chapter 4 inflammation & wound healing. by dr. uche amaefuna-obasi
TRANSCRIPT
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CHAPTER 4INFLAMMATION & WOUND
HEALING.BY
DR. UCHE AMAEFUNA-OBASI
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•THERE ARE MORE TO LECTURES THAN LECTURE SLIDES
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Definition of Inflammation.• It is a localized physical condition in which part
of the body becomes reddened, swollen, hot, and often painful, especially as a reaction to injury or infection.
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The five classic signs of acute inflammation.• Redness.• Heat.• Swelling.• Pain.• Loss of function.
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Rubor
Calor
Tumor
Dolor
5th (functio laesa)
HISTORICAL
HIGHLIGHTS(Egypt, 3000 BC)
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Effects of Inflammation• Elimination of the cause of cell injury.• Elimination of the necrotic cells.• Paves the way for repair.• May lead to harmful results.
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Nomenclature• -itis (after the name of a tissue) e.g.• Appendix Appendicitis• Dermis Dermatitis• Gallbladder Cholecystitis • Duodenum Duodenitis • Meninges Meningitis, etc.
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Causes:• Microbial infections: bacteria, viruses, fungi,
parasites.• Immunologic: hypersensitivity (contact with
some substances), autoimmune reactions.• Physical agents: trauma, heat, cold, ionizing
radiation, etc. • Chemical agents: acids, alkali, bacterial toxins,
metals, etc.
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• Foreign materials: sutures, dirt, etc• Tissue necrosis: ischemic necrosis.
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The participants• 1. White blood cells and platelets:
Neutrophils, monocytes,lymphocytes, eosinophils,basophils.
• 2. Plasma proteins: Coagulation /fibrinolytic system, kinin system, complement system.
• 3. Endothelial cells and smooth muscles of vessels.
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• 4. Extracellular matrix and stromal cells- Mast cells, fibroblasts, macrophages &
lymphocytes.- Structural fibrous proteins, adhesive
glycoproteins, proteoglycans, basement membrane.
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Components of Inflammation
• Cells..- Fixed cells such as vascular cells.- Migratory cells such as PMNs.
• Mediators..- many chemicals released into the
body.• Immune system..
-Innate.-Acquired.
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Migratory cells• Platelets.• Polymorphonuclear leukocytes.• Macrophage/monocytes.• Lymphocytes.• Eosinophils.• Basophils.• Dendritic cells.
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Platelets.
• Small 2-3mm enucleate cells.
• 150-400,000/ml blood.• Derived from
megakaryocytes.• Vital to haemostasis.• Contain or generate
mediators such as amines and eicosanoids.
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Polymorphonuclear (PMN) cells.
• Most abundant (>50% total ) 2500-7500/ml blood.
• ‘Shock troops’ of the system.• Early involvement in the
response.• Contain many microbiocidal
weapons and enzymes.• Phagocytic.• Short lived.• Crucial to host defence.
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Macrophage/monocytes.
• 100-800 /ml blood. 6-7% total.
• Blood borne monocytes mature to macrophages in tissues.
• Crucial to antigen presentation.
• Secrete many important mediators and enzymes.
• Phagocytic.• Long lived.
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Eosinophils.
• Relatively small population 2.5% total; 50-400/ml blood.
• Specialised for anti-parisitic defence.
• Granules contain enzymes and proteins with micro-biocidal properties.
• Important in asthma and allergies.
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Lymphocytes.
• 1000-4000/ml blood; 30% total cells.
• Specialised for the production of antibodies and immune recognition.
• T- and B - cells.• NK cells.• Homing properties.
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Basophils.
• 1-100/ml blood; 0.5% total cells.
• Circulate in blood and ‘home' into tissues.
• Precursors of mast cells.
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Dendritic cells.
• Macrophage – like cells.• Distributed in blood and
tissues.• Long cytoplasmic
processes.• Intimate contact with
lymphocytes.• Play a key role in early
host defence.
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Fixed cells.
• Vascular endothelial cells.• Liver cells.• Airway cells.• Nervous tissue.• Many other cell types.
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Vascular endothelial cells.
• Have a barrier function but can undergo fenestration.
• Contain adhesion molecules crucial for cell transmigration.
• Can elaborate mediators such as NO, PGI2.
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Liver cells.
• Liver cells especially Kupffer cells are involved in phagocytic functions.
• The liver elaborates ‘acute phase’ proteins.
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Airway cells.
• Airway epithelial, and other, cells play a crucial role in host defence and elaborate mucus and micro-biocidal enzymes.
• Especially important in asthma and allergies.
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Nervous tissue.
• Obviously important in pain transmission.
• Many receptors and enzymes in DRG (dorsal root ganglion) cells and elsewhere are up regulated during inflammation.
• Cranial nerves and CNS structures are also important.
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Many other cells and tissues.
• Inflammation can affect virtually any structure in the body!
• Follows physical trauma, injury or infection.
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Two ‘types’ of inflammation.
• Acute…- short lived.- doesn’t always involve the immune system.- healing usually occurs.- little systemic disease.
• Chronic…- long lived.- often inappropriate.- healing poor or absent.- tends to be the most usual indication for therapy.- often severe systemic effects including bone and cartilage breakdown.
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Acute inflammation• Duration: minutes to days. • Predominance of neutrophils.• Fluid & plasma protein exudation.Chronic inflammation• Duration: days to years. • Predominance of lymphocytes and
macrphages. • Vascular proliferation and fibrosis.
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Acute Inflammation• Early response of vascularized tissue toinjury.• Aim of acute inflammation:• Recruitment of neutrophils (1st 3days), and
monocytes (after 3days) to clear the cause of injury and remove necrotic cells.
• Deliver plasma proteins: antibodies, complement, others.
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The two components of acute inflammation.
Vascular changes• Vasodilatation. • Increased vascular permeability. • Stasis.Cellular events• Emigration of cells from micro vessels. • Accumulation at sites of injury.The process is orchestrated by release of chemical
mediators.
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Cellular Events
• Margination, rolling and adhesion.• Transmigration between endothelial cells.• Migration in the interstitium toward the site of
stimulus.• Phagocytosis and degranulation.• Release of leukocyte products.
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The healing response.
• The ultimate objective of inflammation, it involves…- angiogenesis.- remodelling of damaged tissues.- the correct hormonal and cytokine milieu.- sometimes migrating cells also play a role (e.g. platelets).
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What goes on at the tissue level in inflammation?
• Vascular ‘fenestration’ and plasma leakage.• Cellular degranulation.• Leukocyte migration.• Liver acute phase response.
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Vascular changes.
• Post-capillary venules most important site.
• Extravasation of plasma proteins e.g. immunoglobulins.
• Role of PMNs in this process.
• Promotes access of protective proteins to invading organisms.
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Cellular degranulation.
• Principally by PMN (PolyMorphonuclear Neutrophil), monocytes, eosinophils, platelets and mast cells.
• The latter release enzymes, histamine and eicosanoids.
• Very important in allergic reactions and asthma.
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Leukocyte emigration.
• Dutrochet first reported leukocyte emigration in 1824.
• Addison first induced the phenomenon experimentally in 1843.
• Multi-step paradigm for emigration developed from 1970s-1990s by several groups.
• Leukocyte emigration important in many pathologies (Epstein, 1989).
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Leukocyte emigration.
• Mainly PMN, monocytes and eosinophils.
• Mediated by adhesion molecules.
• Brings cells into contact with microorganisms.
• Crucial to host defence.
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Adhesion molecules.
• L-selectins.• V- CAM & I- CAM.• Integrins.• PECAM.
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Adhesion molecules.
• Reversible interaction with L-selectin responsible for rolling phenomena.
• More stable adhesion mediated through increases in ICAM-1 and VCAM-1.
• Integrins (b1 & b2) mediate a stable adhesion and have important signalling properties.
• Most of these adhesion molecules are up-regulated during inflammation in response to cytokines etc.
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Cellular migration - free flowing.
PMN
Vascular endothelium
Direction of blood flow
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- selectin adhesion.
selectins
!
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- integrin attachment, signalling.
integrins
!
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- shape change.
!
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- pseudopodia formation.
PECAM!
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- extravasation..
!
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- full migration.
!
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Acute phase response.
• A diverse collection of proteins and factors including, protease and other enzyme inhibitors.
• Released in from the liver in response to many forms of inflammatory response.
• Often accompanied by a fall in albumin synthesis.
• Clinically useful marker.
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Causes of chronic inflammation •Persistent injury or infection –Ulcer, tuberculosis •Prolonged exposure to a toxic agent –Pulmonary silicosis (silica in the lung) •Autoimmune disease—self-perpetuating immune reaction that results in tissue damage and inflammation –Rheumatoid arthritis –Systemic lupus erythematosus–Multiple sclerosis