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Inflammation and repair rince
- 1. Inflammation PRESENTED BY DR.RINCE MOHAMMED J.R 1 O.M.F.S,G.D.C KOTTAYAM
- 2. Contents Introduction Definition Cardinal Signs Types of inflammation Acute inflammation – Pathogenesis Chemical mediators of acute inflammation Systemic & laboratory manifestations Exudate Vs Transudate Out comes of Acute Inflammation Chronic inflammation Chronic inflammatory cells Chronic inflammation types Summary and conclusion References
- 3. Introduction Inflammation is the reaction of living tissue to injury or infection. It is a protective vascular connective tissue reaction or response intended to remove injurious stimuli as well as the necrotic cells. Repair-causes the replacement of damaged tissues by regeneration of parenchyma cells or by filling of any residual defect by fibrous scar tissues. (Healing)
- 4. Definition A local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, and pain and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissues. (Websters medical dictionary)
- 5. Sometimes harmful – hypersensitivity reactions,immune diseses. Repair also can cause scarring ,fibrosis that may lead to obstruction of movement. Anti inflammatory drugs - enhance favourable effects of inflammation and controls its harmful sequelae. The nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix “- itis ” e.g pancreatitis meningitis pericarditis arthritis
- 6. Cardinal Signs (Celsus) Rubor- redness due to increased blood flow and vasodilation Calor- or heat due to increase blood flow to the periphery Tumor- swelling from inflammatory edema Dolor-pain from swelling and presence of inflammatory mediators Functio laesa-loss of function due to main and structural necrosis (Virchow 1793)
- 7. : Types of inflammation Acute inflammation – immediate and early response to an injurious agent,short duration usually less than 48 hrs PMN as inflammatory cells Chronic inflammation – longer duration,occurs either after the causative agent of acute inflammation persist for a long time or the stimulus induces chronic inflammation from the beginning Lymhocytes,plasma cells,macrophages –inflammatory cells
- 9. Stimuli for acute inflammation Infections (bacterial, viral, fungal, parasitic) and microbial toxins. Tissue necrosis from any cause, including ischemia (as in a myocardial infarct),trauma, and physical and chemical injury Foreign bodies Dirt, sutures etc Immune reactions (hypersensitivity reactions) are reactions in which the normally protective immune system damages the individual's own tissues.
- 10. Acute inflammation - Pathogenesis 3 major components: 1. Alteration of vascular flow and caliber (vasodilation leads to increased blood flow) 2. Increased Vascular Permeability (Vascular Leakage) 3. Emigration of leukocytes from microcirculation (leukocyte activation leads to elimination of offending agent)
- 13. 1.Changes in Vascular Flow and Caliber Transient constriction of arterioles – immediate vascular response after an injury. Vasodilation Arterioles are involved, and leads to increased blood flow, which is the cause of heat and redness at the site of inflammation. Induced by the action of mediators like histamine and nitric oxide, on vascular smooth muscle.
- 14. Increased permeability of the microvasculature leads to exudation of protein rich fluid into the extravascular space causing swelling (tumor). Stasis of the blood flow -Loss of fluid from the vessels leads to Concentration of red cells resulting in decreased velocity and stasis of the blood flow Leukocytic margination-Neutrophils, accumulate along the vascular endothelium.At the same time endothelial cells are also activated by mediators produced at sites of injury, and express increased levels of adhesion molecules.
- 15. 2.Increased Vascular Permeability 15 Hallmark of acute inflammation as it causes escape of protein rich exudate leading to edema. loss of protein from plasma reduces intravascular osmotic pressure, and increases that of interstitium. So marked outflow of fluid Edema
- 16. Mechanism of vascular leakage Contraction of endothelial cells Resulting in gaps in endothelium. most common mechanism. Elicited by histamine, bradykinin, leukotrienes,and substance P. It is called the immediate transient response because it occurs rapidly and is short-lived.
- 17. Endothelial retraction Structural reorganization of cytoskeleton of endothelial cells Reversibile retraction of intercellular junctions Delayed and prolonged Direct endothelial injury Resulting in endothelial cell necrosis.Eg:Burns,bacterial infections Immediate and sustained reaction.
- 18. Leukocyte-dependent endothelial cell injury Marginating leukocytes may damage the endothelium through activation and release of toxic oxygen radicals and proteolytic enzymes making the vessel leaky. Transcytosis occurs across cellular channels.
- 22. 3.Emigration of leukocytes critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to eliminate the offending agents. Leukocytes leave the vasculature routinely through the following sequence of events: 1. Margination, rolling, and adhesion to endothelium 2. Diapedesis (trans-migration across the endothelium) 3. Migration toward a chemotactic stimuli from the source of tissue injury.
- 23. Margination and Rolling With increased vascular permeability, fluid leaves the vessel causing leukocytes to settle-out of the central flow column and “marginate” along the endothelial surface Endothelial cells and leukocytes have complementary surface adhesion molecules which briefly stick and release causing the leukocyte to roll along the endothelium until it adhire firmly. Rolling and adhesion are mediated by selectins, integrins, Immunoglobulin superfamily adhesion molecules.
- 24. Transmigration (diapedesis) After adhesion leukocytes insert their pseudopods into endothelial cell junction and squeeze through this layer into the extarvascular space.. It cross basement membrane by damaging it locally with Collagenases
- 25. Chemotaxis. Once they have exited the capillary, the leukocytes move through the tissue guided by secreted cytokines, bacterial and cellular debris, and complement fragments (C3a, C5a),leukotrienes (LTB4). Most chemotactic agents signal via G-protein-coupled receptors resulting in intracellular Ca2+ release and activation of small GTPases. This leads to actin/myosin polymerization and filopodia formation directed to the chemical agent.
- 27. Phagocytosis and Degranulation During the next and final stage of the cellular response, the neutrophils and macrophages engulf and degrade the bacteria and cellular debris in a process called phagocytosis.It involves Recognition Engulfment Killing (degradation/digestion)
- 28. Recognition and Binding The phagocytic cells are recognized by chemotactic factors released by bacterial products.It is made easier by opsonisation-coating with natural opsonins like C3b, IgG,lectins. Engulfment After a particle is bound to phagocyte receptors,pseudopods flow around it, and form a vesicle (phagosome) that encloses the particle.It fuses with lysosome-phagolysosome.
- 30. Killing (degradation/digestion) Triggers an oxidative burst which forms Reactive oxygen species.it causes Increased oxygen consumption Glycogenolysis Increased glucose oxidation Formation of superoxide ion Killng by halogenation, or lipid/protein peroxidation
- 34. Chemical mediators Cell derived or plasma derived Have “triggering” stimuli Usually have specific targets Can cause a “cascade” Are short lived
- 35. Cell Derived • Histamine • Serotonin • Eicosanoids • Nitric oxide • Platelet activating factor (paf) • Cytokines • Lysosome constituents • Free radicals • Neuropeptides Plasma Protein Derived • Complement System • Coagulation & Kinin System • Fibrinolytic system
- 36. Histamine Vasoactive “amine” Mast Cells, basophils Vasodilatation, Increase vascular permeability, Endothelial activation Produced in response to physical injury,immune reactions, neuropeptides, C3a & C5a, Cytokines
- 37. Serotonin (5HT, 5-Hydroxy-Tryptamine) Platelets and EnteroChromaffin Cells Also vasodilatation, Increase vascular permeability Released during platelet aggregation
- 39. Cyclooxygenase pathway PGD2,PGE2,PGF2α Causes Vasodilation,capillary permeability, and the pain and fever that accompany inflammation. PGI2(prostacyclin) Produced by prostacyclin synthase in endothelial cell,Vasodilation, Inhibits Platelet aggregation TxA2 Produced by Thromboxane synthase in platelets,Vasoconstriction & stimulates platelets aggregation
- 40. Lipoxygenase Pathway LTB4 Produced by neutrophils & some macrophages Chemotactic agent for neutrophils LTC4,LTD4 & LTE4 Produced by mast cells Vasoconstriction,bronchospasm Lipoxins -Endogenous antagonists of Leukotrienes,Vasodilatation Inhibit chemotaxis,
- 41. Platelet-Activating Factor (PAF) Produced by WBCs & endothelial cells Activate platelets, induces platelet aggregation, Causes Vasoconstriction, Bronchoconstriction It contributes to extravascularization of plasma proteins and so, to edema.
- 42. Nitric oxide Potent vasodilator Produced from the action of nitric oxide synthetase from arginine
- 43. Cytokines/chemokines Cytokines are proteins produced mainly by LYMPHOCYTES and MACROPHAGES. Includes interferon, interleukin, TNF etc. Interferon -Activation of macrophages CHEMOKINES are small proteins which are attractants for PMN.
- 45. Plasma protein derived mediators Complement System Coagulation & Kinin System Fibrinolytic system
- 46. Complement System Consists of Plasma proteins Upon activation different complement proteins(C3b) coat/opsonize microbes for phagocytosis & destruction C3a & C5a cause mast cells to release histamine which inturn causes Vasodilation thus increasing vascular permeability C5a activates lipoxygenase pathway causing release of more inflammatory mediators C5a also helps in leukocyte activation, adhesion & chemotaxis
- 47. Coagulation System Hageman factor/Factor12a A protein synthesized by liver Activated factor12 further activates Kinin System,Clotting System,Fibrinolytic System,Complement System
- 48. Kinin System Ultimately leads to formation of bradykinin Bradykinin causes arteriolar dilation, increases vascular permeability & broncho constriction,also pain.
- 49. Fibrinolytic System Ultimately leads to formation of plasmin Plasmin converts C3 to C3a Converts factor-12 to factor-12a Breaks down fibrin to fibrin degradation products which further increases the vascular permeability
- 50. Morphological patterns of acute inflammation Serous (watery) Fibrinous (hemorrhagic, rich in FIBRIN) Suppurative -Produce pus & purulent exudates- neutrophil, necrotic cells & edema fluid Ulcerative
- 51. Systemic manifestations Fever lymphadenitis Myalgia Malaise shock Laboratory manifestations Leukocytosis Increased ESR Elevated serum acute phase proteins (C-reactive protein, fibrinogen, etc) Hypercoagulability 51 Acute inflammation
- 52. Exudate Its presence implies an increase in the normal permeability of small blood vessels in an area of injury and, therefore, an inflammatory reaction. A filtrate of blood plasma. High protein concentration Contains cellular debris & High specific gravity. Transudate It is an ultrafiltrate of plasma, resulting from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability. A fluid with low protein content Little or no cellular material & Low specific gravity. 52
- 58. Chronic inflammation is the inflammation with prolonged duration usually from weeks to months and sometimes to years in which active inflammation, tissue injury and healing process proceed simultaneously.
- 59. Causes Persisting infection or prolonged exposure to irritants Repeated acute inflamations (otitis, rhinitis) Primary chronic inflammation - low virulence, sterile inflammations (silicosis),viral infections Autoimmune reactions (rheumatoid arthritis, glomerulonephritis, multiple sclerosis)
- 60. Features: Infiltration of mono-nuclear cells like lymphocytes, macrophages and plasma cells. The dominant cellular player in chronic inflammation is the tissue macrophage Destruction of tissue by inflammatory cells. Proliferation of new vessels leading to repair (angiogenesis & fibrosis).
- 61. Chronic inflammatory cells 1) MACROPHAGES: Formed from monocytes. Activated by cytokines,endotoxins,Extra cellular matrix proteins and cause tissue destruction, Neovascularisation, fibrosis. In liver _ Kupffer cells Spleen and lymph nodes _ Sinus histocytes Nervous system _ Microglial cells Lungs _ Alveolar macrophages
- 62. 2) LYMPHOCYTES: Both T- & B-lymphocytes are involved. Activated macrophages release TNF & IL1 and activate lymphocytes which produce different antibodies that cause destruction of antigens at the inflammatory site. 3) EOSINOPHILS: Found in parasitic infections and IgE mediated allergic reactions.
- 63. 4) MAST CELLS: Mast cells are tissue cells which are like basophils in shape. They are present in bone marrow and around blood vessels and do not enter the blood. They release histamines and amino acid metabolites. They cause initial changes in acute inflammation and also cause anaphylactic reactions.
- 64. Types of chronic inflammation 1) Agranulomatous: Granuloma is not formed, Inflammation is characterized by all features of chronic inflammation. Examples: • Chronic viral infections e.g., Hepatitis • Chronic autoimmune diseases e.g., Rheumatoid arthritis and Ulcerative colitis • Chronic chemical intoxication e.g., Chronic alcoholic liver disease • Allergic reactions e.g., Bronchial asthma
- 65. 2) Granulomatous inflammation Characterized by aggregates of activated macrophages that assume a squamous cell like epitheloid appearance. GRANULOMA is defined as aggregates of macrophages formed due response of T-lymphocytes to particular antigens. This has a granular cheesy appearance called as caseous necrosis.
- 66. Bacterial: Tuberculosis, Leprosy,Syphilis,gumma etc Parasitic: Schistosomiasis Fungal: Histoplasma capsulatum, Blastomycosis. Inorganic metals / Dust: Silicosis Foreign bodies: Suture, Vascular graft. Unknown: Sarcodiosis..
- 67. Leukocyte Emigration Adhesion Transmigration Chemotaxis Phagocytosis Injurious agent ↑ Vascular permeability Endothelial contraction Retraction Transcytosis Direct endothelial injury Vasodilation Summary
- 68. conclusion Inflammation is fundamentally a protective response, designed to eliminate the cause of injury (e.g., microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues). Inappropriately triggered or poorly controlled inflammation is the cause of tissue injury in many disorders.
- 69. REFERENCES Robbins and Cotran Pathologic Basis of Disease eighth edition Essential pathology for dental students-Harsh Mohan 3rd edition