2 - inflammation and repair (edited ver)

7/31/2019 2 - Inflammation and Repair (Edited Ver)

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Inflammation and

Repair Luis P. Cruz, MD, FPSP, FPSO

Asst.Prof VI

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

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

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

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

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

Mycobacterium tuberculosis

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

CELLULAR AND VASCULARCHANGES

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

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

CELLULAR EVENTS

LEUCOCYTE EXTRAVASATION ANDPHAGOCYTOSIS

Margination, rolling and adhesion2. Transmigration across the

endothelium (diapedesis)

3. Migration in interstitial tissuestoward a chemotactic stimulus

BINDING OF COMPLEMENTARY ADHESION MOLECULESON THE LEUKOCYTE AND ENDOTHELIAL SURFACES

CHEMOTAXIS

• locomotion oriented along a chemical gradient

exogenous : bacterial products – endogenous :

– complement system (C5a)

– cytokines

– lipo-oxygenase pathway

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

Rolling

Selectins transiently bind to receptors

PMNs bounce or roll along

Rolling

Adhesion

Mediated by integrins ICAM-1 and VCAM-1

Transmigration

Mediated/assisted by PECAM-1 & ICAM-1(Integrins)

Diapedesis (cells crawling)

Primary in venules

Collagenases degrade BM Permeability

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

Arachidonic acid metabolites

Metabolites of AA - short-range hormones

AA metabolites act locally at site of generation Rapidly decay or are destroyed

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

Prostacyclin

Thromboxane

PGD2 ; PGE2

Vasodilatation

Inhibits Platelet Aggregation

Vasoconstriction

Promotes Platelet Aggregation

Vasodilatation

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

Inflammation and

Repair Luis P. Cruz, MD, FPSP, FPSO

Asst.Prof VI

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

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

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

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

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

Mycobacterium tuberculosis

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

CELLULAR AND VASCULARCHANGES

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

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

CELLULAR EVENTS

LEUCOCYTE EXTRAVASATION ANDPHAGOCYTOSIS

1. Margination, rolling and adhesion

2. Transmigration across theendothelium (diapedesis)

3. Migration in interstitial tissuestoward a chemotactic stimulus

BINDING OF COMPLEMENTARY ADHESION MOLECULESON THE LEUKOCYTE AND ENDOTHELIAL SURFACES

CHEMOTAXIS

• locomotion oriented along a chemical gradient

– exogenous : bacterial products

– endogenous :

– complement system (C5a)

– cytokines

– lipo-oxygenase pathway

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

Rolling

Selectins transiently bind to receptors

PMNs bounce or roll along Rolling

Adhesion

Mediated by integrins ICAM-1 and VCAM-1

Transmigration

Mediated/assisted by PECAM-1 & ICAM-1(Integrins)

Diapedesis (cells crawling) Primary in venules

Collagenases degrade BM Permeability

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

Arachidonic acid metabolites

Metabolites of AA - short-range hormones

AA metabolites act locally at site of generation Rapidly decay or are destroyed

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

Prostacyclin

Thromboxane

PGD2 ; PGE2

Vasodilatation

Inhibits Platelet Aggregation

Vasoconstriction

Promotes Platelet Aggregation

Vasodilatation

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

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

AA metabolites (eicosanoids)

Cyclooxygenases synthesize

Prostaglandins

Thromboxanes

Lipoxygenases synthesize

Leukotrienes

Lipoxins

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!

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.

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

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

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

Plasma Mediator Systems - Interaction

1. Kinin

2. Clotting

3. Complement

4. Fibrinolytic

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

Complement system

Role in immunity (C5-9 complex)

Membrane Attack Complex (MAC C5-9)

Punches a hole in the membrane

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)

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

Inflammatory Mediators from Complement

Phagocytosis:

C3b and C3bi are opsonins

Control:

Convertases are destabilized by "decay accelerating factor"

Inability to express DAF causes paroxysmal nocturnal hemoglobinuria

C1 inhibitor (C1INH) deficiency causes hereditary

angioneurotic edema

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

B d ki i P t t bi l l

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

LIVER CIRRHOSIS

MORPHOLOGIC PATTERNS IN ACUTE AND

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

site and tissue affected3. responsiveness of the host

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

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

CLINICO-PATHOLOGIC DIFFERENCES BETWEEN

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

Phases of Wound Healing

• Inflammatory Phase

• Proliferative Phase

• Remodelling Phase

• 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

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

• Migration of inflammatory cells• initially PMN’s (neutrophils) predominate

• gradually replaced by macrophages

Inflammatory Phase

Most important cell in wound healing -Macrophage (monocyte)

Interleukin I (IL-1)

Tumor necrosis factor (TNF-a)

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

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

REPAIR

FACTORS INFLUENCING REPAIRGROWTH FACTORS

CELL-CELL AND CELL-MATRIX INTERACTIONS EXTRACELLULAR MATRIX

SYNTHESIS ANDCOLLAGENIZATION

REPAIR

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

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

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

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

Keloid

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

2 - inflammation and repair (edited ver)

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