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Transcript of 2 - Inflammation and Repair (Edited Ver)
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 1/149
Inflammation and
Repair Luis P. Cruz, MD, FPSP, FPSO
Asst.Prof VI
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 2/149
INFLAMMATION AND REPAIR
2nd Century AD: cardinal signs Aulus Celsus
18th century: John Hunter, vascular basis
Rudolf Virchow, prior injuryJulius Cohnheim, pmn emigration
19th century : Eli Metchnikoff, phagocytosis
1927 : Thomas Lewis, vascular permeabilityand migration of pmn’s
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 3/149
INFLAMMATION AND REPAIR
DEFINITION:
1. Reaction of vascularized tissues to local injury
2. Series of changes which take place in living tissue ff. injury
3. Local reaction of the body to injury4. Reaction of irritated and damaged tissues which still retain viability
Reaction of a tissue and its microcirculation to a pathogenic insult, characterized by generation of
inflammatory mediators and movement of fluid and leukocytes from the blood vessel into theextravascular tissues
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 4/149
INFLAMMATION AND REPAIR
Inflammation –
Protective response intended to eliminate the initial
cause of cell injury and the necrotic cells and
tissues arising from the injury
Inflammation is intimately associated with the
repair process which includes parenchymal
cell regeneration and scarring
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 5/149
INFLAMMATION AND REPAIR
MAJOR COMPONENTS OF ACUTE INFLAMMATORY RESPONSE
1. Alterations in vascular caliber
2. Structural changes in microvasculature
3. Emigration of leucocytes/ Accumulation in focus of injury
Sequence of Events :
INITIATION : recognition that injury has occurred
AMPLIFICATION: activation of soluble mediators and cellular systems
TERMINATION : Inhibition of the mediators
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 6/149
INFLAMMATION AND REPAIR
CAUSES OF INFLAMMATION
1. Physical Agents: Heat, Trauma, irradiation
2. Chemical Agents: Organic and Inorganic
3. Microbial Infections: most important
4. Hypersensitivity Reactions5. Necrosis of Tissues
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 7/149
Mycobacterium tuberculosis
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 8/149
INFLAMMATION AND REPAIR
CHANGES IN VASCULAR FLOW & CALIBER
1. Transient vasoconstriction andvasodilatation occurs
2. Slowing of the circulation secondary toincreased permeability of the
microvasculature (STASIS)3. Leucoytic margination
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 9/149
CELLULAR AND VASCULARCHANGES
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 12/149
ADHESION AND TRANSMIGRATION
binding of complementary adhesionmolecules on the leucocyte and endothelialsurfaces
• redistribution of adhesion molecules to surface
• induction of adhesion molecules on endothelium
• chemotaxis : locomotion oriented along a
chemical gradient
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 13/149
INCREASED VASCULAR PERMEABILITY
MECHANISMS
• endothelial cell contraction, leading to formationof widened intercellular junctions and gaps
• cytoskeletal and junctional reorganization• direct endothelial injury, resulting in endothelial
cell necrosis and detachment
• leukocyte-mediated injury
• leakage from regenerating capillaries
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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CELLULAR EVENTS
LEUCOCYTE EXTRAVASATION ANDPHAGOCYTOSIS
1.
Margination, rolling and adhesion2. Transmigration across the
endothelium (diapedesis)
3. Migration in interstitial tissuestoward a chemotactic stimulus
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 19/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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ADHESION AND TRANSMIGRATION
BINDING OF COMPLEMENTARY ADHESION MOLECULESON THE LEUKOCYTE AND ENDOTHELIAL SURFACES
• redistribution of adhesion molecules to surface
• induction of adhesion molecules on endothelium
CHEMOTAXIS
• locomotion oriented along a chemical gradient
–
exogenous : bacterial products – endogenous :
– complement system (C5a)
– cytokines
– lipo-oxygenase pathway
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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Selectins bind selected sugars
Selected + Lectins (sugars) = Selectins
Some selectins are present on endothelial cells (E-Selectin)
Some selectins are present on leukocytes (L-Selectin) Some selectins are present on platelets (P-Selectin)
Weak & transient binding
Results in rolling
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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Rolling
Selectins transiently bind to receptors
PMNs bounce or roll along
Rolling
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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7/31/2019 2 - Inflammation and Repair (Edited Ver)
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Adhesion
Mediated by integrins ICAM-1 and VCAM-1
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 28/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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Transmigration
Mediated/assisted by PECAM-1 & ICAM-1(Integrins)
Diapedesis (cells crawling)
Primary in venules
Collagenases degrade BM Permeability
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 30/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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LEUKOCYTE ACTIVATION
production of arachidonic acid metabolites
degranulation and secretion of lysozyme
modulation of leukocyte activation molecules
PRIMING: increased rate and extent of leukocyte activation by exposure to amediator
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 32/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 33/149
Arachidonic acid metabolites
Metabolites of AA - short-range hormones
AA metabolites act locally at site of generation Rapidly decay or are destroyed
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 34/149
Arachidonic Acid
AA is released from the cell membrane by
phospholipases which have themselves been
activated by various stimuli and/or
inflammatory mediators
AA metabolism occurs via two major
pathways named for the enzymes that initiate
the reactions; lipoxygenase andcyclooxygenase
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 35/149
PGG2
PGH2
PGI2
Prostacyclin
TXA2
Thromboxane
PGD2 ; PGE2
PGF2
Vasodilatation
Inhibits Platelet Aggregation
Vasoconstriction
Promotes Platelet Aggregation
Vasodilatation
Edema
PGI2
TXA2
Arachidonic Acid Pathways
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 36/149
Arachidonic Acid Pathways
Lipoxygenase
5-HETE
Chemotaxis
5-HPETE
Leukotriene generation
Leukotrienes
Vasoconstriciton
Bronchospasm
Increased vascular
permeability
Cyclooxygenase Prostaglandins
Vasodilatation
Increased vascularpermeability
Prostacyclin
Vasodilatation
Inhibits platlelet aggregation
Thromboxane A2
Vasoconstriction
Promotes platlelet aggregation
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 37/149
Inflammation and
Repair Luis P. Cruz, MD, FPSP, FPSO
Asst.Prof VI
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 38/149
INFLAMMATION AND REPAIR
2nd Century AD: cardinal signs Aulus Celsus
18th century: John Hunter, vascular basis
Rudolf Virchow, prior injury
Julius Cohnheim, pmn emigration
19th century : Eli Metchnikoff, phagocytosis
1927 : Thomas Lewis, vascular permeabilityand migration of pmn’s
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 39/149
INFLAMMATION AND REPAIR
DEFINITION:
1. Reaction of vascularized tissues to local injury
2. Series of changes which take place in living tissue ff. injury
3. Local reaction of the body to injury4. Reaction of irritated and damaged tissues which still retain viability
Reaction of a tissue and its microcirculation to a pathogenic insult, characterized by generation of
inflammatory mediators and movement of fluid and leukocytes from the blood vessel into theextravascular tissues
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 40/149
INFLAMMATION AND REPAIR
Inflammation –
Protective response intended to eliminate the initial
cause of cell injury and the necrotic cells and
tissues arising from the injury
Inflammation is intimately associated with the
repair process which includes parenchymal
cell regeneration and scarring
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 41/149
INFLAMMATION AND REPAIR
MAJOR COMPONENTS OF ACUTE INFLAMMATORY RESPONSE
1. Alterations in vascular caliber
2. Structural changes in microvasculature
3. Emigration of leucocytes/ Accumulation in focus of injury
Sequence of Events :
INITIATION : recognition that injury has occurred
AMPLIFICATION: activation of soluble mediators and cellular systems
TERMINATION : Inhibition of the mediators
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 42/149
INFLAMMATION AND REPAIR
CAUSES OF INFLAMMATION
1. Physical Agents: Heat, Trauma, irradiation
2. Chemical Agents: Organic and Inorganic
3. Microbial Infections: most important
4. Hypersensitivity Reactions
5. Necrosis of Tissues
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 43/149
Mycobacterium tuberculosis
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 44/149
INFLAMMATION AND REPAIR
CHANGES IN VASCULAR FLOW & CALIBER
1. Transient vasoconstriction andvasodilatation occurs
2. Slowing of the circulation secondary toincreased permeability of themicrovasculature (STASIS)
3. Leucoytic margination
CELLULAR AND VASCULAR
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 45/149
CELLULAR AND VASCULARCHANGES
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 46/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 47/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 48/149
ADHESION AND TRANSMIGRATION
binding of complementary adhesionmolecules on the leucocyte and endothelialsurfaces
• redistribution of adhesion molecules to surface• induction of adhesion molecules on endothelium
• chemotaxis : locomotion oriented along achemical gradient
INCREASED VASCULAR PERMEABILITY
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 49/149
INCREASED VASCULAR PERMEABILITY
MECHANISMS
• endothelial cell contraction, leading to formationof widened intercellular junctions and gaps
• cytoskeletal and junctional reorganization• direct endothelial injury, resulting in endothelial
cell necrosis and detachment
• leukocyte-mediated injury
• leakage from regenerating capillaries
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 50/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 51/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 52/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 53/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 54/149
CELLULAR EVENTS
LEUCOCYTE EXTRAVASATION ANDPHAGOCYTOSIS
1. Margination, rolling and adhesion
2. Transmigration across theendothelium (diapedesis)
3. Migration in interstitial tissuestoward a chemotactic stimulus
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 55/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 56/149
ADHESION AND TRANSMIGRATION
BINDING OF COMPLEMENTARY ADHESION MOLECULESON THE LEUKOCYTE AND ENDOTHELIAL SURFACES
• redistribution of adhesion molecules to surface
• induction of adhesion molecules on endothelium
CHEMOTAXIS
• locomotion oriented along a chemical gradient
– exogenous : bacterial products
– endogenous :
– complement system (C5a)
– cytokines
– lipo-oxygenase pathway
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 57/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 58/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 59/149
Selectins bind selected sugars
Selected + Lectins (sugars) = Selectins
Some selectins are present on endothelial cells (E-Selectin)
Some selectins are present on leukocytes (L-Selectin)
Some selectins are present on platelets (P-Selectin)
Weak & transient binding
Results in rolling
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 60/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 61/149
Rolling
Selectins transiently bind to receptors
PMNs bounce or roll along Rolling
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 62/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 63/149
Adhesion
Mediated by integrins ICAM-1 and VCAM-1
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 64/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 65/149
Transmigration
Mediated/assisted by PECAM-1 & ICAM-1(Integrins)
Diapedesis (cells crawling) Primary in venules
Collagenases degrade BM Permeability
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 66/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 67/149
LEUKOCYTE ACTIVATION
production of arachidonic acid metabolites
degranulation and secretion of lysozyme
modulation of leukocyte activation molecules
PRIMING: increased rate and extent of leukocyte activation by exposure to amediator
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 68/149
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 69/149
Arachidonic acid metabolites
Metabolites of AA - short-range hormones
AA metabolites act locally at site of generation Rapidly decay or are destroyed
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 70/149
Arachidonic Acid
AA is released from the cell membrane by
phospholipases which have themselves been
activated by various stimuli and/or
inflammatory mediators AA metabolism occurs via two major
pathways named for the enzymes that initiate
the reactions; lipoxygenase andcyclooxygenase
PGG
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 71/149
PGG2
PGH2
PGI2
Prostacyclin
TXA2
Thromboxane
PGD2 ; PGE2
PGF2
Vasodilatation
Inhibits Platelet Aggregation
Vasoconstriction
Promotes Platelet Aggregation
Vasodilatation
Edema
PGI2
TXA2
7/31/2019 2 - Inflammation and Repair (Edited Ver)
http://slidepdf.com/reader/full/2-inflammation-and-repair-edited-ver 72/149
Arachidonic Acid Pathway
Lipoxygenase
5-HETE, 5-HPETE,Leukotrienes
Spasm (Vaso, Broncho)
Cyclooxygenase
Prostaglandins - EDEMA
Prostacyclin vs TXA2 Vasodilatation vs.
Vasoconstriction Platelet aggregation
Inhibits vs. promotes
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Arachidonic Acid Metabolites
Participate in every aspect of acute
inflammation
Effective Anti-inflammatory agents act on AA
pathways
Aspirin and Non-Steroidal Anti-inflammatory
Drugs (NSAID’s) - Cyclooxygenase path
Steroids act, in part, by inhibiting Phospholipase A2
7/31/2019 2 - Inflammation and Repair (Edited Ver)
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AA metabolites (eicosanoids)
Cyclooxygenases synthesize
Prostaglandins
Thromboxanes
Lipoxygenases synthesize
Leukotrienes
Lipoxins
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Platelet-Activating Factor (PAF)
Another phospholipid-derived mediator released by
phospholipases
Induces aggregation of platelets Causes vasoconstriction and bronchoconstriction
100 to 1,000 times more potent than histamine in
inducing vasodilation and vascular permeability
Enhances leukocyte adhesion, chemotaxis,
degranulation and the oxidative burst
It does everything!
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Cytokines
Polypeptides that are secreted by cells
Act to regulate cell behaviors
Autocrine, paracrine or endocrine effects
These “biological response modifiers” are
being actively investigated for therapeutic
use in controlling the inflammatory response.
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1. Macrophages make IL-1 & TNF-
2. T-cells make TNF- (lymphotoxin)
3. Can be autocrine, paracrine, endocrine
4. IL-1, TNF, IL-6 acute phase responses, fever, (appetite,
slow wave sleep, circ. pmn,ACTH,
corticosteroids)5. TNF notable for role in septic shock and maintenance of
body mass (cachexia in cancer from TNF- )
Lymphocyte function
O S O
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MEDIATORS IN INFLAMMATION
VASODILATION - prostaglandins
VASCULAR PERMEABILITY – vasoactive amines; PAF; C3a; C5a;bradykinin; leukotriene
CHEMOTAXIS: C5a; leukotrieneB4; bacterial products
FEVER : interleukin 1; TNF; prostaglandins
PAIN: prostaglandins
TISSUE DAMAGE: neutrophil/macrophage lysozymes; oxygen
metabolites
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MEDIATORS IN INFLAMMATION
Plasma-derived
Circulating precursors
Have to be activated
Cell-derived Sequestered intracellular
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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Plasma Mediator Systems - Interaction
1. Kinin
2. Clotting
3. Complement
4. Fibrinolytic
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Kinin cascade
Leads to formation of bradykinin
Bradykinin causes
Increased vascular permeability
Arteriolar dilatation
Smooth muscle contraction
Bradykinin is short lived (kininases)
Vascular actions similar to histamine
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Complement system
Role in immunity (C5-9 complex)
Membrane Attack Complex (MAC C5-9)
Punches a hole in the membrane
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Complement system
Role in inflammation (c3a and c5a)
Vascular effects
Increase vascular permeability and vasodilation
Similar to histamine
Activates lipoxygenase pathway of arachidonic
acid metabolism (c5a)
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Complement system
Leukocyte activation, adhesion and chemotaxis (c5a)
Phagocytosis
c3b acts as opsonin and promotes phagocytosis by cellsbearing receptors for c3b
I fl t M di t f C l t
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Inflammatory Mediators from Complement
Phagocytosis:
C3b and C3bi are opsonins
Control:
Convertases are destabilized by "decay accelerating factor"
(DAF)
Inability to express DAF causes paroxysmal nocturnal hemoglobinuria
C1 inhibitor (C1INH) deficiency causes hereditary
angioneurotic edema
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V i i
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Vasoactive amines
Histamine
Found in mast cells, basophils and platelets
Released in response to stimuli
Promotes arteriolar dilation and venular endothelialcontraction
results in widening of interendothelial cell junctions withincreased vascular permeability
Serotonin Vasoactive effects similar to histamine
Found in platelets
Released when platelets aggregate
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B d ki i P t t bi l l
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Bradykinin: Potent biomolecule
1. Vasodilatation
2. Increased vascular permeability3. Contraction of smooth muscle
4. Pain on injection
5. Short life, kininase degrades
Factor XII activated by:
1. Plasmin
2. Kallikrein3. Collagen & basement membrane
4. Activated platelets
5. Co-factor = HMWK
Vascular Permeability:
- Bradykinin
- Fibrionopeptides
- Fibrin Split Prod.
- Factor Xa
- Leukotrienes
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LIVER CIRRHOSIS
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LIVER CIRRHOSIS
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MORPHOLOGIC PATTERNS IN ACUTE AND
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CHRONIC INFLAMMATION
BASIC PATTERNS OF INFLAMMATION1. serous inflammation
2. fibrinous inflammation
3. suppurative or purulent inflammation
4. ulceration
FACTORS THAT MODIFY THE INFLAMMATORY RESPONSE
1. nature and intensity of the injury
2.
site and tissue affected3. responsiveness of the host
GRANULOMATOUS INFLAMMATION
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GRANULOMATOUS INFLAMMATION
DEFINITION: Distinctive aggregation of chronic inflammatory reaction in
which the predominant cell type is an activated macrophage(EPITHELOID CELL)
GRANULOMA :
Microscopic aggregation of macrophages transformed intoEPITHELOID CELLS surrounded by a collar of mononuclear cells
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GRANULOMATOUS INFLAMMATION
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GRANULOMATOUS INFLAMMATION
Types of Granuloma1. Foreign body granuloma
2. Immune granuloma
Histologic Features
1. epitheloid cell
2. giant cells (Langhan’s type)
3. inflammatory cells /fibroblasts
4. central caseation necrosis
EPITHELOID CELL
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EPITHELOID CELL
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CLINICO-PATHOLOGIC DIFFERENCES BETWEEN
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ACUTE AND CHRONIC INFLAMMATION
ACUTE CHRONIC
1. Pathologic Features
A. Gross organ larger than normal ...smaller B . Histologiic exudative, polys proliferative, monos
2. Clinical FeaturesA. Onset rapid insiduousB. Duration short long
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Phases of Wound Healing
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Phases of Wound Healing
• Inflammatory Phase
• Proliferative Phase
• Remodelling Phase
Phases of Wound Healing
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Phases of Wound Healing
• Inflammatory Phase (Substrate, Lag, orExudative) - 0 to 4 days
• Proliferative Phase (Collagen, Fibroplasia
or Fibroblastic Stage) - 4 to 42 days• Remodelling Phase (Maturation) - 3 to 6
weeks onwards
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Creation of Hemostasis
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Creation of Hemostasis
• Fibrin = end product of coagulationcascade
– Intrinsic pathway = factor XII activation
– Extrinsic pathway = factor VII activation
• Fibrin = 1o component of provisional matrix
Inflammatory Phase
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Inflammatory Phase
• Migration of inflammatory cells• initially PMN’s (neutrophils) predominate
• gradually replaced by macrophages
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Inflammatory Phase
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Inflammatory Phase
Most important cell in wound healing -Macrophage (monocyte)
Interleukin I (IL-1)
Tumor necrosis factor (TNF-a)
Fibronectin
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Fibronectin
Produced by fibroblasts & epithelial cells
Is a glycoprotein
Facilitates attachment of migrating cells (PMN’s,
monoctyes, fibroblasts & endothelial cells) ontofibrin latticework
Binds and acts as reservoir for various cytokines
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Remodelling Phase
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Remodelling Phase
Accelerated collagen synthesis & degradation(but no net increase in collagen content)
Collagen fibers become more organized
Type III collagen is replaced by Type I collagen
More stable crosslinks are formed
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REPAIR
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FACTORS INFLUENCING REPAIRGROWTH FACTORS
CELL-CELL AND CELL-MATRIX INTERACTIONS EXTRACELLULAR MATRIX
SYNTHESIS ANDCOLLAGENIZATION
REPAIR
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FACTORS MODIFYING THE QUALITY OFTHE INFLAMMATORY-REPARATIVERESPONSE
1. ADEQUACY OF BLOOD SUPPLY
2. NUTRITION
3. PRESENCE OR ABSENCE OF INFECTION
4. HEALTH STATUS
5. INTAKE OF DRUGS , e.g., STEROIDS
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Neutrophils noted at the incision margin
Basal cells at the cut edge begin to exhibit increased mitotic
activity
Epithelial cell migration at the cut edge of the dermis,
depositing basement membrane component
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Continued collagen accumulation and fibroblast proliferation 2nd wk
Diminished leukocyte infiltrates, edema and vascularity
By the end of the 1st month the scar comprises of connective tissuesdevoid of inflammatory cells
TERMINOLOGY
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RESTITUTION : attainment of pre-existing tissue architecture after inflammation RESOLUTION : the inflammatory response has successfully dealt with the injury with little or no damage
ORGANIZATION : inflammatory response causes excessive exudation or tissue death and when local conditions are unfavorable for
removal of debris
REGENERATION : replacement of dead cells by new cells of the same type
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Keloid
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Extend beyond borders of original wound More frequent among blacks
Significant familial predilection
Most common at age 10 to 30 yrs
Rarely subsides, difficult to treat
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