CHAPTER 2

Inflammation
(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
VASCULAR EVENTS CELLULAR EVENTS (PMN or
PolyMorphonuclear Neutrophil,
Leukocyte?, POLY, Neutrophil, Granulocyte, Neutrophilic Granulocyte

MEDIATORS

ACUTE INFLAMMATION
Neutrophil Polymorphonuclear Leukocyte, PMN, PML Leukocyte Granulocyte, Neutrophilic granulocyte Poly- Polymorph

HISTORICAL HIGHLIGHTS
(Egypt, 3000 BC)

Rubor Calor Tumor Dolor

5th (functio laesa)

STIMULI for acute inflammation INFECTIOUS PHYSICAL CHEMICAL

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 (

EXUDATE, NOT
TRANSUDATE)

 MARGINATION (PMNs go toward wall) ROLLING (tumbling and HEAPING) ADHESION TRANSMIGRATION (DIAPEDESIS)

EXTRAVASATION of PMNs

ADHESION MOLECULES (glycoproteins) affecting ADHESION and TRANSMIGRATION

SELECTINS (from endothelial cells) INTEGRINS (from many cells)

CHEMOTAXIS
PMNs 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 cells Have triggering stimuli Usually have specific targets Can cause a cascade Are 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 aas ALSO from circulating plasma ACTIONS
Increased permeability Smooth muscle contraction, NON vascular

PAIN

CLOTTING FACTORS
Also from circulating plasma Coagulation, i.e., production of fibrin Fibrinolysis

EICOSANOIDS
(ARACHIDONIC ACID DERIVATIVES)

Part of cell membranes 1) Prostaglandins (incl. Thromboxanes) 2) Leukotrienes 3) Lipoxins (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

TNF, 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

 PRIMARY

LYSOSOMAL CONSTITUENTS
SECONDARY
Also called SPECIFIC Lactoferrin Lysozyme Alkaline Phosphatase Collagenase

Also called AZUROPHILIC, or NON-specific Myeloperoxidase Lysozyme (Bact.) Acid Hydrolases

FREE RADICALS
O2 (SUPEROXIDE)

H2O2 (PEROXIDE) OH(HYDROXYL RADICAL)

VERY VERY

NEUROPEPTIDES
Produced in CNS (neurons) SUBSTANCE P NEUROKININ A

OUTCOMES OF ACUTE INFLAMMATION

1) 100% complete RESOLUTION 2) SCAR 3)CHRONIC inflammation

Morphologic PATTERNS of Acute INFLAMMATION (EXUDATE) Serous (watery)

Fibrinous (hemorrhagic,
rich in FIBRIN)

Suppurative (PUS) Ulcerative

BLISTER, Watery, i.e., SEROUS

FIBRINOUS

PUS = PURULENT

ABSCESS = POCKET OF PUS

PURULENT, FIBRINOPURULENT

ULCERATIVE

ACUTE INFLAMMATION EXAMPLES

Cardinal signs of (acute) inflammation

Rubor Tumor Calor Dolor = redness = swelling = heat = 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

The 5 Cardinal Signs of

Heat

Redness Swelling Pain Loss Of Func.

The nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix -itis
e.g pancreatitis meningitis pericarditis arthritis

Table 34. Types of Acute Inflammation.

Type
Classic type

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

Common Causes
Bacterial infections; response to cell necrosis of any cause.

Acute inflammation without neutrophils Allergic acute inflammation

Paucity of neutrophils in exudate; lymphocytes and Viral and rickettsial infections (immune response plasma cells predominant; neutropenia, lymphocytosis in contributes). blood. Marked edema and numerous eosinophils; eosinophilia in Certain hypersensitivity immune reactions blood. Burns; many bacterial infections.

Serous inflammation Marked fluid exudation. (inflammation in body cavities) Catarrhal inflammation Marked secretion of mucus. (inflammation of mucous membranes)

Infections, eg, common cold (rhinovirus); allergy (eg, hay fever).

Fibrinous inflammation Excess fibrin formation. Necrotizing inflammation, hemorrhagic inflammation Marked tissue necrosis and hemorrhage.

Many virulent bacterial infections. Highly virulent organisms (bacterial, viral, fungal), eg, plague (Yersinia pestis), anthrax (Bacillus anthracis), herpes simplex encephalitis, mucormycosis.

Membranous Necrotizing inflammation involving mucous membranes. Toxigenic bacteria, eg, diphtheria bacillus (pseudomembranous) The necrotic mucosa and inflammatory exudate form an (Corynebacterium diphtheriae) and Clostridium inflammation adherent membrane on the mucosal surface. difficile. Suppurative (purulent) Exaggerated neutrophil response and liquefactive inflammation necrosis of parenchymal cells; pus formation. Marked neutrophil leukocytosis in blood. Pyogenic bacteria, eg, staphylococci, streptococci, gramnegative 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

Purulent inflammation

Fibrinous 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

Pneumonia
Congested septal capillaries

Extensive erythrocyte, neutrophil and fibrin exudation

= red hepatization

Pathological Stages of Lobar Pneumonia

Congestion
Lung is heavy and red due to vascular engorgement and intraalveolar 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 gastroduodenal 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 INFLAMMATION With 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 inflammation acute 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