INFLAMMATIONINFLAMMATION

Dr Sapna MDr Sapna M

Dept pathologyDept pathology

SNIMS,KERALASNIMS,KERALA

INFLAMMATIONINFLAMMATION

INFLAMMATIONINFLAMMATION

• Protective response intended to eliminate initial cause of cell injury , necrotic cells and tissues resulting from original insult

Introduction:Introduction:

• “Inflame” – to set fire

• Inflammation is “dynamic response of vascularised tissue to injury.”

-itis-itis AppendicitisAppendicitis

CellulitisCellulitis

MeningitisMeningitis

PneumonitisPneumonitis

NephritisNephritis

MyocarditisMyocarditis

TYPES OF INFLAMMATIONTYPES OF INFLAMMATION

• ACUTE

• CHRONIC

Acute Inflammation-FeaturesAcute Inflammation-Features

• Rapid onset

• Short duration( mts. to few days)

• Fluid , plasma protein exudation

• Neutrophil accumulation

ChronicChronic Inflammation-FeaturesInflammation-Features• Onset- insidious

• Longer duration (days to years)

• Lymphocytes ,macrophages ,plasma cells

• Vascular proliferation & fibrosis (scarring)

HEAT REDNESS SWELLING PAIN LOSS OF FUNC.

5 Cardinal Signs of Inflammation5 Cardinal Signs of Inflammation

4 cardinal clinical signs of inflammation 4 cardinal clinical signs of inflammation described by Celsus, 1 A.D.:described by Celsus, 1 A.D.:

• Rubor - redness

• Tumor - swelling

• Calor - heat

• Dolor - pain

• Virchow added a fifth--loss of function(functio laesa)

Steps Of Inflammatory ResponseSteps Of Inflammatory Response

• Remembered as five Rs:

• (1) Recognition of injurious agent

• (2) Recruitment of leukocytes

• (3) Removal of agent

• (4) Regulation of response

• (5) Resolution (repair).

• ACUTE INFLAMMATION

Stimuli for Acute InflammationStimuli for Acute Inflammation

• Infections (b, v, f, p)

• Trauma

• Physical & chemical agents

• Tissue necrosis (MI)

• Foreign bodies

• Immune reactions

Acute Inflammation-components Acute Inflammation-components

Acute Inflammation-componentsAcute Inflammation-components

ACUTE INFLAMMATIONACUTE INFLAMMATION

Vascular changes Cellular events

•VasodilationIncreased vascular permeability.

Acute Inflammation-components Acute Inflammation-components • 1.Vascular changes:

• Vasodilation• ↑ vascular perm.

• 2.Cellular events

• Cellular recruitment & activation

VASCULAR CHANGES VASCULAR CHANGES

• 1.Changes In Vascular Caliber And Flow

• Transient vasoconstriction (sec.)

• Arteriolar vasodilation( redness warmth)

• ↑ bld flow & engorgement capillary beds

↓

protein-rich fluid moves into EV tissues

↓

RBCs conc., ↑ blood viscosity

↓

Stasis

↓

margination of neutrophils

ACUTE INFLAMMATIONACUTE INFLAMMATION• 2. ↑ Vascular Perm.{ mechanisms }

• 1.Endothelial cell contraction

–immediate transient response

:reversible process, by histamine, bradykinin, leukotrienes ,15-30 min.

2 .Retraction of EC

: TNF and IL-1, 24 hours or more

↑ ↑ Vascular Permeability{ mechanisms }Vascular Permeability{ mechanisms }

• 3.Endothelial injury

-immediate sustained response , delayed prolonged leakage

• 4.Leukocyte-mediated endothelial injury

• 5.Increased transcytosis

• 6.Leakage from new blood vessels.

EXUDATE : INFLAMMATIONEXUDATE : INFLAMMATION

• 1.Vascular changes:

• Vasodilation

• Increased vascular permeability.

Cellular Events: Leukocyte Cellular Events: Leukocyte Recruitment and Activation Recruitment and Activation

Leukocyte Recruitment Leukocyte Recruitment • 4 steps

1. Margination, rolling, and adhesion

2. Diapedesis (transmigration across endothelium)

3. Migration toward chemotactic stimulus - Chemotaxis

4. Phagocytosis

Neutrophil MarginationNeutrophil Margination

ROLLINGROLLING:: Leukocytes tumble on endothelial

surface, transiently sticking along the way

• Mediated by SELECTIN family of adhesion molecules

• 3 members of this family

SELECTINSSELECTINS

• E-selectin (CD62E) on EC

• P-selectin (CD62P) EC & platelets

• L-selectin (CD62L) leukocytes

• Selectins bind sialylated oligosaccharides ( sialyl-Lewis X on leukocytes)

ROLLINGROLLING

ADHESION & TRANSMIGRATION ADHESION & TRANSMIGRATION

• Adhesion mediated by integrins

• Activated by chemokines

• TNF and IL-1 activate EC to ↑ expression of ligands for integrins

ADHESIONADHESION

Ligands For Integrins Ligands For Integrins

• ICAM-1(intercellular adhesion molecule1) - binds integrins LFA-1 (CD11a/CD18)

and Mac-1 (CD11b/CD18), • VCAM-1 (vascular cell adhesion

molecule1) - bind integrin VLA-4

DIAPEDESIS DIAPEDESIS

DIAPEDESIS DIAPEDESIS

DIAPEDESISDIAPEDESIS

• Leukocytes migrate thr’u vessel wall by squeezing between cells at IC junctions

• Mediated by PECAM-1 (platelet endothelial cell adhesion molecule 1 (CD31) on leukocytes & EC

CHEMOTAXISCHEMOTAXIS

• Leukocytes migrate toward sites of infection or injury along a chemical gradient

• Chemotactic substances

(1) bacterial products (2) cytokines

(3) C5a (4) LTB4.

6 to 24 hours 24 to 48 hours

LEUKOCYTE ACTIVATION LEUKOCYTE ACTIVATION

LEUKOCYTE ACTIVATION LEUKOCYTE ACTIVATION

• Leukocytes receptors sensing p/o microbes:

–Toll-like receptors (TLRs) - LPS –Seven-transmembrane G-protein-

coupled receptors - bacterial peptides and mediators

PHAGOCYTOSIS PHAGOCYTOSIS • 3 steps

• (1) recognition and attachment of particle to ingesting leukocyte

• (2) engulfment & formation of phagocytic vacuole

• (3) killing and degradation of ingested material.

(1) (1) Recognition & attachment of Recognition & attachment of particle to ingesting leukocyteparticle to ingesting leukocyte

• Opsonins : host proteins that coat microbes and target them for phagocytosis (opsonization).

• Leukocytes express receptors for opsonins

OPSONISATION RECEPTORS

OPSONINS RECEPTORS FOR OPSONINS

IgG FcγRI

Breakdown products of C3

CR1 and 3

Collectins C1q

2.ENGULFMENT 2.ENGULFMENT & FORMATION & FORMATION OF PHAGOCYTIC VACUOLEOF PHAGOCYTIC VACUOLE

3.Killing and Degradation of Microbes 3.Killing and Degradation of Microbes

• Important microbicidal substances : reactive oxygen species (ROS) and lysosomal enzymes

• ROS

• HOCl• (hypochlorous radical)

• Superoxide radicals (superoxide,H2O2, and OH•).

• Reactive nitrogen species( NO)

Lysosomal enzymesLysosomal enzymes

• Lysosomal acid hydrolases-degrade

dead microorganisms

• Elastase - kill bacteria

Defects in Leukocyte FunctionDefects in Leukocyte Function

• Common causes

• BM suppression ( tumors CT,RT)- ↓ leukocyte no.

• Diabetes - abnormal leukocyte function

Defects in leukocyte function:Defects in leukocyte function:• Margination and adhesion

– Etoh, steroids, AR leukocyte adhesion deficiency

• Emigration toward a chemotactic stimulus– drugs– chemotaxis inhibitors

• Phagocytosis– Chronic granulomatous disease

(CGD) :phagocyte oxidase generating ROS

Defects in leukocyte function:Defects in leukocyte function:

• Myeloperoxidase (MPO) deficiency: Absent MPO-H2O2 system

• Chédiak-Higashi syndrome :impair fusion of lysosomes with phagosomes

ACUTE INFLAMMATION - THREE ACUTE INFLAMMATION - THREE OUTCOMESOUTCOMES

• Resolution

• Progression to chronic inflammation

• Abscess

• Scarring or fibrosis

Acute inflammation

Chronic inflammation

RepairResolution

Abscess

Injury

MORPHOLOGIC PATTERNS OF MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATIONACUTE INFLAMMATION

• SEROUS INFLAMMATION

• Watery, protein-poor fluid . Serum/secretions of mesothelial cells

• Skin blister

• Fluid in a serous cavity - effusion.

SEROUS INFLAMMATIONSEROUS INFLAMMATION

FIBRINOUS INFLAMMATIONFIBRINOUS INFLAMMATION

• Severe injuries, ↑ vascular perm. & fibrinogen pass

• Histology: eosinophilic meshwork of threads or amorphous coagulum

• Site : Lining of body cavities

• Resolution

• Organization & scarring

SUPPURATIVE (PURULENT) SUPPURATIVE (PURULENT) INFLAMMATIONINFLAMMATION

• Purulent exudate (pus) - neutrophils, necrotic cells, and edema fluid

• Staphylococci – pyogenic

• Completely walled off ,replaced by connective tissue.

ABSCESSESABSCESSES

• Focal collections of pus

• Central, large necrotic region rimmed by neutrophils

(surrounded by vessels and fibroblastic proliferation )

ABSCESSESABSCESSES

ABSCESSESABSCESSES

ULCERULCER• Local defect / excavation, surface of an

organ/ tissue prod. by necrosis of cells & sloughing of inflammatory necrotic tissue

• Sites (1)mucosa of GIT( Peptic ulcer), GUT

• (2) Lower extremities, older persons with circulatory distur.

CHEMICAL MEDIATORS OF CHEMICAL MEDIATORS OF INFLAMMATIONINFLAMMATION

CELL DERIVED

CHEMICAL MEDIATORS OF CHEMICAL MEDIATORS OF INFLAMMATIONINFLAMMATION

PLASMA PROTEIN DERIVED

CHEMICAL MEDIATORS OF CHEMICAL MEDIATORS OF INFLAMMATIONINFLAMMATION

• CELL-DERIVED MEDIATORS• VASOACTIVE AMINES

• 1.HISTAMINE released by

• (1) physical injury

• (2) immune reactions

• (3) Anaphylatoxins:C3a and C5a

• (4) leukocyte-derived histamine-releasing

proteins

• (5) neuropeptides

• (6) IL-1 and IL-8

HISTAMINEHISTAMINE

• Action: arteriolar dilation , ↑ vascular perm.

• Inactivated by histaminase

• SEROTONIN (5-hydroxytryptamine) effects similar to histamine

CELL DERIVED –NEWLY CELL DERIVED –NEWLY SYNTHESISEDSYNTHESISED

Arachidonic Acid Metabolites: Arachidonic Acid Metabolites: ((eicosanoidseicosanoids) )

• Sources: Leukocytes, mast cells, EC, platelets

• 2 major enzymatic pathways:

• Cyclooxygenase

• Lipoxygenase

• Cyclooxygenase : prostaglandins and thromboxanes

• Lipoxygenase: leukotrienes and lipoxins

Arachidonic Acid (AA) MetabolitesArachidonic Acid (AA) Metabolites• CYCLOOXYGENASE PATHWAY

• Products :PGE2, PGD2, PGF2α, PGI2 (prostacyclin), TXA2

• TXA2: Platelets - thromboxane synthase ,platelet-aggregating agent and vasoconstrictor

CYCLOOXYGENASE PATHWAYCYCLOOXYGENASE PATHWAY

• PGI2 : EC - prostacyclin synthase , vasodilator and inhibitor of platelet aggregation

• PGD2: mast cells; + PGE2 & PGF2α

causes vasodilation & edema

• PGE2 : pain sensitivity, fever.

LIPOXYGENASE PATHWAYLIPOXYGENASE PATHWAY

• 5-Lipoxygenase :AA-metabolizing enzyme in neutrophils

• 5-HPETE (5-hydroperoxyeicosatetraenoic acid)

• Reduced to 5-HETE (5-hydroxyeicosa tetraenoic acid) - chemotactic for neutrophils

• or converted into leukotrienes

Lipoxygenase Pathway- LeukotrieneLipoxygenase Pathway- Leukotriene

• LTA4 gives rise to LTB4 or LTC4

• LTB4: chemotactic agent for neutrophils

• LTC4 , LTD4 & LTE4: mast cells , cause vasoconstriction, bronchospasm, ↑ vascular perm.

LIPOXINSLIPOXINS

• Inhibitors of inflammation

• Endogenous antagonists of leukotrienes.

Principal Inflammatory Actions of Principal Inflammatory Actions of AA Metabolites AA Metabolites

• Vasodilation:PGI2 (prostacyclin), PGE1, PGE2, PGD2

• Vasoconstriction:Thromboxane A2, leukotrienes C4, D4, E4

• ↑ vascular perm. :Leukotrienes C4, D4, E4 & PGE2, PGD2

• Chemotaxis, leukocyte adhesion :Leukotriene B4, 5-HETE

Cyclooxygenase enzyme -COXCyclooxygenase enzyme -COX

• Two forms : COX-1 and COX-2

• COX-1 : gastric mucosa, PGs protective against acid-induced damage.

• COX inhibitors :Aspirin ,NSAIDs: treat pain and fever

Platelet-Activating FactorPlatelet-Activating Factor • Stimulate platelets

• Vasoconstriction & bronchoconstriction

• Vasodilation & ↑vascular perm.

• Leukocyte adhesion, chemotaxis, degranulation, oxidative burst

• Synthesis of mediators , (eicosanoids).

CytokinesCytokines

• Polypeptide products .Mediators of inflammation and immune responses

• Molecularly characterized cytokines - interleukins

• A/c inflam : TNF, IL-1, chemokines

• C/C inflam: IFN-γ , IL-12.

CHEMOKINES CHEMOKINES • 2 functions : leukocyte recruitment in

inflam. & N anatomic organization of cells in lymphoid and other tissues

• Four groups

• Two major groups

• CXC :IL-8

• CC chemokines:MCP-1 , MIP-1α, RANTES (regulated on activation normal T expressed and secreted) and eotaxin .

Reactive Oxygen Species (ROSReactive Oxygen Species (ROS• Synthesized via NADPH oxidase

(phagocyte oxidase) pathway

• Action (1) endothelial damage, with thrombosis & ↑ perm.

• (2) protease activation and antiprotease inactivation

• (3) direct injury to other cells

• Catalase, SOD, glutathione -↓ toxicity

NONO• Synthesized from l-arginine, molecular

O2, NADPH by enzyme NOS.• 3 isoforms of NOS• Type I (nNOS)• Type II (iNOS) present in macrophages

& EC induced by IL-1, TNF,IFN-γ, bacterial endotoxin

• Type III (eNOS)

Nitric Oxide Nitric Oxide

NO -NO -FunctionsFunctions• (1) vasodilation (endothelium-derived

relaxation factor)

• (2) antagonism all stages of platelet activation(a,a,d)

• (3) reduction of leukocyte recruitment at inflammatory sites

• (4)Microbicidal agent

Lysosomal Enzymes of LeukocytesLysosomal Enzymes of Leukocytes

• Acid proteases:acidic pH optima , active within phagolysosomes

• Neutral proteases: elastase, collagenase , cathepsin, active in ECM

• Cleave C3 & C5 to C3a & C5a• Generate bradykinin-like peptides from

kininogen.

AntiproteasesAntiproteases• α1-antitrypsin-major inhibitor of

neutrophil elastase

• α2-macroglobulin

• α1-antitrypsin deficiency - lung , panacinar emphysema

Neuropeptides Neuropeptides • Small proteins, such as substance P

• Transmit pain signals

• Regulate vessel tone

• Modulate vascular permeability

• Lung and GIT- Nerve fibers secrete NP

PLASMA PROTEIN-DERIVED PLASMA PROTEIN-DERIVED MEDIATORSMEDIATORS

• 3 systems

– Complement

– Kinin

– Coagulation

Complement Complement

Immunity and inflammation

• Opsonize particles: phagocytosis and destruction

• ↑ vascular perm. & vasodilatation

• Leuko. chemotaxis

• Generates MAC (C5b-9)

ComplementComplement

Critical steps : activation of C3Critical steps : activation of C3

• (1) Classical pathway : fixation of C1 to antig-antib complexes

• (2) Alternative pathway: bacterial polysaccharides / microbial cell-wall components, involve properdin and factors B , D

• (3) Lectin pathway: plasma lectin binds mannose residues on microbes , activates early component of CP

Complement Complement • 3 pathways form C3 convertase :cleaves

C3 to C3a and C3b• C3b deposits on cell or microbial surface• Binds to C3 convertase complex to form

C5 convertase• C5 convertase cleaves C5 → C5a & C5b• Initiate final stages of assembly of C6 to C9• Thrombin : cleave C5

ComplementComplement• 1.Anaphylatoxins: C3a and C5a ↑vascular

perm. and vasodilation ,induce mast cells to release histamine.

• 2.C5a: activates lipoxygenase pathway• 3.Leukocyte activation, adhesion, and

chemotaxis. C5a • 4.Phagocytosis: C3b & iC3b act as opsonins• 5.Lysis of microbes - MAC

Coagulation and Kinin SystemsCoagulation and Kinin Systems

• 4 systems activated by Hageman factor (factor XIIa)

• (1) Kinin system

• (2) Clotting system

• (3) Fibrinolytic system

• 4) Complement system.

Coagulation and Kinin Systems Coagulation and Kinin Systems

Clotting SystemClotting System• Factor Xa: ↑ vascular perm. and leuk.

Emigration

• Thrombin : leuk. Adhesion

• Fibrinopeptides :↑ vascular perm. and chemotactic for leuk.

FIBRINOLYTIC SYSTEMFIBRINOLYTIC SYSTEM

• FDP : ↑ vascular perm.

• Plasmin :cleaves C3 to C3a causing vasodilation and ↑ vascular perm.

KININ SYSTEMKININ SYSTEM

• Bradykinin :↑ vascular perm, arteriolar dilation, bronchial smooth muscle contraction, pain

• Kallikrein: chemotactic activity

Role of Mediators in Different Role of Mediators in Different Reactions of Inflammation Reactions of Inflammation

• 1.Vasodilation: Prostaglandins, Nitric oxide  Histamine• 2.↑ vascular perm: Histamine and serotonin

C3a and C5a Bradykinin

Leukotrienes C4, D4, E4PAFSubstance P

Mediators in InflammationMediators in Inflammation• 3. Leukocyte recruitment and

activation

TNF, IL-1ChemokinesC3a, C5aLeukotriene B4Bacterial products, e.g., N-formyl methyl peptides

Mediators in InflammationMediators in Inflammation• 4. Fever

IL-1, TNF, PG

• 5. Pain

PG, Bradykinin, Neuropeptides

• 6. Tissue damage

Lysosomal enzymes , ROS,

  Nitric oxide

CHRONIC INFLAMMATIONCHRONIC INFLAMMATION

• Prolonged duration .Active inflammation, tissue injury & healing simultaneously

• Characterized by

• Infiltration with mononuclear cells

• Tissue destruction

• Repair : angiogenesis and fibrosis

Chronic InflammationChronic Inflammation• Time course:

–> 48 hours (weeks, months, years)

• Cell type

–Mononuclear cells (Macrophages, Lymphocytes, Plasma cells)

Chronic InflammationChronic Inflammation• Histology :

– L,M,P

– Fibroblasts & small BV– ↑ CT

– Tissue destruction

MACROPHAGESMACROPHAGES • Derived from circulating blood

monocytes • SITES:• Connective tissues• Liver (Kupffer cells)• Spleen & LN (sinus

histiocytes)• CNS( microglial cells)• Lungs (alveolar macrophages)

•Mononuclear phagocyte system (RES)

MACROPHAGESMACROPHAGES

FUNCTION

–Filters: particulate matter, microbes,senescent cells

–Alert T and B lymphocytes to injurious stimuli

• Lymphocytes, Plasma Cells, Eosinophils, and Mast Cells

Settings For Chronic InflammationSettings For Chronic Inflammation

• 1.Microbes difficult to eradicate Mycobacteria, Treponema pallidum , viruses and fungi

• 2.Immune-mediated inflammatory diseases : RA ,IBD, Asthma

• 3.Toxic agents :Silica, atherosclerosis

GRANULOMATOUS INFLAMMATIONGRANULOMATOUS INFLAMMATION

• Distinctive pattern of chronic inflammation

• Characterized by aggregates of activated macrophages that assume an epithelioid appearance

Diseases with Granulomatous Diseases with Granulomatous InflammationInflammation

• Tuberculosis :M. tuberculosis

• Noncaseating tubercle : a focus of epithelioid cells, rimmed by fibroblasts, lymphocytes, histiocytes, occasional giant cells

• Caseating tubercle: central amorphous granular debris, loss of all cellular detail; acid-fast bacilli

LANGHANS GIANT CELLS - HORSE SHOE SHAPE

LANGHANS GIANT CELL

Granulomatous InflammationGranulomatous Inflammation• Leprosy

• Mycobacterium leprae

• Acid-fast bacilli in macrophages; noncaseating granulomas

• Syphilis:Treponema pallidum, Gumma

Granulomatous InflammationGranulomatous Inflammation

• Cat-scratch disease :Gram-negative bacillus , Rounded or stellate granuloma

• Sarcoidosis : Unknown etiology Noncaseating granulomas

• Crohn disease :Immune reaction against intestinal bacterial, self-antigens noncaseating granulomas

Foreign body granulomas. Foreign body granulomas.

EPITHELIOID CELLSEPITHELIOID CELLS

• Elongated, finely granular, pale eosinophilic cytoplasm

• Nucleus:central, oval or elongate,small nucleoli ,slipper shaped

• Indistinct shape , merge to form aggregates.

• Lymphocytes secrete cytokines → macrophage activation

• Multinucleated giant cells

• Hypoxia and free-radical injury leads to caseous necrosis

• Healing of granulomas accompanied by fibrosis

SYSTEMIC EFFECTS OF SYSTEMIC EFFECTS OF INFLAMMATIONINFLAMMATION

• ACUTE-PHASE REACTION/ SYSTEMIC INFLAMMATORY RESPONSE SYNDROME.

• TNF, IL-1, and IL- 6

Clinical And Pathologic Changes -Clinical And Pathologic Changes -APRAPR

• 1.Fever- pyrogens –stimulate PG synthesis in hypothalamus

LPS(EX .P)

LUECOCYTES(IL-1 &TNF)ENDO.P

AA

PG(PGE2)

STIMULATE NEUROTRANSMITTERSRESET TEMP.

↑ CYCLOOXYGENASE

2.Acute-phase proteins2.Acute-phase proteins• 2.Synthesized in liver • Up-regulated by IL-6

• I) CRP II) Fibrinogen III)Serum amyloid A (SAA) protein.

• Fibrinogen cause rouleaux- ↑ ESR • CRP: ↑ risk of MI or stroke in pts. with

atherosclerotic vascular disease

3. Leukocytosis

• TNF & IL-1-release cells from BM . Shift to left

• CSFs - ↑ output of leukocytes from BM

• Neutrophilia , lymphocytosis , eosinophilia , leukopenia

Other manifestations Other manifestations • ↑ heart rate and BP

• ↓ sweating

• Rigors (shivering)

• Chills

• Anorexia, somnolence & malaise: cytokines on brain cells

• Chronic inflammation: wasting syndrome called cachexia, TNF- mediated appetite suppression & mobilization of fat stores

SEPTIC SHOCKSEPTIC SHOCK

• High levels of TNF cause DIC, hypoglycemia, and hypotensive shock.

1.A 65-year-old woman had fever the past day. On physical examination her temperature is 39 C and blood pressure 90/50 mm Hg with heart rate of 106/minute. A blood culture is positive for Escherichia coli. Her central line pressure falls markedly. She goes into hypovolemic shock as a result of the widespread inappropriate release of a chemical mediator derived from macrophages. Which of the following mediators is most likely to produce these findings? A Nitric oxide B Bradykinin C Histamine D Prostacyclin E Complement C3a

2.The major difference between a transudate and an exudate is

(A) transudate has proteins whereas exudate is essentially devoid of proteins(B) both these are only seen during acute inflammatory processes(C) both are associated with a Suppurative or Purulent inflammatory process(D) transudate is associated with serous inflammation whereas exudate is associated with fibrinous inflammation

3.Granulomatous Inflammation is associated with which of the following

a. distinct acute inflammatory process

b. distinct chronic inflammatory process

c. persistent B-cell response to certain microbes

d. IgM mediated response

4.Which of the following is/are considered an anaphylatoxins(s)

(A) lipoxins(B) leukotrines(C) C3a (D) IL-1 and TNF

5.What is the most common form of increased vascular permeability associated with acute inflammation

(A) direct endothelial injury(B) endothelial cell retraction(C) endothelial cell contraction (D) leukocyte-dependent endothelial damage

6.Endothelial cell contraction & retraction occur in

a) Postcapillary venules

b) Capillaries

c) Arterioles

d) All of the above