INFLAMMATION
Inflammation:
Inflammation is a response of vascularized tissues that delivers leukocytes and molecules of host defense from the circulation to the sites of infection and cell damage in order to eliminate the offending agents,
Note: - Inflammation can occur in avascular tissue, e.g. In cornea (Keratitis).
▶ Classification of inflammation:
According to duration, inflammation is 2 types
1) Acute inflammation: Morphologically acute inflammation is further classified into 4 types-
- ➤ Serous: e.g. Pleural effusion.
- ➤ Fibrinous: e.g. Pericarditis.
- ➤ Suppurative/purulent: e.g. Abscess, boil.
- ➤ Ulcer.
2) Chronic inflammation: further it is of 2 types-
- ➤ Chronic specific inflammation: e.g. tuberculosis.
- ➤ Chronic non-specific inflammation: e.g. chronic osteomyelitis.
▶Beneficial / protective effects of inflammation:
- Inflammation serves to rid the host of both the initial cause of cell injury (e.g. microbes, toxins) and the consequences of such injury (e.g. necrotic cells and tissues).
- Without inflammation, infections would go unchecked.
- Without inflammation, wounds would never heal.
- Without inflammation, injured organs might remain permanent festering sores.
▶ Harmful effects of inflammation: (termed as 'the silent killer')
- Local tissue damage, which also causes pain & functional impairment.
- There are many diseases in which inflammatory reactions are misdirected (e.g. autoimmune disease).
- Inflammatory reactions underlie some chronic diseases, e.g., rheumatoid arthritis, atherosclerosis, lung fibrosis etc.
- Life threatening hypersensitivity reaction to insect bite, drugs and toxins.
- Repair by fibrosis may lead to disfiguring scars.
- Fibrous bands may cause intestinal obstruction or limit the mobility of joints.
- May contribute to cancer.
Differences between acute and chronic inflammation:
Acute inflammation:
(The initial, rapid response to infections and tissue damage is called acute inflammation) Acute inflammation is a rapid, often self-limited, response to offending agents that are readily eliminated (such as many bacteria, fungi & dead cells), that typically develops within minutes or hours and is of short duration (several hours to a few days), characterized by the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils.
▶ Morphological classification of acute inflammation:
1) Serous inflammation: Serous inflammation is marked by the exudation of cell poor flid into spaces created by cell injury or into body cavities lined by the peritoneum, pleura, or pericardium.
Examples: Pleural effusion, blister in skin etc.
2) Fibrinous inflammation: With greater increase in vascular permeability, large molecules such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the extracellular space. A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus (e.g. caused by cancer cells). A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura.
3) Suppurative / purulent inflammation: Is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid.
Example: Abscess, boil etc.
4) Ulcers: An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamedd necrotic tissue.
▶ Causes of acute inflammation:
1) Infections and microbial toxins: - Bacterial, viral, fungal, parasitic etc.
2) Tissue necrosis: Ischaemia, trauma, physical and chemical injuries.
- Physical agents: Thermal injury, as in burns or frostbite.
- Chemical agents: Some environmental chemicals.
- Irradiation.
3) Foreign bodies: Splinters, dirt, sutures etc.
4) Immune reactions: Hypersensitivity.
▶ Cardinal signs of acute inflammation:
- Rubor (Redness).
- Tumor (Swelling).
- Calor (Heat).
- Dolor (Pain).
- Functiolaesa (Loss of function).
Note: First 4 are listed by Roman writer Celsus & last one was added by Scottish surgeon Virchow. ▶ Pathogenesis of cardinal signs of acute inflammation:
❖ Rubor (Redness): Due to vasodilatation (caused by histamine, serotonin, prostaglandin, NO).
❖ Tumor (Swelling): Due to increased vascular permeability.
❖ Calor (Heat): Due to increased blood supply.
❖ Dolor (Pain): Due to compression of free nerve endings and action of bradykinin & prostaglandin.
❖ Functiolaesa (Loss of function): Due to local pain and tissue destruction.
▶ Components of acute inflammation:
Acute inflammation has 3 major components:
- Dilation of small vessels leading to an increase in blood flow,
- Increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation, &
- Emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent.
▶Morphologic features of acute inflammation:
- Vascular change: Vasodilatation and increased blood flow.
- Oedema: Extravasation of plasma fluid and proteins in interstitial space.
- Predominantly neutrophilic infiltration: Leucocyte emigration and accumulation at the site of injury.
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| Figure: Vascular changes in acute inflammation. |
▶Outcome/fates of acute inflammation:
Acute inflammation typically has one of three outcomes-
1) Complete resolution: Resolution means the complete return to normal of a tissue following acute
inflammation. Usually it occurs-
- When the injury is limited or short-lived.
- When there has been little tissue destruction, and the damaged parenchymal cells can regenerate.
2) Healing by connective tissue replacement (scarring, or fibrosis): This occurs when the injured tissue cannot regenerate.
3) Progression to chronic inflammation: If causative agent persists or there is interference of repair.
4) Pus or abscissa form
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| Figure: - Outcome of acute inflammation: resolution, healing by fibrosis, or chronic inflammation |
Events of acute inflammation
A) Vascular events/reactions of blood vessels in acute inflammation:
1) Change in the vascular flow and caliber:
- ➤ Vasodilatation.
- ➤ Increased permeability of the microvasculature.
- ➤ Slowing of circulation or stasis.
- ➤ Activation of endothelial cells.
2) Increased vascular permeability (vascular leakage): Leading to escape of a protein- rich fluid (exudate) into the interstitial space.
3) Responses of lymphatic vessels & lymph nodes.
B) Leukocyte recruitment to sites of inflammation / cellular events:
1) Emigration of leukocytes: From the vessel lumen to the tissues by margination, rolling, adhesion to endothelium and migration across the endothelium in the tissues.
2) Phagocytosis & clearance of the offending agents.
Vascular events/Reactions of blood vessels
Vascular changes/events/reactions of blood vessels in acute inflammation:
A) Changes in vascular flow & caliber:
- Vasodilatation: Is induced by the action of several mediators, notably histamine, on vascular smooth muscle. The result is increased blood flw, which is the cause of heat and redness (erythema) at the site of inflammation.
- Increase permeability of the microvasculature: Causes outpouring of protein rich fluid in the extravascular tissues.
- Stasis/slowing of circulation: ↑vessel diameter & loss of fluid → concentration of red cells in small vessels → increased viscosity of blood→ slowing of the blood flow (stasis) → blood leukocytes (mainly neutrophil) accumulate along the vascular endothelium.
- Activation of endothelial cells: By chemical mediators.
B) Increased vascular permeability/ vascular leakage: Several mechanisms are responsible for the increased permeability of postcapillary venules, a hallmark of acute inflammation.
- Contraction of endothelial cells: Resulting in opening of interendothelial gaps is the most common mechanism of vascular leakage. It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators.
- Endothelial injury:
- ➤ Resulting in endothelial cell necrosis and detachment.
- ➤ Direct damage to the endothelium is encountered in severe physical injuries, for example, in thermal burns, or is induced by the actions of microbes and microbial toxins that damage endothelial cells.
- ➤ Neutrophils that adhere to the endothelium during inflammation may also injure endothelial cells and thus amplify the reaction.
C) Responses of lymphatic vessels & lymph nodes / Cellular Response
- ➤ In inflammation, lymph flow is increased and helps drain edema flid that accumulates because of increased vascular permeability.
- ➤ In addition to flid, leukocytes and cell debris, as well as microbes, may fid their way into lymph.
- ➤ Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to handle the increased load.
- ➤ The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis).
- ➤ Inflamed lymph nodes are often enlarged because of hyperplasia of the lymphoid follicles & increased numbers of lymphocytes and macrophages.
Cellular events in acute inflammation:
The changes in blood flow and vascular permeability are quickly followed by an influx of leukocytes into the tissue.
A) Leukocyte recruitment to sites of inflammation: The sequence of events in the journey of leukocytes from the lumen to the interstitial tissue is called extravasations. It can be divided into following steps -
(1) In the lumen:
- ➤ Margination: More white cells assume a peripheral position along the endothelial surface.
- ➤ Rolling: Individual and then rows of leukocytes tumble slowly along the endothelium and adhere transiently.
- ➤ Adhesion: Binding of leukocytes with endothelial cells by adhesive molecules.
(2) Migration across the endothelium: (also called transmigration/diapedesis).
(3) Migration in the tissues: Toward a chemotactic stimulus (chemotaxis).
B. Phagocytosis & clearance of the offending agents.
Leukocyte adhesion to endothelium:
The attachment of leukocytes to endothelial cells is mediated by adhesion molecules whose expression is enhanced by cytokines. Two major families of proteins involved in leukocyte adhesion & migration.
❖ Endothelial / leukocyte adhesion molecules: The adhesion receptors involved belong to four molecular families-
- Selectins: L-selectin, E-selectin & P-selectin.
- Integrins: LFA-1, MAC-1, VLA-4.
- Others: Ig (CD-31)
❖ Mechanism of adhesion:
- ➤ Redistribution of adhesion molecules to cell surface: Induced by histamine, thrombin, platele activating factor (PAF) etc.
- ➤ Induction of adhesion molecules on endothelium: Induce synthesis surface expression of molecules-by cytokines IL-1, TNF.
- ➤ Increased avidity of binding of integrins: Occurs by conformational change by chemotactic agents.
Leukocyte migration through endothelium/transmigration / diapedesis: Mechanisms are-
- It occurs along the inter-endothelial junctions. It is an active process.
- Chemokines act on the adherent leukocytes and stimulate the cells to migrate through interendothelial spaces toward the chemical concentration gradient, that is, toward the site of injury or infection.
- Leukocytes insert pseudopods, squeeze & crawl and pierce the basement membrane by secreting collagenase.
- Thus, the leukocytes transmigrate from circulation to the tissue space.
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| Figure: The multistep of leukocyte migration through blood vessels. |
Chemotaxis:
After exiting the circulation, leukocytes move in tissues toward the site of injury by a process, called chemotaxis, which is defined as locomotion along a chemical gradient.
All granulocytes, monocytes & to a lesser extent lymphocytes respond to chemotactic stimuli with varying rates of speed.
❖ Chemotactic substances/chemo attractants:
- Exogenous: Bacterial products
- Endogenous:
- ➤ Cytokines, particularly those of the chemokine family (IL-8)
- ➤ Product of complement, particularly C5a.
- ➤ Leukotriene B4.
❖ Process/mechanism of chemotaxis:
Binding of chemotactic agents to specific receptors on the cell membrane of leukocyte
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Activation of several effector molecules including phospholipase C
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Hydrolysis of phosphatidylinositol-4,5-biphosphate (PIP2) to inositol-1,4,5-triphosphate (IP3) & diacylglycerol (DAG)
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Release of Ca** from intracellular stores & influx of extracellular Ca ++
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Increased Ca* triggers the assembly of contractile elements of leukocytes
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Extension of pseudopod from the leukocyte that pulls the remainder of the cell
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Cell movement (chemotaxis)
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| Figure: -Chemotaxis |
Phagocytosis
Phagocytosis is the process by which leukocytes (mainly neutrophil & macrophage) recognize, engulf and kill or degrade the ingested materials (e.g. bacteria).
Steps of phagocytosis: 1) Recognition & attachment; 2) Engulfment; 3) Killing & Degradation.
1) Recognition & attachment of the particle to be ingested: Phagocytosis is initiated by recognition & attachment of the particle to be ingested with the phagocytic receptors. Phagocytic receptors are-
2) Engulfment:
- ➤ Formation of phagosome: After a particle is bound to phagocyte receptors, extensions of the cytoplasm flow around it & the plasma membrane pinches off to form an intracellular vesicle (phagosome) that encloses the particle.
- ➤ Formation of phagolysosome: The phagosome then fuses with a lysosomal granule & forms phagolysosome.
3) Killing and destruction of the microbes and debris: Killing of microbes is accomplished by reactive oxygen species (ROS), also called reactive oxygen intermediates, and reactive nitrogen species, mainly derived from nitric oxide (NO).
a) Reactive oxygen species (ROS): Are produced by the rapid assembly and activation of a multicomponent oxidase, NADPH oxidase (also called phagocyte oxidase), which oxidizes reduced NADPH and, in the process, reduces oxygen to superoxide anion (O2°).
❖ H2O2-Myeloperoxide-halide system:
- ➤ Conversion of superoxide to H2O, by dismutation: 202+2H+→H2O2
- ➤ H2O, react with halide ion by myeloperoxidase: H2O2+ CI→ HOCI
- ➤ Hypochlorite (HOCI): A potent anti-microbial agent that destroys microbes by halogenation (in which the halide is bound covalently to cellular constituents) or by oxidation of proteins and lipids (lipid peroxidation).
❖ Myeloperoxide deficient system: H2O2 is also converted to hydroxyl radical (OH), another powerful destructive agent.
b) Nitric oxide: There are three different types of NOS: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). iNOS, the type that is involved in microbial killing, is induced when macrophages (and, to a lesser extent, neutrophils) are activated by cytokines (e.g., interferon-y/ IFN- y) or microbial products. In macrophages, NO reacts with superoxide (O2) to generate the highly reactive free radical peroxynitrite (ONOO). These nitrogen-derived free radicals, similar to ROS, attack and damage the lipids, proteins, and nucleic acids of microbes.
c) Degradation of microbes: Lysosomal enzymes destroy phagocytosed materials.
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| Figure: Process of phagocytosis. |
What are the Antioxidants in our body:
Anti-oxidants:
Plasma, tissue flids, and host cells possess antioxidant mechanisms that protect healthy cells from potentially harmful oxygen-derived radicals.
These antioxidants are-
- The enzyme superoxide dismutase, which is found in, or can be activated in, a variety of cell types.
- The enzyme catalase, which detoxifies H2O2.
- Glutathione peroxidase, another powerful H2O2 detoxifiers.
- The copper-containing plasma protein ceruloplasmin.
- The iron-free fraction of plasma transferrin.
Opsonins: - These are the substances which attaching antigens to phagocytes.
Opsonization: -
Opsonization refers to the attachment of antigen molecules to the surface of phagocytes by the help of some special molecules (e.g. immunoglobulins & complement).
Examples:
- ➤ Immunoglobulin G (IgG) antibodies.
- ➤ C3b breakdown product of complement.
- ➤ Certain plasma lectins (e.g. mannose-binding lectin & collectins).
❖ Opsonic phagocytosis:
Most micro-organisms are recognized when they are coated by opsonin which bind to specific receptors on the leukocytes.
❖ Non-opsonic phagocytosis: CR3 receptor of leukocytes binds with certain bacteria by recognizing bacterial lipopolysaccharides, without intervention of opsonin. CR3 also binds with fibronectin & laminin of ECM and thus leads to phagocytosis of tissue debris.
Frustrated phagocytosis:
WBC when cannot phagocytose an antigen, they secrete some granular contents which causes damage to the tissue. This mechanism is called frustrated phagocytosis.
If phagocytic cells encounter materials that cannot be easily ingested, such as immune complexes deposited on immovable flat surfaces (e.g. glomerular basement membrane), the attempt to phagocytose these substances triggers strong leukocyte activation, and lysosomal enzymes are released into the surrounding tissue or lumen. This is called frustrated phagocytosis.
Cells of acute inflammation:
- Neutrophil: Within 6-24 hours.
- Macrophages: After 24 hours to 48 hours.
- Eosinophil: In case of parasitic infection.
- Lymphocyte: In case of viral infection.
Functions of acute inflammatory cells:
Neutrophil:
- ➤ Neutrophil phagocytoses & kills the ingested organism by intracellular killing mechanism that is by formation of phagolysosome.
- ➤ Extracellular release of granules or cytotoxic substances by neutrophil can also occur.
Macrophage:
- ➤ Phagocytosis.
- ➤ Presentation of antigen to helper T-cell (Antigen presenting cell).
- ➤ Production of cytokines:
➡IL-1: activates the CD4+ T cell.
➡TNF: takes part in inflammatory reaction.
Eosinophil:
- ➤ They can phagocytose & kill the microorganisms by intracellular killing mechanism.
- ➤ The parasites mainly worm which cannot be phagocytosed due to larger size are mainly killed by extracellular release of granules.
- ➤ Eosinophil secretes histaminase, which inactivates histamine released by basophil & mast cell.
▶Chronic inflammation where neutrophil is the inflammatory cell:
- Chronic pyogenic osteomyelitis.
- Chronic irritation and damage in lungs by smoking and other irritant stimuli.
NOTE: -In acute viral infection, lymphocyte is the predominant inflammatory cell.
Chemical mediators of inflammation
The mediators of inflammation are the substances that initiate and regulate inflammatory reactions.
Properties of chemical mediators of inflammation:
- Mediators are either secreted by cells or generated from plasma proteins.
- They are produced only in response to various stimuli.
- Most of the chemical mediators are short lived.
- One mediator can stimulate the release of other mediators(s).
Types/classification of chemical mediators of acute inflammation: The most important mediators are
❖ According to chemical nature:
- Vasoactive amines (Histamine & serotonin).
- Lipid products (prostaglandins & leukotrienes).
- Cytokines (including chemokines) and
- Products of complement activation.
❖ According to origin:
- Cell-derived mediators (preformed): They are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g. histamine in mast cell granules).
- Newly synthesized/synthesized de novo: (e.g. Prostaglandins, leukotrienes, cytokines) in response to a stimulus.
The cell types that produce mediators of acute inflammation:
❖ Major cell types:
- ➤Macrophages,
- ➤ Dendritic cells, &
- ➤ Mast cells.
❖ Other cells that produce mediators of acute inflammation:
- ➤ Platelets,
- ➤ Neutrophils,
- ➤ Endothelial cells, &
- ➤ Most epithelia.
❖ Example of chemical mediators of acute inflammation:
Functions of chemical mediators:
Morphological patterns of acute inflammation
Exudate and Transudate
❖ Exudation: The escape of fluid, proteins and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation.
❖ Exudate: An exudate is an inflammatory extra-vascular fluid that has high protein concentration (> 3 gm/dl), contains cellular debris and has a high specific gravity (above 1.020).
Mechanism of formation of inflammatory exudate:
An injurious agent
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Alteration in vascular caliber
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Increase in blood flow
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Structural change in the microvasculature
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Increased vascular permeability
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Escape of fluid, plasma proteins & blood cells from the vascular system into the interstitial tissue or body cavities
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Formation of exudate
❖Types of exudates:
- Fluid exudate &
- Cellular exudate.
❖ Composition of inflammatory exudate:
- ➤ Water and macromolecular solute.
- ➤ Plasma proteins: albumin, globulin, fibrinogen, complements.
- ➤ Cells: WBC and RBC.
❖ Harmful effects of exudate:
- Exudate may acts a good medium for bacterial growth due to presence of high protein content.
- Pain by chemical mediators, e.g. bradykinin.
- An excessive fibrin may lead to adhesion.
Functions/benefits of exudate:
- It dilutes the irritant agent and thus lowers injurious effects.
- It brings natural immune products, chemical mediators, antibodies, anti-microbial agents etc. to the site of inflammation.
- Low pH due to lactic acid formed by neutrophil, inhibit bacterial growth.
- It contains fibrin which has 3 main functions:
- ➤ It forms union between the cut/damaged tissues.
- ➤ Forms barrier against bacterial invasion.
- ➤ It aids phagocytosis.
5. Drugs and antibiotics appear at the site of action from the circulation through the exudates.
6. Nutrition to the greatly increased cells.
Functions of cellular exudate:
- Neutrophils and macrophages ingest foreign particles, bacteria and cell debris.
- Plasma cells secrete immunoglobulins.
- Effector T-cells causes damage either by direct cytotoxic action or by delayed type hypersensitivity.
Transudate:
A transudate is a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity (less than 1.012). It is essentially an ultra-filtrate of blood plasma resulting from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability.
Properties of transudate:
- Caused by increased hydrostatic pressure, not by increased vascular permeability.
- Protein content less than 1 gm/dl, mostly albumin.
- Specific gravity less than 1.012.
- Less cellular content.
- Fibrinogen absent.
- It is non-inflammatory.
Differences between exudates & transudate:
Pus & Abscess
❖ Pus is a purulent inflammatory exudate consisting of leukocytes (mostly neutrophils), the liquefied debris of necrotic cells and oedema fluid.
❖ Composition of pus:
- ➤ Dead & dying leukocytes (mostly neutrophils).
- ➤Parenchymal tissue debris (necrotic tissue).
- ➤ Inflammatory exudates: edema fluid & fibrin.
- ➤ Living or dead organisms.
❖ Mechanism of formation of pus & abscess:
Infection by pyogenic organism
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Tissue necrosis
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Infiltration by neutrophils
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The organisms are killed by leukocytes
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The necrotic materials undergo softening by proteolytic enzymes released by dead leukocytes & necrosed tissue (autolysis)
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Formation of pus and if pus is contained within a cavity it is called an abscess
❖ Abscess:
An abscess is a localized collection of pus caused by suppuration buried in a tissue, an organ, or a confined space.
Cause: They are produced by infection with pyogenic (pus forming) organisms.
Histology:
- ➤ A central region of necrotic white cells & tissue cells.
- ➤There is a zone of preserved neutrophils about this necrotic focus.
- ➤ Outside this region vascular dilation and parenchymal & fibroblastic proliferation occurs.
- ➤ Walling by connective tissue.
❖ Fates of an abscess:
- Spontaneous resolution.
- Healing by fibrosis.
- Spontaneous discharge → may have a discharging sinus.
- If pus remains within abscess & is not drained, it undergoes thickening as watery party is gradually absorbed & becomes a mass and may eventfully become calcified.
- Pyogenic bacteria may spread or disseminate, leading to extension.
Chronic inflammation:
❖ Chronic inflammation is inflammation is a response of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations.
Example: Tuberculosis, rheumatoid arthritis, atherosclerosis etc.
❖ Causes of chronic inflammation:
- Persistent infection by certain microorganisms; e.g. tubercle bacilli, Treponema pallidum etc.
- Hypersensitivity & autoimmunity.
- Prolonged exposure to potentially toxic agents, either exogenous or endogenous.
❖ Morphologic features of chronic inflammation:
- Infiltration with mononuclear cells, which include macrophages, lymphocytes and plasma cells.
- Tissue destruction, induced by the persistent offending agent or by the inflammatory cells.
- Attempts at healing, by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels.
❖ Classification of chronic inflammation:
According to aetiology:
A) Primary chronic inflammation: (Chronic inflammation from the onset / denovo)
1) Persistent infection by certain microorganisms:
➤ With granulomatous inflammation:
- Mycobacterium tuberculosis.
- Mycobacterium leprae.
- Treponema pallidum.
- Certain viruses, fungi & parasites.
➤ Without granulomatous inflammation:
- Helicobacter pylori (chronic gastritis, gastric ulcer & duodenal ulcer).
2) Autoimmunity:
- ➤ Rheumatoid arthritis.
- ➤ Systemic lupus erythematosus (SLE).
- ➤ Hashimoto's thyroiditis.
- ➤ Chronic gastritis of pernicious anaemia.
3) Prolong exposure to potentially toxic or aggressive agents:
- ➤Agrresive action of acid-pepsin of gastric juice in peptic ulcer.
- ➤ Cigarette smoking (causing chronic bronchitis).
- ➤ Atherosclerosis by plasma lipid.
- ➤Talc, suture, & other non-degradable materials.
- ➤ Silica (produce silicosis).
4) Unknown:
- ➤ Sarcoidosis.
- ➤ Crohn's disease.
- ➤ Ulcerative colitis.
B) Acute on chronic inflammation: Chronic inflammation developing from acute inflammation.
- Persistence of acute injurious agent: Persistence of microorganism in acute inflammation; e.g. Abscess.
- Interference in healing process: Chronic suppurative osteomyelitis due to presence sequestrum (dead bone).
- Inadequate / delated drainage:
- ➤ Lung abscess.
- ➤ Ischiorectal abscess.
4. Recurrent bouts of acute inflammation:
- ➤ Chronic pyelonephritis.
- ➤ Chronic cholecystitis.
- ➤ Chronic gout.
❖ According to histology:
A) Specific chronic inflammation: e.g. Granulomatous inflammations
B) Non-specific chronic inflammation: e.g. chronic osteomyelitis.
1) Chronic inflammatory ulcers:
- ➤ Peptic ulcer.
- ➤Ulcerative colitis.
2) Chronic suppurative inflammation:
- ➤Chronic pyelonephritis.
- ➤Chronic osteomyelitis.
- ➤ Chronic abscess.
3) Chronic fibrinous/scrofibrinous/serous inflammation: Following acute inflammation.
4) Chronic catarrhal inflammation: Chronic (allergic) rhinitis.
5) Chronic necrotizing inflammation: Chronic amoebiasis.
Cells of the chronic inflammation
- Macrophage: The dominant cellular player in chronic inflammation.
- Lymphocytes.
- Eosinophils.
- Mast cells.
- Occasionally plasma cells.
❖ Functions of chronic inflammatory cells:
Lymphocyte:
- ➤ Production of cell mediated immunity by cytotoxic T-cell.
- ➤Production of humoral immunity by B-lymphocyte.
- ➤Delayed hypersensitivity reaction.
- Helper T-cells release IL-2 which activates cytotoxic T-cells and y-interferon (IFN-y) which activates macrophages.
Eosinophil:
- ➤They can phagocytose & kill the microorganisms by intracellular killing mechanism.
- ➤The parasites mainly worms which cannot be phagocytosed due to larger size are mainly killed by extracellular release of granules.
- ➤ Eosinophil secretes histaminase, which inactivates histamine released by basophil & mast cell.
Mast cells:
- ➤ Anaphylactic reaction (type-I hypersensitivity), by release of histamine.
- ➤ May produce cytokines that contribute to fibrosis.
Plasma cells:
- ➤ Production of antibodies.
Macrophage:
- ➤ The dominant cells in most chronic inflammatory reactions are macrophages.
- ➤ They comprise the mononuclear phagocyte system (reticuloendothelial system).
- ➤ In inflammatory reactions, monocytes begin to emigrate into extravascular tissues quite early and within 48 hours they constitute their predominant cell type according to distribution (please see below for distribution).
- ➤ Extravasation of monocytes is governed by adhesion molecules and chemotactic factors.
- ➤ They are also responsible for much of the tissue injury in chronic inflammation.
Site of synthesis:
- ➤ Derived from hematopoietic stem cells in the bone marrow in postnatal life.
- ➤ From progenitors in the embryonic yolk sac &
- ➤ Fetal liver during early development.
❖ Distribution of macrophages:
- Circulation: Monocyte.
- Lungs: Alveolar macrophage.
- Liver: Kupffer cell.
- Spleen: Sinus histiocyte.
- Lymph node & lymphoid tissue: Reticular cell (reticuloendothelial / mononuclear phagocyte system),
- Kidney: Mesangial cell.
- Brain & spinal cord (CNS): Microglia.
- Bone: Osteoclast.
- Skin: Langerhans cell.
❖ Half-life:
- ➤ Blood monocytes are about 1 day,
- ➤ Tissue macrophages may be several months or years.
- ➤ Other specialized types of macrophages (e.g. microglia, Kupffer cells & alveolar macrophages) may persist throughout life as a stable population of resident cells.
❖ Functions of macrophage:
- Macrophages (like the other type of phagocytes; e.g. neutrophils) ingest and eliminate microbes and dead tissues.
- Initiate the process of tissue repair and are involved in scar formation and fibrosis.
- Initiation and propagation of inflammatory reactions by secreting inflammatory mediators; e.g. cytokines (TNF, IL-1, chemokines etc.) and eicosanoids.
- They take part in cell-mediated immune responses against many microbes by displaying antigens to T-lymphocytes and respond to signals from T cells.
Macrophage activation: There are two major pathways-
❖ Classical macrophage activation: This pathway is induced by -
- Microbial products (e.g. endotoxin).
- T-cell derived signals, importantly the cytokine IFN-y, in immune responses.
- Foreign substances, e.g. crystals and particulate matter.
❖ Alternative macrophage activation:
- ➤ This pathway is induced by cytokines other than IFN-y, such as IL-4 and IL-13.
- ➤ These macrophages are not actively microbicidal; instead, their principal functions are to terminate inflammation and promote tissue repair.
Differences between macrophage & neutrophil:
Granulomatous inflammation:
Granulomatous inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis.
Or,
Aggregates of epithelioid cells, usually surrounded by lymphocytes, form grossly visible small nodules called granulomas. This pattern of chronic inflammation is called granulomatous inflammation.
Classification of granulomatous inflammation:
❖ Classification according to aetiology / aetiological classification:
1) Bacterial:
- ➤ Mycobacterium tuberculosis & M. bovis (causes tuberculosis).
- ➤ Mycobacterium leprae (causes leprosy).
- ➤ Treponema pallidum (causes syphilis).
- ➤ Chlamydia trachomatis (causes lymphogranuloma venerum).
- ➤ Bartonella henselae (causes cat scratch disease).
- ➤ Brucella (causes brucellosis).
2) Fungal:
- ➤ Rhinosporidium seeberi (causes rhinosporidiosis).
- ➤ Histoplasma capsulatum (causes histoplasmosis).
- ➤ Coccidioides immitis (causes cryptococcosis).
3) Parasitic: Schistosoma haematobium (causes schistosomiasis).
4) Inorganic metals: Berylliosis
5) Foreign bodies:
- ➤ Exogenous: Talc, silica, suture materials etc.
- ➤ Endogenous: Keratin, cholesterol crystals, sodium urate etc.
6) Autoimmune: Wegener's granulomatosis.
7) Unknown: Sarcoidosis.
❖ Best examples of granulomatous inflammation:
- Tuberculosis.
- Leprosy.
- Syphilis (tertiary syphilis - gumma).
- Cat-scratch disease.
- Sarcoidosis.
- Crohn disease.
Granuloma:
Aggregates of epithelioid cells, usually surrounded by lymphocytes, form grossly visible small nodules called granulomas. This pattern of chronic inflammation is called granulomatous inflammation.
❖ Classification causes of granulomas:
Morphological classification:
1) Cascating granuloma: It is seen in soft tubercle of tuberculosis.
2) Non-cascating granuloma: It occurs in-
- ➤ Hard tubercle of tuberculosis.
- ➤ Tuberculoid leprosy.
- ➤ Sarcoidosis.
- ➤ Foreign body granuloma.
- ➤ Schistosomiasis.
- ➤ Crohn's disease.
3) Suppurative granuloma: Associated with pus formation.
- ➤ Cat-scratch disease.
- ➤ Lymphogranuloma venereum.
4) Diffuse granulomatous inflammation: e.g. lepromatous leprosy.
❖ Pathological classification:
1) Foreign body granulomas:
- ➤ Foreign body granulomas are incited by relatively inert foreign bodies in the absence of T cell mediated immune response.
- ➤ Typically, they form when the foreign material; e.g. talc (associated with intravenous drug abuse), sutures or other fibers are large enough to preclude phagocytosis by a single macrophage & do not incite either an inflammatory or an immune response. Epithelioid cells & giant cells are apposed to the surface and encompass the foreign body.
- ➤ The foreign material can usually be identified in the center of the granuloma, particularly if viewed with polarized light in which it appears retractile.
2) Immune granulomas:
- ➤ Immune granulomas are caused by a variety of agents that are capable of inducing a persistent T cell-mediated immune response.
- ➤ This type of immune response produces granulomas usually when the inciting agent is difficult to eradicate, such as a persistent microbe or a self-antigen.
- ➤ Macrophages activate T cells to produce cytokines (e.g. IL-2), which activates other T cells, perpetuating the response, and IFNy, which activates the macrophages. It is not established which macrophage-activating cytokines (IL-4 or IFN-y) transform the cells into epithelioid cells and multinucleate giant cells.
❖ Epithelioid cell:
When activated macrophages develop abundant cytoplasm and begin to resemble epithelial cells, are called epithelioid cells.
Some activated macrophages may fuse, forming multinucleate giant cells.
Aggregates of epithelioid cells surrounded by lymphocytes, form grossly visible small nodules which are called granulomas & this pattern of chronic inflammation are called granulomatous inflammation. It is commonly associated with strong Th1-cell activation and production of cytokines (e.g. IFN-y).
Immunopathogenesis or mechanism of formation of TB granuloma / soft tubercle/immune granuloma:
Causative agent of granuloma (infectious agent or immunological agent)
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Polymorphonuclear cells (neutrophils) come at the site of infection.
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After 24 hours, macrophages come at the site of infection.
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When the inciting agent is poorly degradable or particulate macrophages engulf the foreign material and process and present some of it to appropriate T lymphocytes, causing them to become activated.
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The responding T cells produce cytokines, such as IL-2, which activates other T cells perpetuating the response and IFN-y, which is important irt activating macrophages and transforming them into epithelioid cells & multinucleated giant cells.
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There is also accumulation of lymphocytes, fibroblasts and plasma cell.
- If caseation necrosis occurs (e.g. Tuberculosis) Caseating granuloma (Soft tubercle)
- If caseation necrosis does not occur (e.g. Sarcoidosis): -Non-caseating granuloma (Hard tubercle)
❖ Significance of caseating granuloma:
- If caseaous necrosis present, the diagnosis is most likely tuberculosis.
- Caseaous necrosis (soft tubercle) is present in <10% to total case of tuberculosis.
❖ Morphology / microscopic / histologic features of granuloma or tuberculous granuloma or soft tubercle:
- In the usual hematoxylin and eosin preparations, the activated macrophages in granulomas have pink granular cytoplasm with indistinct cell boundaries and are called epithelioid cells because of their resemblance to epithelia.
- The aggregates of epithelioid macrophages are surrounded by a collar of lymphocytes.
- Older granulomas may have a rim of firoblasts and connective tissue.
- Frequently, but not invariably, multinucleated giant cells 40 to 50 μm in diameter are found in granulomas; these are called Langhans giant cells. They consist of a large mass of cytoplasm and many nuclei, and they derive from the fusion of multiple activated macrophages.
- In granulomas associated with certain infectious organisms (most classically Mycobacterium tuberculosis), a combination of hypoxia and free radical-mediated injury leads to a central zone of necrosis. Grossly, this has a granular, cheesy appearance and is therefore called caseous necrosis. Microscopically, this necrotic material appears as amorphous, structureless, eosinophilic, granular debris, with complete loss of cellular details.
- The granulomas in Crohn disease, sarcoidosis, and foreign body reactions tend to not have necrotic centers and are said to be noncaseating.
- Healing of granulomas is accompanied by firosis that may be extensive in involved organs.
Giant cell
Giant cells: Giant cells are large cells having more than one nucleus.
- ➤ They are also known as multinucleate giant cells.
- ➤ They are formed due to fusion of cytoplasm.
- ➤ They are of different sizes and shapes.
Types of giant cells: There are mainly two types of giant cells:
A) Physiological giant cells:
- Megakaryocytes in bone marrow.
- Osteoclasts in bone.
- Syncytotrophoblast of the placenta.
B) Pathological giant cells:
a) Giant cells formed by fusion of monocytes/macrophages:
- Langhans' giant cell: Tuberculous granuloma.
- Foreign body giant cells: Foreign body granuloma (silica, talc etc.).
- Aschoff giant cells: Rheumatic lesions formed by fusion of histiocytes.
- Osteoclastic giant cell: Giant cell tumor of bone.
b) Malignant giant cells:
1) Reed-Sternberg giant cell: Hodgkin's disease.
2) Tumor giant cells:
- ➤ Giant cell tumor of bone. Anaplastic tumor,
- ➤ Choriocarcinoma &
- ➤Poorly differentiated astrocytomas.
c) Giant cells in virus infection: Multinucleated giant cell in HSV infected cell.
❖ Foreign body giant cell:
They are incited by relatively inert foreign bodies. Typically, they are formed when the foreign material such as talc (associated with intravenous drug abuse), sutures or other fibers are large enough to preclude phagocytosis by a single macrophage & do not incite either an inflammatory or an immune response.
❖Criteria of foreign body giant cell:
- ➤Found in chronic inflammation.
- ➤Formed by fusion of macrophages.
- ➤Nuclei are small and arranged haphazardly.
Systemic effects of inflammation
Systemic effects of inflammation / acute phase response:
The systemic effects of acute inflammation are collectively called acute phase response.
Clinical & pathological changes: The acute phase response consists of several clinical & pathological changes, such as:
1) Fever: Raised body temperature is caused by substances called pyrogens. IL-1 and TNF are responsible for fever.
2) Acute phase proteins: These are the plasma proteins, mostly synthesized in liver, whose plasma concentrations may increase several hundred folds as part of the response to acute inflammatory stimuli. Acute phase proteins are:
- ➤ C-reactive protein (CRP).
- ➤ Fibrinogen.
- ➤ Serum amyloid-A protein (SAA).
3) Leukocytosis: It is a common feature in acute inflammation, especially those induced by bacterial infection. Sometimes leucocyte count may reach extraordinarily high levels of 40,000 - 1,00,000 per mm3. These extreme elevations are referred to as leukaemoid reactions.
4) Tachycardia, raised blood pressure, decreased sweating, rigors, chills, anorexia, somnolence and malaise.
5) Sepsis in severe bacterial infection.
Fever:
Characterized by an elevation of body temperature, usually by 1° to 4°C, is one of the most prominent manifestations of the acute-phase response, especially when inflammation is caused by infection.
Mechanism of fever:
Fever is produced in response to substances called pyrogens that act by stimulating prostaglandin (PG) synthesis in the vascular and perivascular cells of the hypothalamus.
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Bacterial products, such as lipopolysaccharide (LPS; called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens)
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They increase the levels of cyclooxygenases that convert arachidonic acid (AA) into prostaglandins.
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In the hypothalamus the PGs, especially PGE2, stimulate the production of neurotransmitters, which function to reset the temperature set point at a higher level.
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Decrease heat loss by the skin.
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Rise of temperature.
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Fever
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