, Yersiniosis
• Fungal: Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis
• Helminthic: Schistosomiasis
• Protozoal: Leishmaniasis, Toxoplasmosis
• Chlamydia: Lymphogranuloma venerum
• Inorganic material: Berrylliosis
• Idiopathic: Acidosis, Cohn’s disease, primary biliary cirrhosis

SYSTEMIC EFFECTS OF INFLAMMATIONS

The systemic effects of inflammation include:
• Fever
• Endocrine & metabolic responses
• Autonomic responses
• Behavioral responses
• Leukocytosis
• Leukopenia
• Weight loss
 
a. Fever
• Fever is the most important systemic manifestation of inflammation. It is coordinated by the hypothalamus & by cytokines (IL -1, IL-6, TNF-α) released from macrophages and other cells.
b. Endocrine and metabolic responses include:
• The liver secrets acute phase proteins such as C-reactive proteins, Serum Amyloid A
• Complement and coagulation proteins; glucocorticoids (increased) vasopressin (decreased)
c. Autonomic responses include:
• Redirection of blood flow from the cutaneous to the deep vascular bed.
• Pulse rate and blood pressure (increased)
• Sweating (decreased)
d. Behavioral responses include:
• Rigor, chills, anorexia, somnolence, and malaise.
e. Leucocytosis
• Is also a common feature of inflammation, especially in bacterial infections. Its usual count is 15,000 to 20,000 cells/mm3. Most bacterial infections induce neutrophilia. Some viral infections such as infectious mononucleosis, & mumps cause lymphocytosis. Parasitic infestations & allergic reactions such as bronchial asthma & hay fever induce eosinophilia.
f. Leukopenia is also a feature of typhoid fever and some parasitic infections.
g. Weight loss
• Weight loss is thought to be due to the action of IL-1 and TNF-α which increase catabolism in skeletal muscle, adipose tissue, and the liver with resultant negative nitrogen balance.
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