CHAPTER 2Inflammation

(5 OBJECTIVES)1) (Concept) Understand the chain,

progression, or sequence of vascular and cellular events in the histologic evolution of acute inflammation

2) (Rote?) Learn the roles of various “chemical mediators” of acute inflammation

3) Know the three possible outcomes of acute inflammation

4) Visualize the three morphologic patterns of acute inflammation

5) Understand the causes, morphologic patterns, principle cells, minor cells, of chronic and granulomatous inflammation

SEQUENCE OF EVENTS• NORMAL HISTOLOGY • VASODILATATION • INCREASED VASCULAR PERMEABILITY • LEAKAGE OF EXUDATE • MARGINATION, ROLLING, ADHESION • TRANSMIGRATION (DIAPEDESIS) • CHEMOTAXIS • PMN ACTIVATION • PHAGOCYTOSIS: Recognition, Attachment,

Engulfment, Killing (degradation or digestion) • TERMINATION • 100% RESOLUTION, SCAR, or CHRONIC

INFLAMMATION are the three possible outcomes

ACUTE INFLAMMATION

•“PROTECTIVE” RESPONSE

•NON-specific

ACUTE INFLAMMATION• VASCULARVASCULAR EVENTS

• CELLULARCELLULAR EVENTS (PMN or PolyMorphonuclear Neutrophil, Leukocyte?, “POLY”, Neutrophil, Granulocyte, Neutrophilic Granulocyte

• ““MEDIATORS”MEDIATORS”

ACUTE INFLAMMATION

Neutrophil

Polymorphonuclear Leukocyte, PMN, PML

“Leukocyte”

Granulocyte, Neutrophilic granulocyte

“Poly-”

Polymorph

RuborRubor

CalorCalor

TumorTumor

DolorDolor

5th (functio laesa)

HISTORICAL

HIGHLIGHTS(Egypt, 3000 BC)

STIMULI for acute inflammation

• INFECTIOUSINFECTIOUS

• PHYSICALPHYSICAL

• CHEMICALCHEMICAL• Tissue Necrosis

• Foreign Bodies (FBs)

• Immune “responses”, or “complexes”

Vascular Changes• Changes in Vascular Flow

and Caliber

• Increased Vascular Permeability

INCREASED PERMEABILITY

• DILATATION

• Endothelial “gaps”

• Direct Injury

• Leukocyte Injury

• Transocytosis (endo/exo)

• New Vessels

LEAKAGE OF PROTEINACEOUS FLUID

(EXUDATEEXUDATE, NOT TRANSUDATE)

EXTRAVASATION of PMNs

• MARGINATION (PMN’s go toward wall)

• ROLLING (tumbling and HEAPING)

• ADHESION • TRANSMIGRATION

(DIAPEDESIS)

ADHESION MOLECULES(glycoproteins) affecting

ADHESION and TRANSMIGRATION

• SELECTINS (from endothelial cells)

• INTEGRINS (from many cells)

CHEMOTAXISPMNs going to the site of “injury”

AFTER transmigration

LEUKOCYTE“ACTIVATION”

• “triggered” by the offending stimuli for PMNs to:

– 1) Produce eicosanoids (arachidonic acid derivatives)• Prostaglandin (and thromboxanes)• Leukotrienes• Lipoxins

– 2) Undergo DEGRANULATION

– 3) Secrete CYTOKINES

PHAGOCYTOSIS• RECOGNITION

• ENGULFMENT

• KILLING (DEGRADATION/DIGESTION)

CHEMICAL MEDIATORS• From plasma or cellsFrom plasma or cells• Have “triggering” stimuliHave “triggering” stimuli• Usually have specific targetsUsually have specific targets• Can cause a “cascade”Can cause a “cascade”• Are short livedAre short lived

CLASSIC MEDIATORS• HISTAMINE

• SEROTONIN

• COMPLEMENT

• KININS

• CLOTTING FACTORS

• EICOSANOIDS

• NITRIC OXIDE

• PLATELET ACTIVATING FACTOR (PAF)

• CYTOKINES

• /CHEMOKINES

• LYSOSOME CONSTITUENTS

• FREE RADICALS

• NEUROPEPTIDES

HISTAMINE• Mast Cells,

basophils• POWERFUL

Vasodilator• Vasoactive

“amine”• IgE on mast

cell

SEROTONIN• (5HT, 5-Hydroxy-

Tryptamine)

• Platelets and EnteroChromaffin Cells

• Also vasodilatation, but more indirect

• Evokes N.O. synthetase (a ligase)

COMPLEMENT SYSTEM• >20

components, in circulating plasma

• Multiple sites of action, but LYSIS is the underlying theme

KININ SYSTEM• BRADYKININ is KEY component, 9 aa’s• ALSO from circulating plasma• ACTIONS

– Increased permeability– Smooth muscle contraction, NON vascular

–PAINPAIN

CLOTTING FACTORS

• Also from circulating plasma

• Coagulation, i.e., production of fibrin

• Fibrinolysis

EICOSANOIDS(ARACHIDONIC ACID DERIVATIVES)

• Part of cell membranes• 1) 1) ProstaglandinsProstaglandins (incl. Thromboxanes)

• 2) 2) LeukotrienesLeukotrienes• 3) 3) LipoxinsLipoxins (new)MULTIPLE ACTIONS AT MANY LEVELS

Prostaglandins(thromboxanes included)

• Pain

• Fever

• Clotting

Leukotrienes

• Chemotaxis

• Vasoconstriction

• Increased Permeability

Lipoxins

• INHIBIT chemotaxis

• Vasodilatation

• Counteract actions of leukotrienes

Platelet-Activating Factor(PAF)

• Phospholipid

• From MANY cells, like eicosanoids

• ACTIVATE PLATELETS, powerfully

CYTOKINES/CHEMOKINES• CYTOKINES are PROTEINS produced by

MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation

–TNFα, IL-1, by macrophages

• CHEMOKINES are small proteins which are attractants for PMNs (>40)

NITRIC OXIDE• Potent vasodilator

• Produced from the action of nitric oxide synthetase from arginine

LYSOSOMAL CONSTITUENTS• PRIMARY• Also called

AZUROPHILIC, or NON-specific

• Myeloperoxidase• Lysozyme (Bact.)• Acid Hydrolases

• SECONDARY• Also called SPECIFIC

• Lactoferrin• Lysozyme• Alkaline Phosphatase• Collagenase

FREE RADICALS• O2 – (SUPEROXIDE)

•H2O2 (PEROXIDE)

•OH- (HYDROXYL RADICAL)

•VERY VERY

DESTRUCTIVE

NEUROPEPTIDES• Produced in CNS (neurons)

• SUBSTANCE P

• NEUROKININ A

OUTCOMES OFACUTE INFLAMMATION

• 1) 100% complete RESOLUTION

• 2) SCAR

• 3)CHRONIC inflammation

Morphologic PATTERNSof Acute INFLAMMATION

(EXUDATE)• SerousSerous (watery)

• FibrinousFibrinous (hemorrhagic, rich in FIBRIN)

• SuppurativeSuppurative (PUS)

• UlcerativeUlcerative

BLISTER, “Watery”, i.e., SEROUS

FIBRINOUS

PUS

=

PURULENT

ABSCESS

=

POCKET

OF

PUS

PURULENT, FIBRINOPURULENT

ULCERATIVE

ACUTE INFLAMMATIONEXAMPLES

Cardinal signs of (acute) inflammation

• Rubor = redness• Tumor = swelling• Calor = heat• Dolor = pain

(described by Celsus 1st. Century AD)

• Functio laesa = loss of function(added by R. Virchow)

Cellulits = acute skin infection commonly caused by Streptococcus pyogenes or Staphylococcus aureus

Heat Redness Swelling Pain Loss Of Func.

The 5 Cardinal Signs of

The nomenclature used to describe inflammation in different tissues employs

the tissue name and the suffix “-itis”

e.g

pancreatitis

meningitis

pericarditis

arthritis

Table 3–4. Types of Acute Inflammation.

Type Features Common Causes

Classic type Hyperemia; exudation with fibrin and neutrophils; neutrophil leukocytosis in blood.

Bacterial infections; response to cell necrosis of any cause.

Acute inflammation without neutrophils

Paucity of neutrophils in exudate; lymphocytes and plasma cells predominant; neutropenia, lymphocytosis in blood.

Viral and rickettsial infections (immune response contributes).

Allergic acute inflammation

Marked edema and numerous eosinophils; eosinophilia in blood.

Certain hypersensitivity immune reactions

Serous inflammation (inflammation in body cavities)

Marked fluid exudation. Burns; many bacterial infections.

Catarrhal inflammation (inflammation of mucous membranes)

Marked secretion of mucus. Infections, eg, common cold (rhinovirus); allergy (eg, hay fever).

Fibrinous inflammation

Excess fibrin formation. Many virulent bacterial infections.

Necrotizing inflammation, hemorrhagic inflammation

Marked tissue necrosis and hemorrhage. Highly virulent organisms (bacterial, viral, fungal), eg, plague (Yersinia pestis), anthrax (Bacillus anthracis), herpes simplex encephalitis, mucormycosis. 

Membranous (pseudomembranous) inflammation

Necrotizing inflammation involving mucous membranes. The necrotic mucosa and inflammatory exudate form an adherent membrane on the mucosal surface.

Toxigenic bacteria, eg, diphtheria bacillus (Corynebacterium diphtheriae) and Clostridium difficile. 

Suppurative (purulent) inflammation

Exaggerated neutrophil response and liquefactive necrosis of parenchymal cells; pus formation. Marked neutrophil leukocytosis in blood.

Pyogenic bacteria, eg, staphylococci, streptococci, gram–negative bacilli, anaerobes.

Different morphological patterns of acute inflammation can be found depending on the cause and extend of injury and site of inflammation

Serous inflammation

Fibrinous inflammation

Purulent inflammation

ulcers

Pneumonia = infection of the lung• Most community acquired

Pneumonias are bacterial of origin

• Often the infection follows a viral upper respiratory tract infection

• Acute bacterial pneumonias present as two anatomical patterns:– Bronchopneumonia– Lobar pneumonia

What causes the white consolidation of the Chest-X-ray?

Normal lung histology

Congested septal capillaries

Extensive erythrocyte, neutrophil and fibrin exudation

Pneumonia

= red hepatization

Pathological Stages of Lobar Pneumonia

• Congestion – Lung is heavy and red due to vascular engorgement and intra-

alveolar fluid with few neutrophils• Red Hepatization

– Massive confluent exudation with red cells, neutrophils and fibrin into alveolar spaces

– Lobes are distinctly red, firm and airless, with liver-like consistency• Gray Hepatization

– Follows with progressive disintegration of red cells and persistence of a fibrino-suppurative exudate resulting in grayish dry appearance

• Resolution or scarring – Resolution due to clearance of the infection and enzymatic digest

of exudate which can be reabosrbed, ingested by macrophages cleared via muco-cilliary escalator

– Scarring due to organization of exudate, infiltration of fibroblasts and deposition of collagen

Red hepatization Gray hepatization

Abscess formation • is the result of a suppurative (purulent)

necrosis of the parechyma resulting in the formation of one or more cavities

• it has a central necrosis, rimmed by neutrophils and surrounded by fibroblasts

Occurs in the lung due to:• Aspiration of infective material• Aspiration of gastric content• Complication of necrotizing bacterial

pneumonia (e.g Staphylococcus)• Septic embolism

Peptic ulcer

An ulcer is a local defect of mucosal lining produced by shedding of necrotic tissue

Peptic ulcers are produced by an imbalance between gastro-duodenal defense mechanisms and the damaging force

70% of all ulcers are due to H. pyolri infection which initiates a strong inflammatory response

Inflammed Lung

Suppurative or purulent inflammation is characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils, necrotic

cells, and edema fluid.

Serous inflammation is marked by the outpouring of

a thin fluid that, depending on the size of injury, is derived from either the plasma or the secretions of mesothelial cells lining the peritoneal, pleural, and

pericardial cavities (called effusion).

FIBRINOUS INFLAMMATIONWith more severe injuries and the resulting greater

vascular permeability, larger molecules such as fibrinogen pass the vascular barrier, and fibrin is formed

and deposited in the extracellular space

An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing

(shedding) of inflammatory necrotic tissue

Systemic effects of acute inflammationacute phase response

• Fever (temperature > 37.8oC or >100 F)• Increased pulse, blood pressure• Chills• Anorexia

• Leukocytosis • Neutrophilia and left shift of neutrophils points to bacterial

infection• Lymphocytosis points to viral infection• Eosinophilia point to allergy or parasitic infection

• Acute phase protein production in liver • fibrinogen, CRP,SAA leads to increased ESR

Outcome of acute inflammation

• Complete restitution

• Abscess formation (encapsulation and pus)

• Chronic inflammation

• Healing with scar formation

SEQUENCE OF EVENTS• NORMAL HISTOLOGY • VASODILATATION • INCREASED VASCULAR PERMEABILITY • LEAKAGE OF EXUDATE • MARGINATION, ROLLING, ADHESION • TRANSMIGRATION (DIAPEDESIS) • CHEMOTAXIS • PMN ACTIVATION • PHAGOCYTOSIS: Recognition, Attachment,

Engulfment, Killing (degradation or digestion) • TERMINATION • 100% RESOLUTION, SCAR, or CHRONIC

inflammation