Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Egypt.
INFLAMMATION BY
Prof. Dr. Mohamed Hamed Mohamed mohamedelariny@yahoo.com +201224067373
2011
INFLAMMATION Definition: It is the immediate local vascular and exudative reaction of living tissue against an injurious agent (irritants). It is the reaction of vascularized living tissues to local injury. The suffix “itis� is usually added to the inflamed organs as tonsil = tonsillitis.
Roles of inflammation: 1-Protection: i-Contain and isolate the injury. ii-Destroy invading organisms and inactive toxins(dilutes, remove or localize).
2-Achieve healing and repair: i-Under ideal conditions the source of the tissue injury is eliminated, the inflammatory response resolves and normal tissue architecture and physiological functions are restored ii- The nature of the acute inflammatory reaction is intense and the affected area is walled-off by the collection of inflammatory cells. This process results in destruction of tissue by products of polymorphonuclear leukocytes and formation of an abscess. iii-Failure to eliminate the pathological insult results in persistence of the inflammatory reaction and spread out in the body. iv-Chronic inflammation often leads to scar formation.
Causes of inflammation: They include A-Endogenous causes: i-immunological reactions (Ag-Ab reaction). ii-some neurological and genetical disorders.
B-Exogenous Causes: I-Non-living irritants: include 1-Physical irritants: as mechanical trauma, cold, heat or radiation. 2-Chemical irritants: as strong or concentrated acids or alkalis. 3-Neutrional irritants: as in vitamin or oxygen deficiencies. II-Living irritants: include 1-Bacteria 2-Viruses 3-Fungi 4-Parasites They produce their effect either through direct irritation or toxin production.
Remember: The body defense mechanism either: i-Local Body defense (local reaction): inflammation. ii-Systemic body reaction: It is help the local one and include -Humoral defense (based upon the production of antibodies). -Cellular systemic defense (leukocytosis). -Fever
The response to injury and infection: The mechanism for triggering the response the body to injury is extremely sensitive. Three major events occur during this response: 1-An increased blood supply to the tissue: It is performed by vasodilation. The inflamed tissue looks like containing greater number of blood vessels. 2-Increased capillary permeability: It is caused by retraction of the endothelial cells. This permits larger molecules than usual to escape from the capillaries, and thus allows the soluble mediators of immunity to reach the site of inflammation.
3-Leukocytes migrate out of the capillaries into the surrounding tissues: In the earliest stages of inflammation, neutrophils are particularly prevalent, but later monocytes and lymphocytes also migrate towards the site of infection.
Cardinal Signs of Acute Inflammation and Its Pathogenesis: 1-Hotness (Calor) 4-Pain (Dolar)
2-Redness (Rubor) 3-Swelling (Tumor or Edema) 5-Loss of Function (Functiolaesa)
1-Redness (Rubor): The inflamed area usually appears red due to a great increase of blood in the inflamed part due to dilation of capillaries and arterioles with opening of all collapsed capillaries. NB: Dilation of capillaries caused by chemical mediator and dilation of arterioles caused by nerve reflex. Triple response of Lewis: Lewis 1927 proved that the dilation of capillaries caused by chemical mediators and the dilation of arterioles caused by axon reflex. It occurs when a blunt instrument (a corner of a ruler) is down firmly across the skin of arm and illustrated the vascular change in the acute inflammation. i-A red line appears rapidly in the site of contact. ii-This red line is surrounded by a bright red-halo (flare) of about 3 cm in diameter. iii-The red line becomes pale due to its swelling (wheal). iv-The swelling increases and finally there is a pale wheal surrounded by a wide red flare. Wheal: it is the swelling which replaced the red line and it is due to dilation of blood capillaries by the action of chemical mediators. Flare: It is the inflamed area around the wheal (appeared after a period) due to dilation of the arterioles, which is mediated by axon reflex (bright halo).
In this experiment, 3 cardinal signs of inflammation are evident *Redness, *Hotness and *Swelling .
Chemical Proof: A comparison of the skin of a normal arm with another arm injected with adrenalin (antihistaminic) before experiment by 10 minutes showed only the flare. This is indicating that the red line and wheal are due to dilation of blood capillaries which is caused by histamine (chemical mediators).
Axon-Reflex Proof: If the nerve supply (sensory nerve ending) is cut 6-10 days before the experiment (allow degenerating the nerve fiber), only red line and wheal are developed and the flare is not appeared. This is indicating that the flare is due to dilation of arterioles which is caused by nerve reflex.
Conclusion: i-Capillaries dilation is mediated by chemical mediators. ii-Dilation of arterioles is mediated by axon reflex. iii-Lymphatics are dilated in attempt to drain the exudate.
2-Hotness (Calor): The inflamed area feels warmer than the adjacent normal area due to: i-Blood from internal organs (warmer) rushes to the inflamed area. ii-High metabolic rate of the inflamed area “as on fire or catching fire".
3-Pain (Dolor): The inflamed area is painful because: i-Pressure on nerve ending by exudate (edema). ii-Liberated chemical mediators from damaging cells e.g. bradykinin sensitizing the nerve endings. iii-Changes in the pH of the exudate (acidic). iv-Changes in the isotonicity of the fluids (hypertonic).
4-Swelling (Edema or Tumor): The inflamed area is swollen due to: i-Accumulation of exudate in the inflamed area (Exudation). ii-Increase the blood inside the blood vessels (Active local hyperemia).
5-Loss of Function (Functiolaesa): It is due to i-Pain. ii-Edema cause mechanical disability. iii- Destruction of tissue. iv-Interference with the activity of specific cells as of glandular organs.
The inflammatory process: It is composed of 4 major components: 1-Plasma Proteins: They leaks to the perivascular space at the site of inflammation (swelling) and include:
i- Albumin and immunoglobulins ii-Zymogens (inactive proteases) which activated and causing the initiation of complement, fibrinolytic, coagulation and kinine system which are responsible for the inflammatory response. iii-Other protein systems are involved.
2-Fixed Tissue Cells: They include:
i-Mast cells. ii-Fibroblasts iii-Endothelium They are very important for initiation and maintaining the inflammatory process through secretion of chemical mediators. They are either the targets of the primary irritant or the most affected by the damage caused to the adjacent cells.
3-Leukocytes and Platelets: They arrive to the site of inflammation by blood. The leukocytes are important to phagocytize and degrade the organisms and debris; meanwhile the platelets do its function within the vascular space through secretion of chemical mediators
Cells participating in inflammation Acute Inflammatory Cells 1-Neutrophils 2-Eosinophils Granulocytes 3-Basophils/ mast cell 4-Lymphocytes (Agranulocytes)
Chronic Inflammatory Cells 1-Macrophages and epithelioid cells 2-Giant Cells 3-Plasma cells
I-Neutrophils (polymorphs, Polys, PMN's, Neuts): Characteristics -High motility due to rapid amoeboid movement. -Respond to a wide variety of chemotaxic compounds. -Phagocytic and bactericidal activities. -Neutrophils are the major cellular defense system against bacteria. -They are a major part of the innate immune system-first line of defense. -Crucial to the entire inflammatory process. -Neutrophils have surface receptors for complement fragment C3b and Fc portion of immunoglobulin. -End cell-don’t divide.
Morphology of neutrophils: - 10-12 Âľm in diameter with a multilobed nucleus. - Contain abundant cytoplasmic granules. 1-Azurophil Granules (primary granules) large, oval and electron dense 2-Specific Granules (secondary granules) smaller, less dense and more numerous. 3-Tertiary granules (gelatinase granules).
Function of Neutrophils in the inflammation: 1-Phagocytosis Ingest, neutralize, and kill/destroy ingested material
Killing mechanisms: a. Production of oxygen free radicals b. Hydrogen peroxide c. Lysosomal enzymes
2-Mediate tissue injury: i-Lysosomal enzymes are released into the extracellular space during phagocytosis causing cell injury and matrix degradation ii-Activated leukocytes release reactive oxygen species and products of arachidonic acid metabolism which can injure tissue and endothelial cells iii-These events underlie many human diseases (e.g. Rheumatoid arthritis)
3-Regulate inflammatory response: Via releasing chemical mediators: i-Leukotrienes ii-Platelet activating factor
II-Eosinophils: Characteristics 1-Numerous at inflammatory sites which result from
-Parasites. -Allergic or Immunologic Disease. -Some fungi and Salt toxicosis. 2-May present in any exudate (1-5% WBC). 3-Phagocytic but less so than neutrophils 4-Present in tissues in contact with environment (Intestine, Skin, Mucous membranes, Lungs) 5-Sensitive to corticosteroid therapy Release from bone marrow Cytokines important for production (IL-3, IL-5 and GM-CSF) 6-Ratio of eosinophils Blood: 1:
bone marrow: 200:
tissue 500
Morphology: -Granules vary in size (dependent upon species), blobbed nucleus in all animals except in rodent (C-shape). -Granules stain with acid dye eosin - hence their name -Slightly larger than neutrophils (12- 14 Âľm in diameter) -Lysosomal granules contain a wide variety of catalytic enzymes similar to those in neutrophils, except they do not contain lysozyme -Antiparasitic proteins present in granules include
i-Major basic protein
ii-Eosinophil cationic protein
Function: i-Work to kill or damage helminthes and other pathogens ii-Cause and assist in hypersensitivity reactions (Type-I hypersensitivities). iii-Regulator of inflammation - particularly to mast cell products iv-Killing helminthes by antibody-dependent cell-mediated cytotoxicity
III-Basophils and Mast Cells: Characteristics: i-Basophils are rare circulating granulocytes ii-Mast cells are found in perivascular sites iii-Both derived from bone marrow. iv-Contain abundant cytoplasmic metachromatic granules.
1-Metachromatic granules stain pink to blue with toluidine blue. 2-Result of high content of sulphated mucopolysaccharides (heparin). v-Granules also contain histamine, proteases, + potent inflammatory mediators vi-Receptors that bind the Fc portion of IgE antibody vii-Major source of histamine - acute inflammation viii-Produce cytokines (TNF-", IL-1,-3,-4,-6-,-8. IFN) ix-Major cellular mediator of Immediate Hypersensitivity Reactions (Type I) x-Don’t die after release of granules. xi-In birds stimulate the gonadotrophic hormone.
Morphology: Mast cells -Round nuclei with abundant cytoplasm filled with granules -Found in connective tissue in perivascular spaces -Contact with environment - (lung, gut, mm, skin)
-2 subtypes 1-Mucosal mast cells: seen in gastrointestinal and respiratory tract 2-Connective tissue mast cells: found in the skin. Basophils: -from blood and multilobed or S-shape nuclei Are recruited to sites in hypersensitivities.
Functions: 1-Intimately involved in acute inflammation Release of histamine smooth muscle contraction and increase vascular permeability. 2-Involved in recruitment of Eosinophils (secrete ECF-A). Cause other cells to secrete eotaxins 3-Generate Cytokines.
IV-Macrophages/Monocytes: Characteristics: Macrophages: i-Derived from circulating blood monocyte of bone marrow origin. ii-Some originate from immature resident mononuclear phagocytes. iii-“Histiocytes� another name for tissue macrophages.
Monocytes: -Do not have a large reserve pool in the bone marrow -Remain longer in circulation, (24-72 hours) -Are functional cells but require activation to become macrophages secrete various chemical mediators. -Monocytes migrate into tissues and then are called macrophages. -Motile - but sluggish -Life span: 30-60 days but can proliferate.
Morphology: -Larger (15-20 Âľm) than neutrophils. -Prominent, usually central nuclei, which may be folded or bean-shaped. -Contain many lysosomes and have cytoplasmic extensions.
Function: 1-Phagocytosis: i-Antimicrobial and phagocytic (Oxygen radicals) cell. ii-Recruit other leukocytes (secrete several chemokines and cytokines) iii-Stimulate or modulate other cell activity (vascular effects)
2-Secretory function: Macrophages are capable of the production of large number of proinflammatory, procoagulatory and immune regulatory products.
3-Help in repair: i-Clean up or phagocytize necrotic debris in the wound. ii-Simulate the growth of new local vessels (secret growth factors) iii-Induce fibroblasts to migrate, divide and produce collagen. iv-Induce systemic effects.
4-Regulation of granulocyte and monocyte pools: During the inflammatory response or tissue injury, there is increased production of granulocyte and monocytes in the bone morrow.
The increased production is controlled by hormonal-like factors secreted by macrophages at the site of tissue injury and via blood reach to the bone marrow stimulating the stem cell to divided and differentiates to mature effectors cells.
NB: These substances known as some of these factors are: i-M-CSF: ii-G-CSF: iii-GM-CSF:
(macrophage colony stimulating factor). (granulocyte colony stimulating factor). (granulocyte-macrophage colony stimulating factor). tumor cell growth: via production of TNF.
5- Modulation of 6-Source of multinucleated giant and epithelioid cells
Types of giant cells: 1-Inflammatory giant cells. 2-Tumor giant cells. 3-Specific giant cells.
1-Inflammatory Giant cells:
These types of cells are produced by fusion of several macrophages together to phagocytize largest particles and they include:
A-Langhan’s giant cells: They have many nuclei form wreath at the periphery i.e. arranged around the periphery of the cytoplasm in the form of horse-shoe shape. They usually observed in TB, Actinomycosis and Actinobacillosis.
B-Foreign body giant cells: They have numerous nuclei (50-100) of the same size and shape and distributed haphazardly in the cytoplasm (in the center, at one or both poles). They observed in the presence of foreign material in the tissues as in the cases of silicosis or presence of splinters or thorns or cat gut.
C-Touton giant cells: The cells are two-toned (the nuclei arranged peripherally around central eosinophilic cytoplasm with a rim of foamy cytoplasm peripheral to the nuclei). NB: The Nuclei arranged as Langhan’s giant cells and they show in areas containing lipids.
2-Tumor Giant cells: The nuclei are relatively few about 8 and of variable size and shape (produced by nuclear division without cytoplasm division). They observed in malignant neoplasms of CT.
3-Specific giant cells: They are pathognomonic for some specific diseases as. i-Aschoff cells of rheumatic fever in the heart. ii-Warthin-Finkeldy giant cells in measles. iii-Spermatid giant cells in testicular degeneration.
NB: Dendritic cells:
Dendritic cells: i-Langerhans cells of epidermis. ii-Follicular cells of nodal and splenic follicles. iii-Interdigitating dendritic cells (in the T-lymphocyte areas of lymph node and spleen). The relatedness of dendritic cells to other mononuclear phagocytes is based on their ability to function as potent antigen–presenting cells but they are relatively poor at phagocytosis
V-Lymphocytes and Plasma Cells: Characteristics: i-Principally involved in immune reactions -Immediate antibody response. -Delayed cellular hypersensitivity responses. ii-Less motile than neutrophils and monocytes and non-phagocytic. Plasma cells produce and release antibody (originate from B cells). -Produced by lymphoid organs. -Migrate to lymphoid tissue (spleen, lymph node). -Recirculate. Morphology: Heterogeneous in size (8-10 Âľm) and morphology
There are 2 types (T cells and B cells)
T-Lymphocytes: T-cells differentiate in the thymus into 4 subsist 2 regulators T- helper T- suppressor 2 effectors T- cytotoxic T- delayed hypersensitivity i-CD4 helper T cells: divided into Th1: regulate the cellular immunity through interleukins and ÎłINF. Th2: stimulate the B cells to differentiate to plasma cells
ii-CD8: It either T-cytotoxic: cytotoxic for tumor and infected cells with living organisms. T-suppressor: suppress the activated T and B cells.
iii-Td for delayed hypersensitivity
Functions of T cells: i-T- cell don't respond to free Ag but the Ag must be presented by APCs in context with MHC molecules and these MHC molecules must be recognized as self molecule by T-cells before the T-cell recognize the Ag. This dual recognition of Ag Only in context with MHC is known as MHC restriction. ii-T-cells are responsible for cellular immunity or cell-mediated immunity as immune response without Ab involvement.
B-lymphocytes: Functions of B lymphocytes: i-The mature B-cells has immunoglobulin surface receptors (IgM/IgD), they act as receptors for Ag (MHC-II and complement). ii-Some cells differentiated to plasma cells to produce Ab. iii-Other cells differentiated to memory cells that can survive for months without further antigenic stimulation and on re-exposure to the same Ag. Some of these cells are rapidly producing Ab. iv-Plasma cells and other become memory cells.
Natural killer cells (NK): 1-It represent heterogeneous group of cells composed of cells from different lineages and they are defined only by their functional attributes not by their histogenesis. 2-They can kill cells targets with out regard to Ag recognition or MHCI expression therefore they are capable of MHC unrestricted cytotoxicity. 3-Large granular lymphocytes (LGLs) represent a subset of NK cells but not all NK cells are LGLs. 4-These cells: i-Don’t express TCR ii-Don't rearrange the genes associated with TCR. iii-May or may not express CD8.
Functions of NK: i-Recognize changes on virus – infected cells and destroy them by an extra cellular killing produce molecule that damage infected cells membrane destruction. ii-Recognize changes in the cell membranes of cancer cells recognize them. iii-Recent observation suggests that NK cells kill cells express low levels at MHCI molecules. iv-TL12 and TNF stimulate NK cells to release interferon.
VI-Platelets as Inflammatory Cells: NOTE: In addition to their role in hemostasis and coagulation, platelets are very important in inflammation. Primary hemostasis is a part of the inflammatory response.
Products from activated and/or aggregated platelets: -Fibrinogen -Coagulation factors VIII and V -Histamine -Ca++ cations -Complement-cleaving proteases -Growth factors
-Fibronectin -Serotonin -ADP, ATP -Thromboxane A2 -Platelet Activating Factor -P-selectins
Contributions to the inflammatory response: -Release constituents that increase vascular permeability -Release constituents that may provide local amplification -Release cationic inflammatory mediators -Release enzymes that can directly activate C5 -Chemotactic activity for leukocytes Explain that the platelets act as inflammatory cells during inflammation?
PLATELETS AS INFLAMMATORY CELLS i-Lysosomal-like granules constituents ii-Release action is a secretory degranulation iii-Respond to vascular injury iv-Accumulate in vessels adjacent to inflamed areas v- Interact with immune-complexes as well as microorganisms vi-Initiate intravascular inflammation vii-Enzymes can further damage endothelium viii-Adhesion to subendothelium (collagen)