inflammation and repair darpan
DESCRIPTION
seminarTRANSCRIPT
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Darpan NenavaPG Ist year
INFLAMMATION AND REPAIR
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History
Introduction
Definition
Types of inflammation
Acute inflammation
Chemical mediators
Chronic inflammation
Healing and repair
CONTENTS
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HISTORICAL PERSPECTIVES
Earliest reference to inflammation in medical literature (1650 BC,
Egypt) in the Smith Papyrus
associated inflammation with heat via symbol of flame
Ancient Greeks used a term which meant inflammation also indicating a
hot thing– The greek term persists in our
word "phlegmon" used to describe internal inflammatory
lesions
Cornelius Celsus(1st century AD Rome):cardinal signs of
inflammation redness, swelling, heat, pain
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Rubor = rednessTumor = swellingCalor = heatDolor = pain
(described by Celsus 1st. Century AD)
Functio laesa = loss of function
(added by R. Virchow 19th Century)
CARDINAL SIGNS OF (ACUTE) INFLAMMATION
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The inflammatory response is closely intertwined with the process of repair.
During repair the injurious tissue is replaced by regeneration, filling of the defect by fibrous tissue(scaring).
INTRODUCTION
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The nomenclature used to describe inflammation in different tissues
employs the tissue name and the suffix “-itis”
e.g
pancreatitis
meningitis
pericarditis
arthritis
INTRODUCTION
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Inflammation- “It is a complex reaction to injurious agents such
as microbes and damaged necrotic cells that consist of vascular response, migration and activation of
leucocytes and systemic reactions.”
OR
“Inflammation is a complex reaction in tissue that consist mainly of responses of blood vessels and
leukocyte”
DEFINITION
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TYPES OF INFLAMMATION
Acute“The immediate and early response to an injurious agents”
Min to Days
1. Characterized by fluid and protein2. PMN’s3. Exudates 4. SG >1.020
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TYPES OF INFLAMMATION
Chronic“Inflammation of prolonged duration, week or months and there is active inflammation tissue destruction, with attempts at repair are proceeding simultaneously” Week to Year
1. Lymphocytes2. Macrophages
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Exudates- 1. Increase vascular permeability2. High protein and cell debris 3. SG > 1.020
Transudate-
4. Normal vascular permeability5. Low protein(mostly albumin)6. SG < 1.020
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Edema-
1. Exudates and transudate 2. In interstitial or in cavity
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Acute inflammation major components
Transient vasoconstriction
Vasodilatation
Increase epithelial permeability
Extravasations of PMN’s
With five cardinal signs of inflammation
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Acute inflammation major components
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Inflammatory response consist of
Vascular reaction
Cellular reaction
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Vascular and cellular changes
Transient vasoconstriction
Vasodilatation
Exudation of protein rich fluidBlood stasis
Margination
Emigration/ Transmigration
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Vascular changesIncrease intravascular hydrostatic pressure
Endothelial gaps in intercellular junction
Fluid exits vessels
Protein exits vessels
Decrease intravascular osmotic pressure
Immediate transient response
Histamine, bradykinin, leucotrienes and substance P
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Vascular changes
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Lewis experiment of triple response
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Red line appears within seconds resulting from vasodilatation of capillaries and venules
Flare is a bright reddish appearance or flush surrounding the red line results from vasodilatation of the adjacent arterioles
Wheal is the swelling or edema of the skin occurring from transudation of fluid in extra vascular space
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Vascular permeability
Vasodilatation- increase blood flow Increased intravascular hydrostatic pressure
Transudate - ultra filtration of blood plasma (contain little protein, very transient just get the process started)
Exudates- Protein rich with PMNsExudates is characteristic of acute inflammation
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Vascular permeability
Intravascular osmotic pressure decreases
Osmotic pressure of interstitial fluid
Outflow of water and ions – edema
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How do endothelial cells become permeable?
Gap due to Endothelial cell contraction
Direct endothelial cell injury (Immediate system response)
Leukocyte- dependent endothelial injury
Increase transcytosis of fluid
Leakage from new vessels
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Gap due to Endothelial cell contraction
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Direct endothelial cell injury (Immediate system response)
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Leukocyte- dependent endothelial injury
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Increase transcytosis of fluid
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Leakage from new vessels
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Cellular events Margination and rollingAdhesion and transmigrationMigration into interstitial tissue
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Selectin
Weak and transient binding Results in rolling
Integrins
Unregulated and activated for increase affinity to CAMS Results in firm adhesion
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Margination Normal flow- RBCs and WBCs flow in the center of the vessels.A cell poor plasma is flowing adjacent to endothelium As blood flows slow WBCs collect along the endothelium
Margination
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Endothelium activation
The underlying stimuli causes release of mediators Activate the endothelium causing selectin and other mediators to be moved quickly to the surface
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Four families of adhesion molecules are involved in leukocyte migration
Selectins
E-selectin (on endothelium)
P-selectin (on endothelium & platelets; is preformed and stored in Weible Palade bodies)
L-selectin (leukocytes)
Ligands for E-and P-Selectins are sialylated glycoproteins (e.g Sialylated Lewis X)
Ligands for L-Selectin are Glycan-bearing molecules such as GlyCam-1, CD34, MadCam-1
Immunoglobulin family
ICAM-1 (intercellular adhesion molecule 1)
VCAM-1 (vascular adhesion molecule 1)
Are expressed on activated endothelium
Ligands are integrins on leukocytes
Integrins ( a + b chain)
Heterodimeric molecules
VLA-4 (b1 integrin) binds to VCAM-1
LFA1 and MAC1 (CD11/CD18) = b2 integrin bind to ICAM
Expressed on leukocytes
Mucin-like glycoproteins
Heparan sulfate (endothelium)
Ligands for CD44 on leukocytes
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Rolling and Adhesion
Selectin transiently binds to the receptors
PMNs bounces or roll along the endothelium
Mediated by integrins ICAM-1 and VCAM-1
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TRANSMIGRATION
• Mediated/assisted by VCAM 1 and ICAM 1(integrins)
• Diapedesis (cell crawling)
• Primary in venules
• Collagenase degrade basement membrane
• Increase permeability
CHEMOTAXIS
• Movements towards the site of injury along a chemical gradient
• Chemotactic factor include
1. Components (20 serum protien)
2. Arachadonic acid metabolites
3. Soluble bacterial products
4. Chemokines 5. Cytokines
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Selectins
Integrins
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Inflammatory Cells
The circulating cells includes- Neutrophils Monocytes Eosinophils Lymphocytes Basophils Platelets
The connective tissue cells are- Mast cells Fibroblast Macrophages Lymphocytes
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Inflammatory Cells
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Phagocytosis and degranulation
Involves three sequential steps
1. Recognition and attachment of the particle to be ingested by leucocytes
2. Phagocytosis (engulf and destroys )
3. Killing/degranulation –oxygen dependent :reactive O2 species in Lysosomes
Oxygen independent- bacterial permeability agents , Lysosomes , lactoferin
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Leukocyte express several receptors that recognize external stimuli and
deliver activating signals
• Mannose Receptor
• Receptors for microbial products-toll like receptors(TLRs)
• G protein-coupled receptors
• Receptors for opsonins
• Receptors for cytokines
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Engulfment
After particle is bound to phagocyte receptors, extension of cytoplasm(pseudopods flows around it)
Plasma membrane pinches off
Forms a vesicle enclosing particle
Phagosome fuses to lysosomal granules
Killing of microbes by lysosomal enzymes in phago Lysosomes
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KILLING AND DEGRANULATION
• Final step
• Microbial killing is accomplished largely by reactive oxygen species(ROS)also called as reactive oxygen intermediates
• And reactive nitrogen species mainly derived from NO
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Chemical mediators in inflammation
Plasma derived-circulating precursors have to be activated Cell derived-sequestered intracellularly synthesized de novo
Most mediators bind to receptors on cell surface but some have direct enzymatic or toxic activity.
Mediators are tightly regulated
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Mediators in acute inflammation
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Plasma derived mediators
Complement
Kinin
Clotting
Fibrinolytic
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Cell derived mediators-Vasoactive amines
Histamine –
1. Found in mast cells , basophils and platelets2. Release in response to stimuli3. Promotes arterioles dilation and venules
endothelial contraction 4. Results in widening of inter-endothelial cell
junction with increase in vascular permeability
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Serotonin/5 hydroxytryptamine-
1. Vaso-active effects similar to histamine but less potent
2. Found in chromaffin cells of GIT, spleen, nervous system, mast cells and platelets
3. Release when platelet aggregation
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Bradykinin-
Potent bio-molecule
1. Vasodilatation
2. Increase vascular permeability
3. Contraction of smooth muscle
4. Short life
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Arachodonic acid/eicosanoids
AA is component of cell membrane phospholipids
AA is activated by some stimuli or mediators like C5a so as to form AA metabolites
Metabolites of AA –short range hormone
Acts locally at the site of generation
Rapidly decay or destroys
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AA metabolites occurs by two major pathways named for the enzymes that initiates the reaction,
lypoxygenase and cycloxygenase
Cycloxygense synthesize-prostaglandin, thromboxane
Lypoxygenase synthesize- leucotrines and lipoxins
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Cycloxygense pathwayCycloxygense is a fatty acid enzyme act on activated AA to form prostaglandin which further activated by enzyme to form3 metabolites-
Prostaglandin-Increase vascular permeability, vasodilatation, inhibit inflammatory cell function
Prostacyclin- Vasodilatation and inhibits platelet aggregation
Thromboxane A2-Vasoconstriction,broncoconstriction, enhances inflammatory cell function Promotes platelet aggregation
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Lipoxygenase pathway
Enzyme lypoxygenase acts an activator to AA to form 5-HETE (hydroperoxy eico-astetraeonic acid) which on further per oxidation forms 2 metabolites
Leucotrines
Lipoxins
Causes Vasoconstriction
Bronchospasm
Increase vascular permeability 56
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AA metabolites
Participate in every aspect of acute inflammation Affective anti-inflammatory agent
E.g..
Aspirin, NSAIDS-cycloxygenase pathway
Steroids acts by inhibiting phospolipase A2
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Lysosomal components
Inflammatory cells contains lysosomal granules which release mediators of inflamation
Granules of neutrophils-2 types azurophil or primary(myeloperoxidase, acid hydrogenasecollagenase, elastase, collagenase)
Specific or secondary (lectoferrin, lysozyme, alkaline phosphatase, collagense) Granules of monocyte-protease, collagenase, elastase, plasminogen activator
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Platelet activating factor
Another phospholipids derived mediator release by phospholipase Induces
Aggregation of plateletsVasoconstrictionBroncho-constriction
100-1000 times more potent then histamine in inducing vasodilatation and vascular permeabilityEnhances leukocyte adhesion, chemo taxis, degranulation and oxydative burst
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Cytokines
Polypeptides that are secreted by cells
Act to regulate cell behavior
Autocrine, paracrine, endocrine effects
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IL-1 /TNFAcute phase reaction-
Increases sleep
Acute phase protein hemodynamic effects
Decreases appetite
Endothelial effects-
Increases Leukocyte adhesion, PG synthesis, pro-coagulants
Decreases anticoagulants
Increases IL-1,IL-8, IL-6 62
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Neuropeptides
Secreted by sensory nerves and various leucocytes
Role in initiation and propagation of inflammatory response
Substance P and neurokinnin A are neuropeptides
Has many biological function like transmission of pain signals, regulation of B.P., increasing vascular permeability
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Different morphological patterns of acute inflammation can be found depending on the cause and extend of injury and site of
inflammation
Serous inflammation
Fibrinous inflammation
Purulent inflammation
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Outcomes of acute inflammation
Resolution
Fibrosis
Abscess formation
Progression to chronic inflammation
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MONONUCLEAR PHAGOCYTES
They are important in acute inflammation, as well as being a key element in chronic inflammation
Like neutrophils, monocytes bear C3b receptors on their surfaces famous role as
scavengers
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CHRONIC INFLAMMATION
Chronic inflammation is an inflammation of prolonged duration(weeks or months) in which inflammation, tissue injury, and attempts at repair co exits, in varying combination.
It may follow acute inflammation or begin as a low grade, smoldering response like on rheumatoid arthritis, atherosclerosis, tuberculosis, pulmonary inflammation
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Causes of chronic inflammation
Persistent infection-that are difficult to eradicate
Immune mediated inflammatory disease
Prolonged exposure to potentially toxic agents, either exogenous or endogenous
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Persistent infection-that are difficult to eradicate
Evoke an immune reaction called delayed –type hypersensitivity
Sometimes occurs as granulomatous reaction
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Immune mediated inflammatory disease
Caused by excessive and inappropriate activation of immune system
Immune reaction develops in individual own tissueResults in autoimmune disease
Ex. Rheumatoid arthritis, multiple sclerosis
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Prolonged exposure to potentially toxic agents, either exogenous or
endogenousExogenous agent: silica results in inflammatory lung disease called silicosis
Endogenous agent: toxic plasma lipid component causes atherosclerosis
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Morphological features of chronic inflammation
1. Infiltration with mononuclear cell-macrophages, lymphocytes, plasma cell
2. Tissue destruction-induced by persistent offending agents or by inflammatory cells
3. Attempts at healing, replacement of damaged tissue
4. (angiogenesis, fibrosis)
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Role of Macrophages
Dominant cell
Component of mononuclear phagocyte system
Scattered in connective tissue or in liver(kuffer cell), spleen and lymph nodes(sinus histeocytes), lungs (alveolar macrophages), CNS(microglea)
Journey from bone marrow to tissue macrophages is regulated by growth and differentiation factors, cytokines, adhesion molecule and cellular interaction
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Begins to appear in acute inflammation and predominant after 48 hrs
Extravasations is same like neutrophils
When monocyte reaches to extra vascular tissue undergo transformation into large phagocytic cell called macrophage
Macrophages are activated by stimuli including microbial product that engage TLRs and other cellular receptors, cytokines(IFN-Y)
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Activated macrophages-
Serves to eliminate injurious agents
Initiate the process of repair
Responsible for much of the tissue injury
Increases level of lysosomal enzyme
ROS and NOS system
Production of cytokines, growth factors, other mediators
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Other cells in chronic inflammation
Lymphocytes-
Mobilized in cell mediated and antibody mediated immune reaction
Antigen stimulated lymphocytes are – T and B cells
Uses same adherent molecule (selectin, integrin, ligands) and chemokines to migrate into inflammatory sites
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Plasma cells-
Develops from activated B lymphocytesProduce antibodies against foreign bodies Present in germinal center of lymph nodes
Eosinophils-
Are abundant in immune reaction mediated by IgE and in parasitic infectionChemokine toxin is important for eosinophilic recruitmentThey also contribute to tissue damage in immune reactions such as allergies
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Mast cells-
Widely distributed in connective tissue Contribute in acute and chronic inflammation Releases mediators such as histamine and prostaglandin
Responses occurs in allergic reaction to food, insect venom, or drugs, anaphylaxis
Mast cells also take part in chronic inflammation As they secrete a plethora of cytokine they have the ability to promote and limit inflammatory reaction
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Systemic effects of inflammation
Fever - Acute phase response increases 1 to 4 degree temp
Produce in response to substance pyrogens that stimulates the prostaglandin synthesis.
Bacterial products stimulate leukocyte to release IL-1, TNF which causes increase in the enzyme cycloxygenase causing conversion of AA into prostaglandin
Stimulate the production of neurotransmitter (cyclic adenosine monophosphate) which in turn regulates the temp 82
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Acute phase protein –
Are Plasma proteins whose concentration increases thousand times in inflammation
C reactive protein, amyloid protein, fibrinogen by hepatocytes
Causes amylodoisis of organ, increases risk of myocardial infarction, atherosclerosis, thrombosis, infarction.
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Leukocyte count -
Usually climbs to 15,000 to 20,000
Bone marrow output is increased
Other systemic effects are –
Increase pulseIncrease blood pressureDecrease sweatingShivering, chillsAnorexiaMalaise sometimes in severe bacterial infection =sepsis
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Repair of the damaged tissue is separated into two processes:
REGENERATION
HEALING
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Definitions:
Regeneration: growth of cells and tissue to replace lost structures.
Healing: is a tissue response – to a wound to inflammatory processes to cell necrosis in an organ incapable of regeneration.
It consists of variable proportion of two distinct processes – regeneration and laying down of fibrous tissue, or scar formation.
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Regeneration V/s Healing
Regeneration requires an intact tissue scaffold.
By contrast healing with scar formation occurs if the extracellular matrix (ECM) framework is damaged causing alteration in tissue architecture.
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Growth factors and cytokines involved in regeneration and wound healing
Epidermal growth factor (EGF) Mitogenic; stimulate keratinocytes migration and granulation tissue formation.
Transforming growth factor alpha (TGF-α) Similar to EGF; replication of hepatocytes.
Hepatocytes growth factor / Scatter factor (HGF) Proliferation of hepatocytes & epithelial / endothelial cells
Vascular endothelial cell growth factor (A,B,C,D) Increased vascular permeability; mitogenic for endothelial cells
Platelet deived growth factor (PDGF-A,B,C,D) Chemotaxis and activation of PMNs, macrophages & fibroblast; Mitogenic for fibroblast endothelial cells; stimulates angiogenesis and wound contracture.
Fibroblast growth factor 1,2 and family (FGF-1,2..) Chemotactic and mitogenic for fibroblast. Angiogenesis, wound contraction & matrix deposition
Transforming growth factor-beta (TGF-β) Keratinocyte migration; Angiogenesis & fibroplasia; regulates integrin expression.
Keratinocyte growth factor (KGF) also called FGF-7 Keratinocyte migration, proliferation & differentiation.
Insulin like growth factor (IGF-1) Synthesis of sulfated protioglycan, collagen.
Tumour necrosis factor (TNF) Activates macrophages, regulate other cytokines.
Interleukins (IL-1 etc.) Synthesis of IL-1 ; Angiogenesis ( IL-8).
Interferon (IFN-α etc.) Inhibit fibroblast proliferation & synthesis of MMPs.
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There are three general modes of signaling-
Autocrine
Paracrine
Endocrine
Autocrine: Cells respond to the molecule that they themselves secrete
Paracrine: One cell type that contains an appropriate receptor responds to the legand produced by the adjacent cell.
Juxtacrine: the signaling molecule is anchored in a cell and bind a receptor in the plasma membrane of another cell.
Endocrine: The signaling molecule, hormone, is synthesized by cells of endocrine organs and acts on target cells distant from there site of synthesis. 89
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Extracellular Matrix & Cell Matrix Interactions
Synthesis & degradation of ECM is involved in morphogenesis, wound healing, chronic fibrotic processes & also in tumors invasion and metastasis
Constituent of ECM-
Fibrous structural proteins e.g. collagen & elastin.
Adhesive glycoproteins.
Proteoglycans and hyaluronic acid.
These macromolecules assemble into two forms Interstitial matrix and Basement membrane
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Interstitial matrix & Basement membrane
IM consists of:-
Fibrillar & nonfibrillar collagen
Elastin
Fibronectin
Proteoglycan
Hyaluronate
Other components
BM consists of:-
Amorphous nonfibrillar collagen (type-4)
Laminin
Heparin sulphate
Proteoglycan
Other glycoproteins
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Repair by Healing, Scar Formation, and Fibrosis
Fibro-proliferative response that “patches” rather than restores a tissue.
Involving a number of processes:
Induction of an inflammatory process with removal of damaged and dead tissue.
Proliferation and migration of parenchymal deposition.
Formation of new blood vessels (angiogenesis) and granulation tissue.
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Repair by Healing, Scar Formation, and Fibrosis
Synthesis of ECM proteins and collagen deposition.
Tissue remodeling
Wound contraction
Acquisition of wound strength
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Inflammatory reaction contain the damage, eliminates the damaging stimulus, removes injured tissue, initiates the deposition of ECM components For tissue that are incapable of regeneration repair is accomplished by connective tissue deposition , producing a scar.
If damages persists, inflammation becomes chronic, tissue damages and repair may occur concurrently. Connective tissue deposition in these condition is usually referred to as FIBROSIS.
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GRANULATION TISSUE
As early as 24 hours fibroblasts and vascular endothelial cell begin proliferating to form a specialized type of tissue that is the hallmarks of healing, called granulation tissue.
Characteristic: the formation of new small blood vessels (angiogenesis) and the proliferation of fibroblasts .
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Angiogenesis
Blood vessels are assembled during embryonic development by vasculogenesis.
Process of blood vessel formation in adults is known as angiogenesis or neo- vascularization, branching and extension of adjacent blood vessels also occur by recruitment of endothelial progenitor cells (EPCs) from bone marrow.
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Angiogenesis from Endothelial Precursor Cells
Angio-blasts proliferate, migrate to peripheral sites, differentiate into endothelial cells that form arteries, veins, lymphatics . Also can generate pericytes and smooth muscle cells of vessel wall (periendothelial cells)
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Angiogenesis from Pre-Existing Vessels
Major steps:Vasodilatation increased permeabilityProteolytic degradation of the BM of the parent vessel ( by metalopoteinase) and disruption of cell-to-cell contact between endothelial cell of vessel (by plasminogen activator).Migration of endothelial cellsProliferation of endothelial cellsMaturation of endothelial cells & remodeling into capillary tube.Recruitment of periendothelial cells & formation of mature vessel.
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ANGIOGENESIS FROM PRE-EXISTING VESSELS
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Scar formationScar formation can be divided in three processes-
Emigration and proliferation of fibroblasts
Deposition of ECM
Tissue remodeling
Fibroblast migration & proliferation
Migration of fibroblast to the site of injury & their subsequent proliferation are triggered by multiple growth factors (TGF , PDGF, EGF, FGF)) and the cytokines (IL-1 & TNF)
Source of these factors are platelets, inflammatory cells (notably macrophages) & activated endothelium.
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ECM deposition & Scar formation
As repair continues proliferating endothelial cells and fibroblasts decreases.
Fibrillar collagen provides the strength in healing wounds.
Ultimately the granulation tissue scaffolding is converted into a scar composed of spindle shaped fibroblasts , dense collagen, fragment of elastic tissue and other ECM components.
As the scar matures the richly vascularized granulation tissue is converted into pale avascular scar.
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Tissue Remodeling
Balance between ECM synthesis and degradation results in remodeling of the connective tissue.Degradation is achieved by matrix metaloproteinases (MMPs).
MMPs includes :-Interstitial collagenases(MMP-1,2 &3)Gelatinases (MMP-2 & 9)stromelysins (MMP- 3,10 & 11)Membrane bound MMP
Activated collagenases are rapidly inhibited by tissue inhibitors of metalloproteinases (TIMPs)
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CUTANEOUS WOUND HEALING
It is divided into three phases-
Inflammation
Granulation tissue formation and re-epithelization
Wound contraction, ECM deposition and remodeling
Wound healing is by primary or secondary intention which is based on the nature of the wound rather than the healing process itself.
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HEALING BY PRIMARY INTENTION
Healing of clean, uninfected surgical incision approximated by surgical suture is reffered as primary union or healing by first intension .
Five phases of healing are –
1.Immediately- capillaries of either side of wound are thrombosedGap is filled with bloodCoagulation and sealing of defectIf clot reaches the surface, it dries to form a crust or scab
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Inflammatory phase 2nd day-Neutrophils appear at margins of incision
Acute inflammatory response on either side of narrow incision space
Swelling, redness, pain at the wound site Epithelial cells at edge of wound undergo mitosis and begin to migrate across the wound
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Proliferative phase
Cellular proliferation involves three processes
Angiogenesis-the wound surface or edge is relatively ischemic and healing cannot effectively proceed until sufficient flow is restored
Also called as neo-vascularisation
Involves formation of new blood vessels by proliferation and migration of endothelial cells from preexisting blood vessels
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Epithelial cell proliferation
The epidermis at the cut ends thickens (mitotic division of basal cells)
Within 48 to 72 hrs epithelial cells from both the margins grows towards the cut end depositing the basement membrane as they moves
They fuses in the midline, beneath the scab, thus producing a continuous but thin epithelial layer
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The neutrophils are largely replaced by macrophages. Granulation tissue progressively invades the incision space.
Collagen at first are vertically oriented, not bridging the incision site
Epithelial cells proliferation thickens
The thickening of epidermal covering layer yields mature epidermal architecture with surface keratinisation
By day 3:-
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By day 5:-
Incisional space is filled with granulation tissue.
Neo-vascularization is maximal.
Collagen begin to bridge the incision.
Epidermis recovers its normal thickness.
Surface keratinization starts
Day 7- interstitial matrix production
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Day 10th
Fibrous Union phase begins on about 10th day
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Remodeling
Day 30
Scar is largely devoid of inflammatory cells and covered by an essentially normal epidermis
3 Months
Devascularisation of tissue, remodeling of collagen by enzyme action , scar is now minimum and merges with surrounding tissues
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Healing by second intention
Edges are separated.
More extensive loss of cells and tissue.
Prone for infection
Regeneration of parenchymal cells can not completely restore the original architecture, and
Hence, abundant granulation tissue grows is referred to as secondary union.
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Early phase
Edges cannot be brought together and defect remains
Base of wound may covered with plasma
Plasma oozes out from the base of the wound
Wound are filled with the blood from the cut ends of capillaries, fibrin threads and platelets
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One week approximately-
Fibrovascular granulation tissue gradually fills the wound space and epithelium grows over its surface
The exudative inflammatory changes and migration of neutrophills subsides
Formation of loose connective tissue by fibroblast
Macrophages come to clear the debrisGranulation tissue grows into the wound from the base
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Second week-
During the second week continuous accumulation of collagen and proliferation of fibroblastLeukocyte infiltration, edema, increased vascularity is greatly reduced Increased collagen deposition within the incision scar and disappearance of vascular channels
Months
Contraction of wound by myofibroblast present in granulation tissue Wound contraction occur in case of shrinkage of granulation tissue that pulls the edges together
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Wound strength
First week:- 10 % of unwounded
Next 4 weeks:- rapid increase
3rd month:- rate slows down & reaches a plateau at about 70 % to 80 % of tensile strength.
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Local & Systemic factors that influence Wound Healing
• Systemic factors:-– Nutrition: Vit-c def.
retards healing– Metabolic state:
Diabetes retards healing.
– Circulatory status: atherosclerosis and venous diseases retards healing
– Hormones: glucocorticoids have anti-inflammatory effects & inhibits collagen synthesis.
• Local factors:-– Infection (most imp.)
retards healing– Mechanical factors:-
early motion retards healing
– Foreign bodies: inhibits healing
– Size location & type of wound: richly vascularised sites heal quickly
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Complications In Cutaneous Wound Healing
Deficient scar formation
Excessive formation of the repair components
The accumulation of excessive amounts of collagen may give to a raised scar known as a hypertrophic scar
If scar tissue grows beyond the boundaries of the original wound and does not regress, it is called a keloid
Exuberant proliferation – Desmoids, or aggressive fibromatoses (interface between benign proliferations and malignant tumors)
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Healing of extraction socket
The removal of tooth initiates the same sequence of inflammation, epithelialization, fibroplasia and remodeling seen in skin wound
Socket heals by secondary intension
After extraction the empty socket consist of cortical bone(radiographic lamina dura )covered by torn periodontal ligament with a rim of oral epithelium
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The socket fills with blood clot which seals the socket from oral environment
During first week inflammatory stage takes placeWBCs enter the socket and clear the microorganism, begins to break down any debris, bony fragments left in the socket
Fibro-plasia begins with ingrowths of fibroblast and capillaries
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The epithelium migrates down the socket wall
Reaches a level at which it contacts the epithelium
Other side of socket
Encounters the bed of granulation tissue under the clot
Osteoclast accumulates over the crestal bone
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During second week
Large amount of granulation tissue fills the socket
Osteoid deposition along the lining of the socket
The process begin during second week continue
Third and forth week of healing
The cortical bone continues to resorb from the crestal bone and walls of the socket
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New trabecular bone is laid down across the socket
As bone fills the socket epithelium moves towards the crest and eventually becomes level with the adjacent crestal gingiva
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Postoperative complication appears 2–3 days afterthe extraction.
The blood clot disintegrates and is dislodged, resulting in delayed healing and necrosis of the bone surface of the socket.
This disturbance is termed fibrinolytic alveolitis and is characterized by an empty socket, fetid breath odor, a bad taste in the mouth, denuded bonewalls, and severe pain that radiates to other areas of the head
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FIBRINOLYTIC ALVEOLITIS (DRY SOCKET)
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Clinical photograph of fibrinolytic alveolitis (drysocket) in the region of the maxillary second molar
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Phases of fracture healingThere are three major phases of fracture healing, two of which can be further sub-divided to make a total of five phases;1. Reactive Phase
i. Fracture and inflammatory phase(immediately)ii. Granulation tissue formation(24-48 hrs)
2. Reparative Phase iii. Cartilage Callus formation(2 -3 weeks)iv. Lamellar bone deposition(external callus removed, intermediate callus is converted into compact bone, internal callus into cancellous bone)
3. Remodeling Phase v. Remodeling to original bone contour(months to year)
HEALING OF FRACTURED BONE
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REFERENCES
• Robbins and Cotrans.Pathologic basis of diseases,9th edition; 43-108
• Mohan Harsh.Essentials of pathology,4th edition;90-109
• Sant Mrinali. A textbook of pathology,1st edition; 86-90
• Peterson.contemporary oral and maxillofacial surgery,4th edition;54-55
• Fragiskos D. Fragiskos. Oral Surgery; 199
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THANK YOU
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