Patho #8 Dr. Najlaa Dawood - Modified
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Inflammation
• Definition
• A dynamic process of chemical and cytological reactions that occur
in response of vascularized tissue to stimuli that cause cell injury.Inflammation results in:
- accumulation of leukocytes, and fluid in extravascular tissue.
- systemic effects.
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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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Inflammation
Nomenclature
• -itis (- after name of tissue) e.g.
• Appendix Appendicitis
• Dermis Dermatitis• Gallbladder Cholecystitis
• Duodenum Duodenitis
• Meninges Meningitis, etc
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Inflammation
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
• Foreign material: sutures, dirt, etc
• Tissue necrosis: ischemic necrosis
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Inflammation
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
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
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Inflammation
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 fibrosis8
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Acute Inflammation
• Early response of vascularized tissue to injury
• Aim of acute inflammation:
• Recruitment of neutrophils (1st 3 days), and monocytes
(after 3 days) 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 microvessels
• Accumulation at sites of injury
The process is orchestrated by release of chemical mediators
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Acute Inflammation
(pneumonia)
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Local Manifestations of Acute
Inflammation
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Vascular Changes
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The five classic signs of acute
inflammation• Heat
• Redness
• Swelling
• Pain
• Loss of function
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The five classic signs of
acute inflammation
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Heat Redness Swelling Pain Loss Of Function.
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Vascular Changes
• Arteriolar dilatation follows transient vasoconstriction
• Increased vascular permeability and stasis:
• Arteriolar vasodilatation → ↑hydrostatic pressure → transudate• Late phase: Leaky vessels → loss of proteins → exudate
• Margination of leukocytes
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Fluid Movement in Microcirculation
in Normal Tissue
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Fluid Movement in Microcirculation
in Inflamed Tissue
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How does inflammation lead to
leakiness of endothelial cells? (1)
• Endothelial cell contraction
• Reversible
• Immediate transient response with short life (15-30
minutes)• Induced by: histamine, bradykinin, leukotriens,
neuropeptide substance P
• Mostly in postcapillary venules
• Endothelial cell retraction
• Reversible
• Starts 4-6 hours after injury and stays for 24 hours
• Induced by: IL-1 and TNF, IFN-g
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Edema in Inflammation
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Edema in Inflammation
TRANSUDATE
• Mechanism: Hydrostaticpressure imbalance across
vascular endothelium
• Fluid of low protein content
(ultrafiltrate of bloodplasma)
• Specific gravity <1.012
EXUDATE
• Mechanism: Alteration innormal permeabiltiy of
small blood vessels inarea of injury
• Fluid of high protein
content (>3g/dl) &increased cellular debris
• Specific gravity >1.020
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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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Neutrophil Margination
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Neutrophil Margination
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Selectins
• Receptors expressed on the surfaces of endothelial cells and leukocytes that bindselected sugars (sialylated oligosaccharides)
• Not expressed on resting endothelial cells,but expressed within 30 minutes of stimulation
• Low affinity binding with a fast-off-rate
• Single chain transmembrane glycoprotein
• Binding to ligand needs Ca• Distribution:• E-selectin (CD62E): endothelial cells
• P-selectin (CD62P): Platelets & endothelial cells
• L-selectin (CD62L): Leukocytes
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Integrins
• Heterodimeric cell surface proteins (a & b chains)
• Binds to ligands present in:
• Extracellular matrix
• Complement system
• Surface of other cell• Cytoplasmic domains bind with cytoskeleton
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Adhesion between leukocytes and
endothelial cells
• Weak adhesion and rolling• Mediated by selectins
• Firm adhesion• Ig superfamily molecules expressed on endothelial cells
such as:• ICAM-1
• VCAM-1
• Integrins expressed on leukocytes:• LFA-1 (CD11a/CD18)
• Mac-1 (CD11b/CD18)
• P150,95 (CD11c/CD18)
• VLA-4
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Upregulation of Selectins
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Cytokine Induction of Adhesion
Molecules
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Chemotactics Increase Affinity of
Integrins to Adhesion Molecules
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Endothelial and Leukocyte
Adhesion Molecule Interactions
ENDOTHELIUM WBC FUNCTION
• P & E-selectins Sialyl-Lewis X Rolling
• GlyCAM-1, CD34 L-selectin Rolling
• VCAM-1 VLA-4 Adhesion
• ICAM-1 CD11/CD18 Adhesion,(LFA1, MAC1)
• CD31 (PECAM-1) CD31 Transmigration 33
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General Structure of CAM Families
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The Process of Rolling, Activation
and Firm Adhesion of Leukocytes
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Molecules Mediating Endothelial-
Neutrophil Interaction
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Firm Adhesion via Integrin ICAM
Interactions
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Transmigration of Neutrophils
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Diapedesis
• Transmigration of leukocytes between endothelial cells at
the intercellular junctions
• Facilitated by PECAM-1 (CD31)/PECAM-1 interaction
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The Process of Extravasation of
Leukocytes
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The Process of Extravasation of
Leukocytes
1. Selectins and their carbohydrate counterligands mediate
leukocyte tethering and rolling.
2. Leukocyte integrins their ligands includingimmunoglobulinlike intercellular adhesion molecules,
mediate firm adhesion.
3. Chemokines play a role in firm adhesion by activating
integrins on the leukocyte cell surface.4. The leukocytes are directed by chemoattractant
gradients to migrate across the endothelium, and through
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Sequence of Events Following
injury
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Chemotaxis
• Migration of cells along a chemical gradient
• Chemotactic factors:
• Soluble bacteial products, e.g. N-formyl-methionine termini
• Complement system products, e.g. C5a
• Lipooxygenase pathway of arachidonic acid metabolism, e.g.
LTB4
• Cytokines, e.g. IL-8
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Eff t f Ch t ti
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Effects of Chemotactic
Factors on Endothelial Cells
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Effects of Chemotactic Factors on
Leukocytes
• Stimulate locomotion
• Degranulation of lysosomal enzymes• Production of AA metabolites
• Modulation of the numbers and affinity of leukocyte
adhesion molecules
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Biochemical Events in Leukocyte
Activation
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Phagocytosis
• The process of ingestion and digestion by cells of
solid substances, e.g., other cells, bacteria,
necrotic tissue or foreign material• Steps of phagocytosis:
• Recognition, attachment and binding to cellular receptors
Opsonins
• IgG, C3b, collectins-
• Engulfment
• Fusion of phagocytic vacuoles with lysosomes
• Killing or degradation of ingested material
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Phagocytosis
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Phagocytosis
• Recognition and attachment by receptors:
• Mannose receptors: bind to terminal mannose residues on microbes
cell walls.
• Scavenger receptors: oxidized LDL, and microbes.
• Opsonin receptors (high affinity): IgG, C3b, collectins
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Phagocytosis
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O D d t B t i id l
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Oxygen Dependent Bactericidal
Mechanisms
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Chemical Mediators of
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Chemical Mediators of
Inflammation
• What are their sources?
• Circulating plasma proteins
• Coagulation / fibrinolytic factors
• Complement• Kinins
• Cell derived
• Formed elements normally sequestered in granules:
• Vasoactive amines
• Newly synthesized in response to stimulation
• PGs, LT, O2 species, NO, Cytokines, PAF
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Systemic Mediators of
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Systemic Mediators of
Inflammation
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Chemical Mediators of
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Chemical Mediators of
Inflammation
• General characteristics
• Bind to specific cellular receptors, or have enzymatic
activity
• May stimulate target cells to release secondary mediators
with similar or opposing functions
• May have limited targets, or wide spread activities
• Short lived function
• Short half-life (AA metabolites)
• Inactivated by enzymes (kininase on bradykinin)
• Eliminated (antioxidants on O2 species)
• Inhibited (complement inhibitory proteins)
• If unchecked, cause harm
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Vasoactive Amines
Release of histamine• Physical injury
• Binding of IgE to Fcreceptors
• Anaphylatoxins (C3a, C5a)binding
• Histamine releasing ptn
derived from PMNs• Neuropeptides (substance
P)
• Cytokines (IL-1, IL-8)
Release of serotonin
• Platelets aggregation
• PAF
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Histamine and Serotonin
• Stored in granules in mast cells (histamine), and platelets
(serotonin)
• Cause arteriolar dilatation and increases permeability
(immediate phase reaction)• Induce endothelial cell contraction in venules
• Binds to H1 receptors
• Inactivated by histaminase
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Lysosomal constituents
• Released in:• After cell death
• Leakage upon formation of phagocytic vacuoles
• Frustrated phagocytosis (fixed on flat surfaces)
• After phagocytosis of membranolytic substance, e.g.urate
• Neutral proteases effects:• Elastases, collagenases, and cathepsin
• Cleave C3 and C5 producing C3a & C5a
• Generate bradykinin like peptides• Minimizing the damaging effects of proteases is
accomplished by antiproteases:• Alpha 2 macroglobulin
• Alpha 1 antitrypsin
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Arachidonic Acid Metabolism
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Cell membranePLA2
AA
Cyclooxygenase Lipooxygenase
PGE2
PGF2
PGD2
PGI2
TXA2
PAF
LTB4
LTC4, D4, E4
HETE
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Generation of AA Metabolites
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Products of the cycloxygenase
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Products of the cycloxygenase
pathway of AA metabolism
• TXA2• Vasoconstriction
• Stimulates platelets aggregation
• PGI2• Vasodilatation
• Inhibits platelets aggregation
• PGD2, PGE2, PGF2a
• Vasodilatation• Edema formation
• Pain (PGE2)66
Products of the lipoxygenase
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Products of the lipoxygenase
pathway of AA metabolism
• 5-HETE and LTB4• Chemotactic
• LTC4, LTD4 and LTE4• Vasoconstriction
• Bronchospasm
• Increased vascular permeability
• Lipoxins (LXA4 & LXB4)
• Vasodilatation• Inhibit neutrophil chemotaxis and adhesion
• Stimulate monocyte adhesion67
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Platelet-activating Factor
• Generated from membranes phosphlipids byPhospolipase A2
• Aggregates and degranulates platelets
• Potent vasodilator and bronchoconstrictor
• Increase vascular permeability
• Effects on leukocytes
• Increase adhesion to endothelial cells• Chemotactic
• Degranulation
• Oxygen burst68
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Cytokines
• Hormone-like polypeptides produced by cells, involved incell to cell communication
• Pleiotropic effects
• Secretion is transient
• Redundant• Effects: autocrine, paracrine, endocrine
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TNF & IL-1
• Produced mainly by macrophages
• Secretion stimulated by: bacterial products, immune
complexes, endotoxins, physical injury, other cytokines.
• Effects on endothelial cell, leukocytes, fibroblasts, and
acute phase reactions.
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Major Effects of IL-1 & TNF
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Chemokines• A group of related chemotactic polypeptides, all of which have 4 cysteine
residues• Regulate adhesion, chemotaxis and activation of leukocytes.
• Important for proper targeting of leukocytes to infection sites.
• The largest family consists of CC chemokines, so named because the first2 of the 4 cysteine residues are adjacent to each other.
• Examples of CC chemokines:• CCL2: Monocyte chemoattractant protein 1 (MCP-1)
• CCL3 & CCL4: Macrophage inflammatory protein 1 (MIP-1a & 1b)
• CCL5: RANTES (regulated and normal T-cell expressed and secreted)
• CCL11: Eotaxin
• Examples of CXC chemokines:• CXCL8: IL-8, neutrophil chemotactic
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Nitric Oxide
• Produced from arginine by the effect of nitric oxide synthase(NOS)
• Role in inflammation:
• Vasodilator (smooth muscle relaxant).
• Antagonist of platelets adhesion, aggregation and stimulation.
• Reduces leukocytes adhesion and recruitment.
• Microbiocidal in activated macrophages.
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↓ inflammatory
response
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Nitric Oxide
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Oxygen derived free radicals
At low levels
• Increase:
• Chemokines• Cytokines
• Adhesion molecules
At high levels
• Endothelial damage
& thrombosis• Protease activation
& inhibition of
antiproteases
• Direct damage to
other cells76
Protective mechanisms against free radicals include: transferrin,ceruloplasmin, catalase, superoxide dismutase, and glutathione
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Intrinsic Pathway
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XII XIIa
XI XIa
IX IXa
X Xa
Prothrombin Thrombin
VIIVIIa
TF
Fibrinogen Fibrin
VIIIa
Va
Intrinsic PathwayHMWK
Prekallikerin
Surface
Extrinsic Pathway
Cross linked fibrin
XIIIa
Cl tti / fib i l ti t
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Clotting / fibrinolytic system
• Fibrin clot at site of injury helps in containing the
cause
• Fibrin clot provides a framework for inflammatory cells
• Xa causes increased vascular permeability and
leukocytes emigration
• Thrombin causes leukocytes adhesion, platelets
aggregation, generation of fibrinopeptides, and ischemotactic
• Fibrinopeptides are chemotactic & induce
vasopermeability
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Clotting / fibrinolytic system
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Clotting / fibrinolytic system(continued)
• XIIa also activates the fibrinolytic pathway to
prevent widespread thrombosis.
• Fibrin split products increase vascular permeability
• Plasmin cleaves C3 to form C3a, leading to
dilatation and increased permeability
• Plasmin activates XIIa amplifying the entire
process80
Thrombin as an Inflammatory
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Thrombin as an Inflammatory
Mediator
• Binds to protease-activated receptors (PARs)
expressed on platelets, endothelial cells, sm.
muscles leading to:
• P-selectin mobilization
• Expression of integrin ligands
• Chemokine production
• Prostaglandin production by activating cyclooxygenase-2• Production of PAF
• Production of NO 81
Ki i S t
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Kinin System
• Leads to formation of bradykinin from HMWK
• Effects of bradykinin
• Increased vascular permeability
• Arteriolar dilatation
• Bronchial smooth muscle contraction• Pain
• Short half-life (inactivated by kininases)
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XII Kallikerin
Interaction between the four plama mediator systems
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XIIa
XI XIa
IX IXa
X
Prothrombin Thrombin
Fibrinogen Fibrin
VIIIa
Va
HMWK
Prekallikerin
Surface
Fibrin split products
XII
Prekallikerin
Kallikerin
HMWK Bradykinin
Xa
Plasminogen Plasmin
C3 C3a
Fibrinopeptides
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Complement Activation
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Complement Activation
Pathways
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The Complement System in
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The Complement System in
Inflammation
• C3a and C5a (anaphylatoxins) increased vascular permeability, and cause mast cell to secretehistamine
• C5a activates lipoxygenase pathway of AA• C5a activates leukocytes, increased integrins affinity
• C5a is chemotactic
• C3b and iC3b are opsonins
• Plasmin and proteolytic enzymes split C3 and C5
• Membrane attack complex (C5-9) lyse bacterialmembranes 86
Complement Role in
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p
Inflammation
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Defects in the Complement
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p
System
• Deficiency of C3 → susceptibility to infections.
• Deficiency of C2 and C4 → susceptibility to SLE.
• Deficiency of late components → low MAC → Neisseriainfections.
• ↓ inhibitors of C3 and C5 convertase (↓ DAF) → hemolyticanemia
• ↓C1 inhibitor → angioneurotic edema
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Morphologic Appearance of Acute
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p g pp
Inflammation
• Catarrhal
• Acute inflammation + mucous hypersecretion (e.g. common cold)
• Serous
• Abundant protein-poor fluid with low cellular content, e.g. skin blisters
and body cavities
• Fibrinous:
• Accumulation of thick exudate rich in fibrin, may resolve by fibrinolysis
or organize into thick fibrous tissue (e.g. acute pericarditis)
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Morphologic Appearance of Acute
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p g pp
Inflammation
• Suppurative (purulent):
• Pus: Creamy yellow or blood stained fluid consisting of neutrophils,
microorganisms & tissue debris e.g. acute appendicitis
• Abscess: Focal localized collection of pus• Empyema: Collection of pus within a hollow organ
• Ulcers:
• Defect of the surface lining of an organ or tissue
• Mostly GI tract or skin
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S b t Ab
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Subcutaneous Abscess
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Lung Abscess
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Lung Abscess
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Foot Ulcer
Burn Bister
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Burn Bister
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Outcomes
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of Acute Inflammation
• Complete resolution (back to normal)
• Clearance of injurious stimuli
• Removal of the exudate, fibrin & debris
• Reversal of the changes in the microvasculature• Replacement of lost cells (regeneration)
• Healing
• organization by fibrosis through formation of Granulation tissue.
Why?• Substantial tissue destruction or
• Tissue cannot regenerate or
• Extensive fibrinous exudates
• Abscess formation
• Pro ression to chronic inflammation
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Outcomes
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of Acute Inflammation
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RESOLUTION
FIBROSIS
ABSCESS
FORMATION
REPAIR &
ORGANIZATION
CHRONIC
INFLAMMATION
ACUTE
INFLAMMATION
Usual result
Pyogenic organism
Excessive destruction
Persistence
Role of Lymphatic System
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y yin Inflammation
• The local inflammatory reaction may fail incontaining the injurious agent
• Secondary lines of defense:• Lymphatic system:
• Lymphatic vessels drain offending agent, edema fluid & cellular debris, and may become inflamed (LYMPHANGITIS).
• Lymph nodes may become inflamed (LYMPHADENITIS).
• Secondary lines of defense may contain infection, or may beoverwhelmed resulting in BACTEREMIA.
• MPS:• Phagocytic cells of spleen, liver & BM
• In massive infections, bacterial seeding may occur in distant tissues.
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ChronicInflammation
Chronic Inflammation
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Chronic Inflammation
• Inflammation of prolonged duration (weeks, months, or years) that starts either rapidly or slowly.
• Characterized by an equilibrium of:
• Persistent injurious agent
• Inability of the host to overcome the injurious agent
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Chronic Inflammation
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Chronic Inflammation
• Characteristics:• Chronic inflammatory cell infiltrate
• Lymphocytes
• Plasma cells
• Macrophages
• Tissue destruction
• Repair
• Neovascularization
• Fibrosis
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Chronic and Acute
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Pneumonia
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Chronic Inflammation
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Chronic Inflammation
• Under what circumstances, does it develop?
• Progression from acute inflammation
• Tonsillitis, osteomyelitis, etc.
• Repeated exposure to toxic agent
• Silicosis, asbestosis, hyperlipidemia, etc.
• Viral infections
• Persistent microbial infections
• Mycobacteria, Treponema, Fungi, etc.
• Autoimmune disorders• Rheumatoid arthritis, SLE, systemic lupus, etc.
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Role of Activated Macrophages in
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Chronic Inflammation
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Macrophage-lymphocyte
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interaction
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Histopathology of Granuloma
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Histopathology of Granuloma
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Caseating Granuloma
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Caseating Granuloma
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Morphologic Appearance of
Ch i I fl ti
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Chronic Inflammation
• Ulceration• Ulcer: Local defect or loss of continuity in surface epithelia
• Chronic abscess cavity
• Induration & fibrosis
• Thickening of the wall of a hollow viscus• Caseous necrosis
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Tissue Repair
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The two processes of repair
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p p
• Regeneration• Replacement of damaged cells by similar
parenchymal cells, e.g. liver regeneration
• Requires intact connective tissue scaffold
• Fibrosis• Replacement by connective tissue
• ECM framework is damaged
Healing is a combination of regenerative and fibrotic processes
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The Proliferative Potential of
Different Cell Types
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Different Cell Types• Labile cells (continuously dividing & continuously dying)
• Stem cells divide: self renewal and differentiation
• Examples:
• Skin epidermis
• GIT epithelium
• Bone marrow cells
• Stable cells (quiescent)• Examples:
• Liver
• Kidney,
• Smooth muscles.
• Permanent (nondividing),• Examples:
• Cardiac muscle
• Neurones
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Regulation of Cell
P l ti
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Populations
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Cell-cycle Landmarks
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Stem Cells
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• Self renewal capacity
• Asymmetric replication
• Capacity to develop into multiple lineages
• Extensive proliferative potential
Embryonic stem cells: Pluripotent cells that can give rise to all tissues of the body
Adult stem cells: Restricted differentiation capacity (lineage
specific).
Induced pluripotent stem cells (iPS cells) are derived by introducing
into mature cells genes that are characteristic of ES cells. iPS cells
acquire many characteristics of stem cells.
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Production of induced pluripotent stem cells
(iPS cells)
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(iPS cells).
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Examples of Adult Stem Cells
Locations (2)
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Locations (2)
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Polypeptide Growth Factors
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yp p
• Chemical mediators that affect cell growth by binding to specificreceptors on the cell surface or intracellularly. They are the mostimportant mediators affecting cell growth
• Present in serum or produced locally
• Exert pleiotropic effects; proliferation, cell migration, differentiation,
tissue remodeling• Regulate growth of cells by controlling expression of genes that
regulate cell proliferation (proto-oncogenes)
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Examples of Growth Factors (2)
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• FGFs (fibroblast growth factors)
• Mitogenic for fibroblast & epithelial cells; angiogenesis; chemotacticfor fibroblasts
• Wound healing
• VEGF (vascular endothelial growth factor)
• Angiogenesis
• Increased vascular permeability
• HGF/scatter factor (hepatocyte growth factor)
• Mitogenic to most epithelial cells including hepatocytes
• Promotes scattering and migration of cells
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Transforming Growth Factor Beta
(TGF-b):
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(TGF-b):
• TGF-b binds to 2 receptors (types I &II) withserine/threonine kinase activity
• Receptors phosphorylates cytoplasmic transcription
factors smads
• Smads enter the nucleus and associate with other DNA
binding proteins activating or inhibiting gene transcription
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Transforming Growth Factor Beta
(TGF-b):
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(TGF-b):
• Inhibitor of most epithelial cells andleukocytes. Increases expression of cellcycle inhibitors (Cip/Kip, INK4/ARF)
• Stimulates proliferation of fibroblasts &
smooth muscles• Stimulates fibrosis (fibroblasts chemotaxis,
production of ECM, ↓ proteases, ↑ proteaseinhibitors)
• Strong anti-inflammatory effect
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Examples of Signal Transduction Systems
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Summary of GF, receptors and signaling
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• Growth Factors, Receptors, and Signal Transduction
Polypeptide growth factors act in autocrine, paracrine, orendocrine manner.
• Growth factors are produced transiently in response to an
external stimulus and act by binding to cellular receptors.
Different classes of growth factor receptors include receptors
with intrinsic kinase activity, G protein-coupled receptors andreceptors without intrinsic kinase activity.
• Growth factors such as epidermal growth factor (EGF) and
hepatocyte growth factor (HGF) bind to receptors with
intrinsic kinase activity, triggering a cascade of
phosphorylating events through MAP kinases, which
culminate in transcription factor activation and DNA
replication. 146
Summary of GF, receptors and signaling (2)
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• G protein-coupled receptors produce multiple effects via thecAMP and Ca2+ pathways. Chemokines utilize such receptors.
• Cytokines generally bind to receptors without kinase activity;
such receptors interact with cytoplasmic transcription factors
that move into the nucleus.
• Most growth factors have multiple effects, such as cell
migration, differentiation, stimulation of angiogenesis, and
fibrogenesis, in addition to cell proliferation
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Extracellular MatrixA j t f ll ti id th b kb & t It
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A major component of all tissues, provides the backbone & support. Itregulates growth, movement and differentiation of cells.
• Basement membrane:• Type IV collagen
• Adhesive glycoproteins
• Laminin
• Interstitial matrix:
• Fibrillary and nonfibrillar collagens• Elastin
• Proteoglycans
• Fibronectin
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Components of the Extracellular
Matrix (2)
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Matrix (2)
• Proteoglycans• Form highly hydrated gel like material
• Protein core with many attached long polysaccharides(glycosaminoglycans)
• Act as a reservoir for bFGF• Integral cell membrane proteins (e.g. syndecan)
• Adhesive glycoproteins• Fibronectin
• Domains bind collagen, elastin, proteoglycans, etc.• Bind to integrins via RGD (arginine-glycine-aspartic acid ) domains
• Laminin• Connects cells to collagen and heparan sulfate
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Proteoglycan
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Fibronectin
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Repair by Connective Tissue
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• Severe injury with damage to parenchymal cells and stroma
precludes parenchymal regeneration• Repair occurs by CT
• Components of CT repair:
• Neovascularization (angiogenesis)
• Proliferation of fibroblasts
• Deposition of ECM
• Remodeling
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Angiogenesis
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• From Endothelial precursor cells
• From pre-existing vessels
VEGF effects on endothelial cells :
• ↑ migration
• ↑ proliferation
• ↑ Differentiation
• ↑ permeability Angioipoietins 1 and 2, PDGF, and TGF-b stabilize
the newly formed vessels. 159
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Angiogenesis from Endothelial
Precursor Cells
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Angiogenesis from Pre-existing
Vessels
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• A parent vessel sends out capillary sprouts to
produce new vessels
• Steps involved:• Degradation of the parent vessel BM
• Migration of endothelial cells (EC)
• Proliferation of endothelial cells
• Maturation of EC and organization into capillary tubes
• Growth factors involved:
• Basic fibroblast growth factor (bFGF)• Vascular endothelial growth factor (VEGF)
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Angiogenesis
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Angiogenesis from Pre-existing
Vessels
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Healing by First Intention
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Focal Disruption of
Basement
Membrane and loss
of only a fewepithelial cells
e.g. Surgical Incision
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Healing by Second Intention
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• Larger injury,
abscess, infarction
Results in much
larger Scar and then
CONTRACTION
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Wound Healing
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• Fibrin clot formation → filling the gap
• Induction of acute inflammatory response by aninitial injury• Neutrophils (1st 24 h), Monocytes by 3rd day
• Parenchymal cell regeneration• Migration and proliferation of parenchymal and
connective tissue cells and granulation tissue
• Synthesis of ECM proteins
• Remodeling of parenchymal elements to restoretissue function
• Remodeling of connective tissue to achieve woundstrength
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Fibrosis
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• Emigration and proliferation of fibroblasts
• Growth factors: PDGF, FGF, EGF,
TGF-b• Deposition of ECM
• Growth factors: PDGF, FGF, TGF-b
and cytokines (IL-1 &TNF)
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Scar Remodeling
• Shift and change of the composition of the ECM of the scar as
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Shift and change of the composition of the ECM of the scar as
a result of synthesis and degradation• Metalloproteinases: Enzymes produced by many cells and
capable of degrading different ECM constituents
• Interstitial collagenases
• Gelatinases• Stromelysins
• Metalloproteinases (Zn dependent) activated proteases
(plasmin). Inactivated by tissue inhibitors of metalloproteinases
(TIMP) and steroids.
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Phases of Wound Healing
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Wound Strength
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• Sutured wounds have 70% of the strength of unwoundedskin
• After sutures are removed at one week, wound strength
is only 10% of unwounded skin
• By 3-4 months, wound strength is about 80% of
unwounded skin
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Factors affecting Healing:
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• SYSTEMIC• Nutritional
• Protein deficiency
• Vitamin C deficiency
• Zinc deficiency
• Systemic diseases• Diabetes mellitus
• Arteriosclerosis
• Renal failure
• Infections (systemic)• Corticosteroid treatment
• Age
• Immune status
• LOCAL
• Infection
• Poor blood supply
• Type of tissue
• Presence of foreignbody material
• Ionizing irradiation
• Mechanical factors
• Excessive movement• Hematoma
• Apposition 172
Pathologic Aspects of Repair
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• Aberrations of growth may occur • Exuberant granulation:
• Excessive amount of granulation tissue during wound healing
• Keloid:
• Excessive collagen accumulation during wound healing resulting in raisedtumorous scar
• Excessive fibrosis:
• Cirrhosis, pulmonary fibrosis, rheumatoid arthritis (RA)
• Tissue damage
• Collagen destruction by collagenases in RA
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Keloid
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Keloid
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