Vtpa 342 Inflammation

Front 1

Inflammation is

Back 1

the reaction of vascularized living tissues to
`` local injury which
`` comprises a series of
`` changes in
`` `` the terminal vascular bed,
`` `` in the blood, and
`` `` in the connective tissues
`` that are designed to
`` `` eliminate the offending irritant and
`` to repair the damaged tissue

Front 2

The inflammatory response is a complex and highly ordered sequence of events that

Back 2

serves to
`` concentrate the body’s
`` `` humoral and
`` `` cellular
`` defenses at the site of
`` `` injury or
`` `` infection,
`` avoiding wasteful dilution of these resources
`` and also minimizing the risk of
`` `` unintentional injury to healthy tissues.

Front 3

“cardinal signs” of inflammation:

Back 3

calor (warmth),

dolor (pain),

tumor (swelling)

and rubor (redness and hyperaemia)

Rudolf Virchow (1821 – 1902) added the fifth “cardinal sign” of inflammation;
`` namely, functio laesa
`` `` (inhibited or lost function)

Front 4

Inflammation

Severity 4

Back 4

Minimal –
`` negligible gross changes
`` often visible only histologically

Mild –
`` low degree of hyperemia and edema
`` with little or no
`` `` exudation and
`` `` tissue destruction.

Moderate –
`` obvious signs of inflammation
`` `` vascular and
`` `` cellular
`` with tissue destruction
`` usually
`` `` not life-threatening and
`` `` not compromising significantly organ function

Severe –
`` considerable tissue damage is present
`` with abundant exudation
`` usually
`` `` life-threatening or
`` `` compromising significantly organ function

Front 5

Inflammation

Duration 5

Back 5

Peracute

Acute

Subacute

Chronic

Chronic Active

Front 6

Inflammation

Peracute inflammation is

Back 6

manifested a
`` few hours after its initiation

it is usually caused by a potent stimulus

Gross:
`` ``edema,
`` `` hyperemia, and/ or
`` `` hemorrhage
`` `` `` only a few leucocytes without exudation

Example:
`` anaphylaxis

Front 7

Inflammation

Acute inflammation begins

Back 7

within
`` `` 4-6 hours after stimulus
`` and lasts
`` `` 3-4 days

Gross:
`` rubor,
`` `` hyperemic,
`` calor,
`` `` warm,
`` tumor,
`` `` swollen,
`` dolor
`` `` painful);
`` hemorrhage,
`` exudation of
`` `` fibrin and
`` `` neutrophils

Examples:
`` Fibrinous bronchopneumonia,
`` Parvoviral enteritis

Front 8

Inflammation

Subacute inflammation is characterized by

Back 8

gradual decline in vascular contribution
`` `` edema and
`` `` hyperemia
`` and mixed cellular infiltrate
`` `` neutrophilic and
`` `` mononuclear
`` `` `` lymphocytes,
`` `` `` macrophages,
`` `` `` plasma cells

Example:
`` Prolonged fibrinous bronchopneumonia

Front 9

Inflammation

Chronic inflammation is usually

Back 9

caused by a persistent stimulus that
`` the host cannot get rid of

Ongoing inflammatory process consisting of
`` `` macrophages
`` `` `` (innate immunity)
`` `` and lymphocytes
`` `` and plasma cells
`` `` `` (acquired immunity)

Tissue reparative process:
`` angiogenesis
`` `` angioblast proliferation and
`` `` vascularization,
`` fibroplasia
`` `` fibroblast proliferation and
`` `` fibrosis

FIBROSIS (scarring) is
`` the most reliable indicator of chronicity.

Examples:
`` tuberculosis,
`` foreign body reaction,
`` abscess

Front 10

Inflammation

Chronic-active inflammation is characterized by

Back 10

both
`` chronic inflammatory characteristics
`` `` mononuclear inflammation and
`` `` fibrosis
`` and acute characteristics
`` `` neutrophilic and
`` `` fibrinous exudation

Examples:
`` Chronic-active pyoderma
`` `` bacterial suppurative inflammation of skin;
`` Chronic active fibrionus pericarditis
`` `` hardware disease

Front 11

Serous exudate

Back 11

`` Transparent,
`` yellow,
`` uncoagulated,
`` thin fluid (
`` `` exudate

usually on
`` `` serosal surfaces
`` derived either from
`` `` plasma
`` or less likely from
`` `` secretions of mesothelial cells lining the serosa

Serous exudate is called also
`` serous effusion

Examples:
`` Serous pericarditis,
`` Serous exudate in skin blister
`` `` resulting from a burn

Front 12

Fibrinous exudate

Back 12

With more severe endothelial injuries that
`` result in greater vascular permeability,
`` larger molecules such as
`` `` fibrinogen
`` pass the vascular barrier,
`` and fibrin is
`` `` formed and
`` `` deposited
`` in the
`` `` extracellular space or
`` `` body cavities

Front 13

Fibrinous exudate

Morphology:

Gross: 5

Back 13

Serosal surface:
`` Small amount:
`` `` ground-glass appearance on
`` `` `` hyperemic serosa
`` `` `` `` (e.g. parvoviral enteritis)
`` Large amount
`` `` yellow,
`` `` soft,
`` `` elastic,
`` `` friable material
`` (e.g. fibrinous pleuritis)

Lungs:
`` yellow-red
`` `` interlobular and
`` `` intraalveolar
`` exudate that is in-part responsible for
`` `` consolidation of pulmonary tissue in
`` `` `` fibrinous bronchopneumonias
`` (e.g. shipping fever in Bo

Mucosal surfaces:
`` granular membrane consisting of
`` `` fibrin and
`` `` sloughed necrotic epithelium,
`` usually attached to underlying eroded/ulcerated mucosa
`` `` (diphtheritic membrane)

Joint:
`` white-yellow
`` friable material
`` floating within synovial fluid

Anterior ocular chamber:
`` floating white flakes

Front 14

Fibrinous exudate

o Microscopic:

Back 14

eosinophilic
`` meshwork of threads
`` or
`` `` amorphous,
`` `` homogeneous
`` coagulum

Front 15

Fibrinous exudate

Outcome: 2

Back 15

Fibrinous exudates may be
`` removed by fibrinolysis
`` and clearing by macrophages
`` This process of resolution may
`` `` restore normal tissue structure

When the fibrin is not removed,
`` it may stimulate the
`` `` ingrowth of
`` `` fibroblasts and
`` `` blood vessels
`` and thus lead to
`` `` organization process resulting in
`` `` `` fibrosis and
`` `` `` scarring

Front 16

Aging of serosal fibrinous exudate:

Back 16

If fibrinous membranes peel off easily from the serosal surfaces,
`` then the fibrin has been there
`` `` less than ~ 4 days
`` `` (acute inflammatory process)

If fibrinous membranes are attached to the serosa and are difficult to peel off,
`` then organization process of fibrin
`` `` has begun and it is
`` `` older than ~ 4 days
`` `` subacute-chronic inflammation, or
`` `` chronic-active

Note - do NOT peel fibrinous mucosal exudate
`` rinse off luminal contents only
`` tf do not describe as friable

Front 17

Fibinous Exudate

Examples 6

Back 17

Fibrinous polyserositis
`` Po: Glasser’s disease
`` `` Haemophilus parasuis

Fibrinous bronchopneumonia
`` Bo: Shipping fever –
`` `` Manheimia haemolytica

Fibrinous pericarditis
`` Bo: hardware disease

Fibrinous enteritis/enterocolitis
`` All spp:
`` `` Salmonellosis;
`` Bo:
`` `` Coccidiosis

Feline infectious peritonitis
`` FIP virus

Fibrinous erosive tracheitis
`` Bo: Infectious bovine rhinotracheitis
`` `` (IBR) virus

Front 18

If fibrinous exudate is mixed/infiltrated by many neutrophils, it is

Back 18

called
`` `` fibrinopurulent or
`` `` fibrinosuppurative
`` exudate

Front 19

Suppurative or purulent exudate

Back 19

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

Certain bacteria
`` `` (e.g. Arcanobacterium pyogenes)
`` produce this localized suppuration and
`` are therefore referred to as
`` `` pyogenic (pus-producing) bacteria

Front 20

Suppurative or purulent exudate

Morphology

Gross 3

Back 20

within tissue or cavity
`` Opaque,
`` thick,
`` creamy fluid
`` `` pus

Unlike fibrinous exudate,
`` it is extremely difficult to determine
`` `` duration of suppurative exudate
`` `` unless it is accompanied by
`` `` `` fibrosis in which case
`` `` `` `` it is chronic

Pus is liquid;
`` therefore, it tends to
`` `` settle by gravity within cavities
`` Accordingly, in suppurative meningitis,
`` `` it will be more abundant in the
`` `` ventral portions of the meninges
`` `` `` along brain stem
`` `` then in dorsal portions of cerebrum

Front 21

Suppurative or purulent exudate

Morphology

Microscopic

Back 21

homogeneous,
`` disintegrated and
`` liquefied necrotic tissue
`` and neutrophils

Front 22

Suppurative or purulent exudate

Diagnostic significance: 2

Back 22

Presence of neutrophils indicates
`` that lesion is
`` `` acute or
`` `` chronic-active

It is predominantly caused
`` by bacteria

Front 23

Abscess is

Back 23

localized accumulation of pus
`` surrounded by fibrous wall
`` `` (capsule)

Pus usually contains
`` `` bacteria
`` which are stimulus for
`` `` continuous migration of
`` `` ` neutrophils

The fibrous wall
`` `` isolates and
`` `` prevents
`` this infectious process from spreading

Ideally,
`` neutrophils
`` `` gain control over infection,
`` `` kill bacteria and
`` `` together with macrophages
`` `` `` clean debris

Capsule in this case becomes
`` thicker and thicker until
`` `` `` the entire abscess is organized by
`` `` `` `` ingrowth of
`` `` `` `` `` angioblasts and
`` `` `` `` `` fibroblasts

However, some bacteria (
`` `` e.g. Corynebacterium pseudotuberculosis)
`` are
`` `` resilient and
`` `` not easily killed
`` by neutrophils

Consequently,
`` a large amount of pus surrounded by
`` `` thin capsule represents
`` `` `` an abscess in which
`` `` `` `` body defenses are barely able to cope with
`` `` `` `` `` infection and
`` `` `` `` `` isolation
``Caseous lymphadenitis of sheep
`` `` with onion-like abscess appearance
`` is a good example

The abscess “onion-rings” represent
`` previous fibrous capsules that were
`` `` overwhelmed by the spreading suppuration,
`` with a new capsule forming around the ever-enlarging abscess

Front 24

Hemorrhagic inflammation –

Back 24

usually peracute inflammation with
`` vascular necrosis

Front 25

Mucoid = catarrhal inflammation –

Back 25

on mucus membranes
`` (e.g. nasal cavity)

Front 26

Non-suppurative inflammation –

Back 26

mononuclear
`` lymphocytes,
`` plasma cells,
`` macrophages
inflammatory infiltration

(e.g. viral infection in the CNS)

Front 27

Granulomatous inflammation is

Back 27

a distinctive pattern of
`` chronic inflammatory reaction
`` characterized by focal accumulations of
`` `` activated macrophages,
`` `` `` which often develop an epithelioid appearance

Front 28

A granuloma is

Back 28

a focus of chronic inflammation consisting of
`` a aggregation of
`` `` epithelioid macrophages
`` `` `` often with giant cells
`` `` surrounded by
`` `` `` lymphocytes,
`` `` `` occasionally plasma cells and
`` `` `` fibroblasts.

Examples:
`` `` Mycobacterial,
`` `` fungal,
`` `` foreign body
`` granulomas

Front 29

Inflammation

Morphologic diagnosis

Back 29

It is interpretive summary of
`` `` the gross or
`` `` microscopic
`` description of pathological changes which
`` `` must indicate
`` `` `` location and
`` `` `` process
`` ``together with a few most useful adjectives
`` `` `` severity,
`` `` `` duration,
`` `` `` distribution,
`` `` `` type of exudate,
`` `` `` and/or other modifier

Front 30

Inflammation

Morphologic diagnosis

Severity 4

Back 30

Minimal

Mild

Moderate

Severe

Front 31

Inflammation

Morphologic diagnosis

Duration 5

Back 31

Peracute

Acute

Subacute

Chronic

Chronic-active

Front 32

Inflammation

Morphologic diagnosis

Distribution 6

Back 32

Focal

Multifocal

Locally extensive

Diffuse

Bilateral

Zonal

Front 33

Inflammation

Morphologic diagnosis

Exudate 6

Back 33

Serous

Fibrinous

Purulent

Granulomatous

Caseous

Non-suppurative

Front 34

Inflammation

Morphologic diagnosis

Other 6

Back 34

Erosive

Ulcerative

Necrotizing

Proliferative

Fibrous

Anat. location

Front 35

Inflammation

Morphologic diagnosis

itis

Back 35

When process is inflammation

Dont Forget it !!!!!!!!!

ie Hepatiits

Front 36

ACUTE INFLAMMATION

Back 36

The vascular and cellular inflammatory reactions are
`` mediated by
`` `` chemical mediators that are derived from
`` `` `` plasma proteins or
`` `` `` cells
`` `` in response to the inflammatory stimulus

Front 37

Stimuli for acute inflammation: 6

Back 37

Infections
`` `` bacterial,
`` `` viral,
`` `` parasitic
`` and microbial toxins

Trauma
`` `` blunt and
`` `` penetrating

Physical and chemical agents
`` thermal injury,
`` `` burns or
`` `` frostbite;
`` `` irradiation;
`` `` environmental chemicals

Tissue necrosis
`` `` from any cause

Foreign bodies
`` `` splinters,
`` `` dirt,
`` `` sutures

Immune reactions
`` also called hypersensitivity reactions


Each of these stimuli may induce
`` reactions with some distinctive features,
`` but all inflammatory reactions
`` `` share the same basic features

Front 38

Inflammation

VASCULAR CHANGES

Back 38

Normally,
`` `` plasma proteins and
`` `` circulating cells
`` are sequestered inside
`` `` the vessels
`` and move in the direction of flow

In inflammation,
`` blood vessels undergo a series of changes that are
`` designed to maximize the movement of
`` `` plasma proteins and
`` `` circulating cells
`` out of the circulation and
`` into the site of injury or infection

Front 39

Changes in blood flow and vascular caliber and permeability

The vascular changes occur in the following order :

Back 39

Vasodilation induced by
`` `` histamine,
`` `` prostaglandins and
`` `` nitric oxide:
`` `` `` arteriolar dilatation
`` increased blood volume
`` `` opening of new capillary beds in the area
`` `` `` hyperemia
`` `` `` ↑ heat and
`` `` `` ↑ redness

Increased permeability of the microvasculature
`` induced by
`` `` histamine,
`` `` bradykinin,
`` `` leukotrienes,
`` `` anaphylatoxins
`` `` `` C3a and
`` `` `` C5a
`` `` cytokines]
`` outpouring of protein-rich fluid into
`` `` the extravascular tissues

The loss of fluid results in
`` concentration of cellular fraction of blood
`` `` in capillaries and
`` `` venules,
`` increased viscosity of the blood,
`` and slower blood flow
`` `` (stasis)

Neutrophils accumulate along the vascular endothelium,
`` stick to the endothelium,
`` and soon afterward
`` `` migrate through the vascular wall into
`` `` `` the interstitial tissue

Front 40

A hallmark of acute inflammation is

Back 40

increased vascular permeability
`` leading to the escape of a protein-rich fluid
`` `` `` (exudate)
`` `` into the extravascular tissue

The loss of proteins from the plasma
`` `` due to increased endothelial leakage
`` reduces the intravascular osmotic pressure
`` and increases the osmotic pressure of the interstitial fluid

Together with the increased hydrostatic pressure
`` `` owing to increased blood flow through the dilated vessels,
`` this leads to a marked outflow of fluid
`` and its accumulation in the interstitial tissue

The net increase of extravascular fluid results in
`` `` edema

Front 41

Mechanisms of increased endothelial leakage 5

Back 41

Immediate and Transient Leakage

Delayed Leakage

Immediate and Sustained Leakage

Leukocyte Mediated Endothelial injury

Leakage from new Blood Vessels

Front 42

Immediate and transient leakage is

Back 42

caused by formation of endothelial gaps
`` induced by
`` `` histamine,
`` `` bradykinin,
`` `` leukotrienes

It occurs rapidly after
`` exposure to the mediator
`` and is usually reversible
`` and short-lived
`` `` (15 to 30 minutes)

Mediators initiate
`` contraction of cytoskeletal proteins
`` `` (myosin)
`` leading to contraction of the
`` `` endothelial cells and
`` `` formation of intercellular gaps

Front 43

Delayed leakage is

Back 43

caused by formation of endothelial
`` gaps induced by
`` `` cytokines
`` `` `` interleukin-1 (IL-1),
`` `` `` tumor necrosis factor (TNF),
`` `` and interferon-γ (IFN-γ)

In contrast to the histamine effect,
`` the cytokine-induced response is
`` `` somewhat delayed
`` `` ` (4 hours)
`` `` and long-lived
`` `` `` (12 - 24 hours)

Similar to the histamine effect,
`` cytokines induce increase vascular permeability by
`` `` structural reorganization of the cytoskeleton,
`` `` `` such that the endothelial cells retract from one another
`` `` `` and form intercellular gaps

Front 44

Immediate and sustained leakage is

Back 44

caused by
`` direct endothelial injury,
`` resulting in endothelial cell
`` `` necrosis and
`` `` detachment

This effect is usually encountered in
`` `` necrotizing injuries
`` and is due to
`` `` direct damage to the endothelium
`` `` by the injurious stimulus
`` `` `` burns,
`` `` `` bacterial toxins

In most instances,
`` leakage starts
`` `` immediately after injury
`` and is sustained at a high level for
`` `` several hours
`` until the damaged vessels are
`` `` thrombosed or
`` `` repaired

Front 45

Leukocyte-mediated endothelial injury.

Back 45

Activated leukocytes
`` adhere to endothelium
`` `` relatively early in inflammation

They may release
`` `` toxic oxygen species
`` `` and proteolytic enzymes,
`` which then may cause
`` `` endothelial injury or
`` `` detachment

Front 46

Leakage from new blood vessels

Back 46

during repair,
`` endothelial cells
`` `` (angioblasts)
`` proliferate
`` and form new blood vessels,
`` `` a process called angiogenesis

New vessel sprouts
`` remain leaky until
`` the endothelial cells
`` `` mature and
`` `` `` form intercellular junctions

Front 47

In summary,

in acute inflammation,

fluid loss from vessels with increased permeability

occurs in distinct phases: 3

Back 47

an immediate transient response
`` lasting for ~ 30 minutes
`` mediated by
`` `` histamine,
`` `` bradykinin and
`` `` leukotrienes

a delayed response
`` starting at about
`` `` 4 hours
`` and lasting for
`` `` 12-24 hours
`` mediated by
`` `` cytokines

a prolonged response that is
`` most noticeable after
`` `` direct endothelial injury by
`` `` `` toxins and
`` `` `` leukocytes

Front 48

Exudate

Charcteristics 6

Back 48

Apperance
`` Turbid to opaque,
`` `` variable color

Etiology
`` Inflammation

Prtein Content
`` >30 g/L

Clottable
`` Sometimes

Necleated Cells
`` >1.5 x 109/L*
`` `` * >5-9 x 109 cells per liter are present before an exudate is suspected in horses

Bacteria
`` Sometimes

Front 49

Transudate

Charcteristics 6

Back 49

Appearance
`` Clear or
`` lightly yellow

Etiology
`` Hemodynamic imbalance

Protein Content
`` <30 g/L

Clottable
`` Rarely

Nucleated Cells
`` <1.5 x 109/L

Bacteria
`` Almost never

Front 50

Inflammation

CELLULAR EVENTS

A critical function of inflammation is to

Back 50

activate and deliver leukocytes to the site of injury

Leukocytes
`` ingest offending agents,
`` kill microbes, and
`` get rid of
`` `` necrotic tissue and
`` `` foreign substances

A price that is paid for the defensive potency of leukocytes is
`` that they may
`` `` induce tissue damage and
`` `` prolong inflammation,
`` since the leukocyte products that destroy
`` `` microbes and
`` `` necrotic tissues
`` can also injure normal host tissues

Front 51

Mechanisms of increased endothelial leakage 5

Back 51

Immediate and Transient Leakage

Delayed Leakage

Immediate and Sustained Leakage

Leukocyte Mediated Endothelial injury

Leakage from new Blood Vessels

Front 52

Immediate and transient leakage is

Back 52

caused by formation of endothelial gaps
`` induced by
`` `` histamine,
`` `` bradykinin,
`` `` leukotrienes

It occurs rapidly after
`` exposure to the mediator
`` and is usually reversible
`` and short-lived
`` `` (15 to 30 minutes)

Mediators initiate
`` contraction of cytoskeletal proteins
`` `` (myosin)
`` leading to contraction of the
`` `` endothelial cells and
`` `` formation of intercellular gaps

Front 53

Delayed leakage is

Back 53

caused by formation of endothelial
`` gaps induced by
`` `` cytokines
`` `` `` interleukin-1 (IL-1),
`` `` `` tumor necrosis factor (TNF),
`` `` and interferon-γ (IFN-γ)

In contrast to the histamine effect,
`` the cytokine-induced response is
`` `` somewhat delayed
`` `` ` (4 hours)
`` `` and long-lived
`` `` `` (12 - 24 hours)

Similar to the histamine effect,
`` cytokines induce increase vascular permeability by
`` `` structural reorganization of the cytoskeleton,
`` `` `` such that the endothelial cells retract from one another
`` `` `` and form intercellular gaps

Front 54

Immediate and sustained leakage is

Back 54

caused by
`` direct endothelial injury,
`` resulting in endothelial cell
`` `` necrosis and
`` `` detachment

This effect is usually encountered in
`` `` necrotizing injuries
`` and is due to
`` `` direct damage to the endothelium
`` `` by the injurious stimulus
`` `` `` burns,
`` `` `` bacterial toxins

In most instances,
`` leakage starts
`` `` immediately after injury
`` and is sustained at a high level for
`` `` several hours
`` until the damaged vessels are
`` `` thrombosed or
`` `` repaired

Front 55

Leukocyte-mediated endothelial injury.

Back 55

Activated leukocytes
`` adhere to endothelium
`` `` relatively early in inflammation

They may release
`` `` toxic oxygen species
`` `` and proteolytic enzymes,
`` which then may cause
`` `` endothelial injury or
`` `` detachment

Front 56

Leakage from new blood vessels

Back 56

during repair, endothelial cells
`` `` angioblasts
`` proliferate
`` and form new blood vessels,
`` `` a process called angiogenesis

New vessel sprouts
`` remain leaky until
`` `` the endothelial cells mature
`` `` and form intercellular junctions

Front 57

In summary,

in acute inflammation,

fluid loss from vessels with increased permeability

occurs in distinct phases: 3

Back 57

an immediate transient response
`` lasting for
`` `` 30 minutes
`` mediated by
`` `` histamine,
`` `` bradykinin and
`` `` leukotrienes

a delayed response
`` starting at about
`` `` 4 hours
`` and lasting for
`` `` 12-24 hours
`` mediated by
`` `` cytokines

a prolonged response that is
`` most noticeable after
`` `` direct endothelial injury by
`` `` `` toxins and
`` `` `` leukocytes

Front 58

Exudate

Characterisitcs 6

Back 58

Appearance
`` Turbid to opaque,
`` variable color

Etiology
`` Inflammation

Protein Content
`` >30 g/L

Clottable
`` Sometimes

Nectleated Cells
`` >1.5 x 109/L*
`` `` * >5-9 x 109 cells per liter are present before an exudate is suspected in horses

Bacteria
`` Sometimes

Front 59

Transudate

Characteristics 6

Back 59

Apperarnce
`` Clear or
`` lightly yellow

Etiology
`` Hemodynamic imbalance

Protein Content
`` <30 g/L

Clottable
`` Rarely

Nucleated Cells
`` <1.5 x 109/L

Bacteria
`` Almost never

Front 60

Inflammation

CELLULAR EVENTS

A critical function of inflammation is

Back 60

to activate and deliver leukocytes to
`` the site of injury

Leukocytes
`` `` ingest offending agents,
`` `` kill microbes,
`` `` and get rid of
`` `` `` necrotic tissue and
`` `` `` foreign substances

Front 61

Inflammation

CELLULAR EVENTS

A price that is paid

for the defensive potency of leukocytes is

Back 61

that they may
`` `` induce tissue damage
`` `` and prolong inflammation,
`` since the leukocyte products that destroy
`` `` microbes and
`` `` necrotic tissues
`` can also injure normal host tissues

Front 62

The sequence of leukocytic events can be divided into: 4

Back 62

In the lumen:
`` margination,
`` rolling, and
`` adhesion to endothelium

Normal vascular endothelium
`` does not interact with
`` `` circulating blood cells
`` and prevents their extravasation

Activated endothelium permits
`` `` attachment and
`` `` exit of leukocytes
`` from the blood vessels

Transmigration across the endothelium
`` (also called diapedesis)

Migration in interstitial tissues
`` toward a chemotactic stimulus
`` `` (chemotaxis)

Phagocytosis
`` and synthesis of biochemical mediators

Front 63

Leukocyte Migration

6 Steps

Back 63

Margination

Rolling

Firm Adhesion

Diapedesis

Chemotaxis

Phagocytosis

Front 64

Transudate

Characteristics 6

Back 64

Apperarnce
`` Clear or
`` lightly yellow

Etiology
`` Hemodynamic imbalance

Protein Content
`` <30 g/L

Clottable
`` Rarely

Nucleated Cells
`` <1.5 x 109/L

Bacteria
`` Almost never

Front 65

Inflammation

CELLULAR EVENTS

A critical function of inflammation is

Back 65

to activate and deliver leukocytes to
`` the site of injury

Leukocytes
`` `` ingest offending agents,
`` `` kill microbes,
`` `` and get rid of
`` `` `` necrotic tissue and
`` `` `` foreign substances

Front 66

Inflammation

CELLULAR EVENTS

A price that is paid

for the defensive potency of leukocytes is

Back 66

that they may
`` `` induce tissue damage
`` `` and prolong inflammation,
`` since the leukocyte products that destroy
`` `` microbes and
`` `` necrotic tissues
`` can also injure normal host tissues

Front 67

The sequence of leukocytic events can be divided into: 4

Back 67

In the lumen:
`` margination,
`` rolling, and
`` adhesion to endothelium

Normal vascular endothelium
`` does not interact with
`` `` circulating blood cells
`` and prevents their extravasation

Activated endothelium permits
`` `` attachment and
`` `` exit of leukocytes
`` from the blood vessels

Transmigration across the endothelium
`` (also called diapedesis)

Migration in interstitial tissues
`` toward a chemotactic stimulus
`` `` (chemotaxis)

Phagocytosis
`` and synthesis of biochemical mediators

Front 68

Leukocyte Migration

6 Steps

Back 68

Margination

Rolling

Firm Adhesion

Diapedesis

Chemotaxis

Phagocytosis

Front 69

Margination

Back 69

Process of leukocyte accumulation

Venular blood flow slows early in
`` inflammation
`` `` (stasis)

and white cells assume
`` a peripheral position
`` along the endothelial surface

Front 70

Rolling

Back 70

individual and then rows
`` of leukocytes
`` tumble slowly along
`` the endothelium and
`` adhere
`` `` transiently

Front 71

Firm Adherence

Back 71

coming to rest at some point
`` along endothelium

Front 72

Diapedesis begins:

Back 72

leukocytes insert pseudopods into
`` the junctions between
`` `` the endothelial cells,
`` squeeze through interendothelial junctions,
`` and assume a position between
`` `` the endothelial cell and
`` `` the basement membrane

Front 73

Chemotaxis

Back 73

Leukocytes
`` traverse the basement membrane
`` and escape into the extravascular space
`` towards the focus of infection

Front 74

Phagocytosis

Back 74

to ingest and kill microbes –

Front 75

Neutrophils, monocytes, lymphocytes, eosinophils, and basophils all

Back 75

use the same pathway to
`` migrate from the blood into tissues

Front 76

Leukocyte adhesion and transmigration are regulated largely by

Back 76

the binding of
`` complementary adhesion molecules
`` on the
`` `` leukocyte and
`` `` endothelial
`` surfaces

Chemical mediators
`` `` chemoattractants and
`` `` certain cytokines
`` affect these processes by
`` altering the
`` `` surface expression or
`` `` avidity of
`` such adhesion molecules

Front 77

The adhesion receptors

involved in

leukocyte adhesion and transmigration

belong to four molecular families:

Back 77

Selectins

Integrins

Immunoglobulins

Mucin like Glycoproteins

Front 78

Selectins

Back 78

are sugar-binding proteins
`` on endothelium
`` `` E-selectin,
`` `` P-selectin),
`` on platelets
`` `` P-selectin),
`` and on leukocytes
`` `` L-selectin

E- and P-selectins bind to
`` glycoproteins
`` `` sialylated forms of oligosaccharides -
`` `` `` sialylated Lewis X
`` on leukocytes and
`` `` mediate the rolling phase

Front 79

Integrins

Back 79

β1 and β2

are transmembrane heterodimeric glycoproteins
`` made up of
`` `` α and β chains,
`` that are
`` `` expressed on leukocytes and
`` `` bind to ligands
`` `` `` ICAM-1,
`` `` `` VCAM-1
`` on endothelial cells
`` `` firm adhesion

Front 80

Immunoglobulin superfamily:

Back 80

ICAM-1
`` `` intercellular adhesion molecule 1
`` and
VCAM-1
`` `` vascular cell adhesion molecule 1
`` on endothelium serve as
`` ligands for
`` `` integrins found on leukocytes

Front 81

Mucin-like glycoproteins

Back 81

(heparan sulfate)

contain a carbohydrate domain
`` `` (“sticky sugar”)
`` that serve as ligands for selectins
`` `` E,
`` `` P,
`` `` L

Front 82

Endothelial molecules 5

Back 82

P-selectin
`` rolling

E-selectin
`` rolling

ICAM-1
`` Firm adhesion

VCAM-1
`` Firm adhesion

CD31
`` leukocyte migration through endothelium

Front 83

Leukocyte molecules 5

Back 83

Glycoprotein (Sialyl-Lewis X)
`` rolling

Glycoprotein (Sialyl-Lewis X)
`` rolling

Integrins β2
`` firm adhesion

Integrins β1
`` firm adhesion

CD31
`` leukocyte migration through endothelium

Front 84

Rolling of leukocytes: 2

Back 84

Appearance of P- and E-selectins on endothelial surface:
`` Histamine and thrombin stimulate
`` the redistribution of
`` `` P-selectin from its normal
`` `` `` intracellular stores in granules
`` `` `` `` (Weibel-Palade bodies)
`` to the cell surface.

TNF and IL-1
`` `` (produced by activated leukocytes)
`` act on the endothelial cells
`` and within
`` `` 1 to 2 hours
`` E-selectin is expressed

Endothelial selectins bind carbohydrate ligands
`` expressed on leukocytes

This low-affinity binding is easily disrupted by
`` the flowing blood

As a result,
`` the bound leukocytes
`` `` detach and bind again,
`` and thus begin to roll along
`` `` the endothelial surface

Front 85

Firm adhesion of leukocytes to endothelial cells

Back 85

TNF and IL-1 also induce
`` endothelial expression of ligands for integrins,
`` `` mainly VCAM-1 and
`` `` ICAM-1

Leukocytes normally express these integrins in a
`` low-affinity state

Meanwhile, chemokines
`` `` that were produced at the site of injury
`` enter the blood vessel,
`` bind to endothelial cell membrane proteins
`` and are displayed at high concentrations on
`` `` the endothelial surface adjacent to the inflamed tissue

These chemokines activate the
`` rolling leukocytes

Consequently, integrins on the leukocytes are also
`` activated and they
`` `` firmly adhere to their ligands
`` `` VCAM-1 and
`` `` ICAM-1
`` on the endothelium
`` `` firm adhesion

The leukocytes stop rolling,
`` their cytoskeleton is reorganized,
`` and they spread out on the endothelial surface
`` `` (which is ‘paved by leukocytes’)

The type of inflammatory infiltrate
`` `` recruited to the sight of injury
`` depends on type of
`` `` chemokines attached to the endothelium
`` `` `` IL-8 will recruit neutrophils
`` `` `` macrophage inflammatory protein (MIP-1) attracts macrophages

Front 86

Transmigration (emigration) or diapedesis of leukocytes through endothelium

Back 86

Chemokines act on the
`` adherent leukocytes
`` and stimulate them to
`` `` migrate through interendothelial spaces
`` toward the chemical concentration gradient,
`` `` that is, toward the inflamed site

When neutrophils reach interendothelial cell junction,
`` CD31 adhesion molecules on neutrophils
`` `` recognize and bind to
`` `` `` their twins,
`` `` `` `` CD31,
`` `` on the endothelial cell junctions

This is “an exit signal”
`` and neutrophils
`` `` squeeze through endothelial cell junctions,
`` `` secrete proteinases
`` `` `` to get through the basement membrane
`` and crawl into the perivascular tissue

Once leukocytes enter the extravascular connective tissue,
`` they are able to adhere to the extracellular matrix by
`` `` β1 integrins

The type of emigrating leukocyte
`` varies with
`` `` the age of the inflammatory response and
`` `` with the type of stimulus

In most forms of acute inflammation,
`` neutrophils predominate in the inflammatory infiltrate during
`` `` the first 6 to 24 hours,
`` and then they are replaced by
`` `` monocytes in
`` `` `` 24 to 48 hours

Several reasons account for this sequence:
`` i) neutrophils are more numerous in the blood,
`` ii) they respond more rapidly to chemokines, and
`` iii) they may attach more firmly to the adhesion molecules that are
`` `` rapidly induced on endothelial cells
`` iv) after entering tissues,
`` `` neutrophils are short-lived;
`` `` `` they undergo apoptosis and disappear after
`` `` `` `` 24 to 48 hours,
`` v) monocytes survive longer

There are exceptions to this pattern of cellular exudation

In viral infections,
`` lymphocytes may be the first cells to arrive;

in some hypersensitivity reactions,
`` eosinophilic granulocytes may be the main cell type

These differences are determined by
`` inflammatory mediators
`` `` e.g. chemokines

Front 87

Chemotaxis

Back 87

Chemotaxis is
`` directed movement of cells toward a chemical attractant
`` or leukocytic locomotion oriented along a chemical gradient

Both exogenous and endogenous substances can
`` act as chemoattractants

The most common exogenous agents are
`` bacterial products
`` `` peptide with N-formyl-methionine terminal amino acid or
`` `` lipids

Endogenous chemoattractants include several chemical mediators:
`` components of the complement system,
`` `` particularly C5a
`` products of the lipoxygenase pathway,
`` `` mainly leukotriene B4
`` cytokines,
`` `` particularly those of the chemokine family
`` `` `` IL-8,
`` `` `` MIP-1

Front 88

So, how does the leukocyte sense the chemotactic agents,

and

how do these substances induce directed cell movement?

Back 88

All the chemotactic agents mentioned above bind to specific receptors on the surface of leukocytes

Probably more receptors for chemokines are
`` occupied on one side of the cell,
`` `` (the side nearest to the inflamed tissue,)
`` providing a clue for the chemotactic direction

Signals initiated from these receptors result in
`` activation of several effectors that
`` ultimately increase
`` `` cytosolic calcium and
`` `` induce polymerization of actin-myosin filaments
`` `` `` (“tiny cellular muscles”)
`` `` at the leading edge of the cell
`` `` ` (closest to the inflamed area)

The leukocyte moves by
`` extending pseudopodia that
`` `` pull the back of the cell in
`` `` `` the direction of extension

Locomotion involves rapid assembly of
`` actin monomers into
`` linear polymers at the pseudopod's leading edge,
`` followed by disassembly of such filaments
`` `` away from the leading edge

Front 89

Leukocyte activation

Back 89

`` Microbes,
`` products of necrotic cells,
`` antigen-antibody complexes, and
`` cytokines,
`` `` including chemotactic factors,
`` induce a number of responses in
`` `` leukocytes
`` that are part of the defensive functions referred to
`` `` under the name of
`` `` `` leukocyte activation

Front 90

Leukocyte activation

Activation results from

Back 90

several signaling pathways that are
`` triggered in leukocytes,
`` `` resulting in increase in cytosolic calcium and
`` `` activation of enzymes such as
`` `` `` protein kinase C and
`` `` `` phospholipase A2

Front 91

The functional responses that are induced on leukocyte activation

include the following: 4

Back 91

Production of arachidonic acid metabolites
`` `` (eicosanoids)
`` from phospholipids,
`` as a result of activation of
`` `` phospholipase A2
`` by increased intracellular calcium


Degranulation and secretion of lysosomal enzymes
`` and activation of the oxidative burst

Secretion of cytokines,
`` which amplify and
`` `` regulate inflammatory reactions
``Activated macrophages are the
`` chief source of the cytokines that are
`` `` involved in inflammation

Modulation of leukocyte adhesion molecules
`` different cytokines cause
`` `` increased endothelial expression of adhesion molecules
`` `` and increased avidity of leukocyte integrins,
`` allowing firm adhesion of activated neutrophils to
`` `` endothelium

Front 92

Phagocytosis and the release of enzymes by neutrophils and macrophages are responsible for

Back 92

eliminating the injurious agents

Front 93

Phagocytosis involves three distinct but interrelated steps:

Back 93

recognition and binding of the particle to be ingested by the leukocyte

its engulfment,
`` with subsequent formation of a phagosome

killing or degradation of the ingested material

Front 94

Phagocytosis

Recognition and binding

Back 94

Typically the phagocytosis of
`` `` microbes and
`` ``dead cells
``is initiated by
`` `` recognition of the particles by
`` `` receptors expressed on the leukocyte surface

Front 95

Phagocytosis

Recognition and binding

Mannose receptors and scavenger receptors are

Back 95

two important receptors that
`` `` bind microbes
`` which are subsequently ingested by macrophages

The mannose receptor is a macrophage lectin that binds
`` `` terminal mannose and
`` `` fucose residues of
`` glycoproteins and glycolipids expressed only
`` `` on microbial cell walls
`` `` and not on the host cells

Front 96

Phagocytosis

Recognition and binding

The efficiency of phagocytosis is

Back 96

greatly enhanced
`` when microbes are
`` `` opsonized by
`` `` `` specific proteins
`` `` `` `` (opsonins)
`` `` for which the phagocytes express
`` `` `` high-affinity receptors

Front 97

Opsonin

Back 97

protein that binds to
`` antigens and
`` enhances their phagocytosis

Front 98

opsonization,

Back 98

The process of coating a particle,
`` `` such as a microbe,
`` to target it for
`` `` phagocytosis

substances that do this are opsonins

Front 99

The major opsonins are

Back 99

IgG antibodies
`` (acquired immunity),

complement protein
`` C3b,

mannose-binding lectin

C-reactive protein

last three are part of
`` `` innate immunity
`` all of which are recognized by
`` `` specific receptors on phagocytes

Front 100

Receptors for opsonins

Back 100

promote phagocytosis of opsonized microbes
`` and deliver signals that activate the phagocytes

Front 101

Phagocytosis

Engulfment

Back 101

Binding of a particle to phagocytic leukocyte receptors
`` initiates the process of
`` `` active phagocytosis of the particle

During engulfment,
`` extensions of the cytoplasm
`` `` (pseudopods)
`` flow around the particle to be engulfed,
`` eventually resulting in
`` `` complete enclosure of the particle within
`` a phagosome created by the plasma membrane of the cell

The membrane of phagosome then
`` fuses with the membrane of a lysosome,
`` resulting in discharge of the lysosomal contents
`` `` into the phagolysosome

The process of phagocytosis is complex
`` and is dependent
`` `` inter alia
`` on polymerization of
`` `` actin filaments
`` `` similar, to chemotactic process

Front 102

Phagocytosis

Killing and degradation

Back 102

The ultimate step in the elimination of
`` `` infectious agents and
`` `` necrotic cells
``is their
`` `` killing and
`` `` degradation
`` within activated
`` `` neutrophils and
`` `` macrophages

Front 103

Phagocytosis

Killing and degradation

Microbial killing is accomplished largely by

Back 103

oxygen-dependent mechanisms

Phagocytosis stimulates production of
`` reactive oxygen intermediates
`` `` ROIs, also called
`` `` reactive oxygen species

Front 104

Oxygen dependent killing

Back 104

The H2O2 generated by the NADPH oxidase system is
`` generally not able to efficiently kill microbes by itself

However, the azurophilic granules of neutrophils
`` contain the enzyme myeloperoxidase
`` `` (MPO),
`` which,
`` `` in the presence of a halide
`` `` `` such as Cl-,
`` converts H2O2 to hypochlorite
`` `` (HOCl),
`` which is a potent antimicrobial agent
`` that destroys microbes by halogenation
`` `` (in which the halide is bound covalently to cellular constituents)
`` or by oxidation of
`` `` `` proteins and
`` `` `` lipids
`` ``(lipid peroxidation)

The H2O2-MPO-halide system is
`` the most efficient bactericidal system in
`` `` neutrophils

MPO-deficient leukocytes are
`` capable of killing bacteria
`` `` (although more slowly than normal cells),
`` by formation of
`` `` superoxide (O2ָ)
`` `` and hydroxyl radicals
`` `` `` (OH•)

In addition, reactive nitrogen intermediates
`` `` e.g. nitric oxide (NO)
`` `` `` which also helps to kill microbes
`` `` are generated

Front 105

Oxygen-independent killing 6

Back 105

Various substances in leukocyte lysosomal granules
`` have antimicrobial activity

Bactericidal permeability increasing protein
`` ``(BPI)
`` causes increased permeability in the outer membrane of the microorganisms

Lysozyme hydrolyzes the muramic acid-N-acetyl-glucosamine bond in
`` the glycopeptide coat of
`` `` all bacteria

Eosinophilic major basic protein
`` has limited bactericidal activity
`` but is cytotoxic to many parasites

Defensins,
`` `` small cationic peptides,
``are cytotoxic to microbes
`` `` (and certain mammalian cells

Lactoferrin suppresses bacterial growth by
`` binding and sequestrating iron

Enzymes
`` `` elastase,
`` `` collagenase
`` in leukocytic granules contribute to
`` `` microbial killing.

Front 106

Phagocytosis

After microbial killing,

Back 106

lysosomal acid proteases
`` degrade the microbes within phagolysosomes

After phagocytosis,
`` neutrophils rapidly undergo
`` `` apoptosis
`` and are ingested by macrophages

Front 107

Leukocyte-induced tissue injury

If persistent and unchecked

Back 107

leukocyte infiltrate itself becomes
`` the offender,
`` and leukocyte-dependent tissue injury
`` `` underlies many
`` `` `` acute and
`` `` chronic diseases

During activation and phagocytosis,
`` leukocytes release microbicidal and other products
`` `` not only within the phagolysosome but also
`` `` into the extracellular space

Release of lysosomal contents may occur:
``if the lysosome releases its substances into
`` `` the transiently open phagosome
`` `` regurgitation during feeding
``if leukocytes are exposed to potentially ingestible materials,
`` `` such as immune complexes deposited on immovable flat surfaces
`` `` glomerular basement membrane
`` attachment of leukocytes to the immune complexes triggers
`` ``leukocyte activation,
`` `` ``but the fixed immune complexes cannot be phagocytosed,
`` `` `` and lysosomal enzymes are released into the medium
`` frustrated phagocytosis

Front 108

The most important lysosomal substances that cause tissue injury are: 2

Back 108

Lysosomal enzymes

Reactive oxygen intermediates:

Front 109

Tissue Injury

Lysosomal enzymes:

Back 109

Neutral proteases are capable of
`` degrading various extracellular components
`` `` collagen,
`` `` basement membrane,
`` `` fibrin,
`` `` elastin,
`` `` cartilage
`` resulting in the tissue destruction that
`` `` accompanies inflammatory processes

These harmful proteases, however, are held in check by
`` antiproteases in
`` `` the serum and
`` `` tissue fluids
`` `` `` α1-antitrypsin,
`` `` `` α2-macroglobulin

Front 110

Tissue Injury

Reactive oxygen intermediates:

Back 110

Oxygen-derived free radicals may be released extracellularly from
`` activated leukocytes

Extracellular release of low levels of these potent mediators can
`` increase the expression of chemokines
`` `` `` IL-8
`` `` cytokines, and
`` `` endothelial leukocyte adhesion molecules,
`` amplifying the cascade that
`` elicits the inflammatory response

At higher levels, release of these potent mediators can
`` be damaging to the host

Front 111

Tissue Injury

Oxygen-derived free radicals

Are implicated in the following processes: 3

Back 111

Endothelial cell damage with
`` increased vascular permeability

Inactivation of antiproteases
`` `` (α1-antitrypsin)
``This leads to unopposed protease activity,
`` `` with increased destruction of extracellular matrix

Injury to other cell types
`` `` parenchymal cells,
`` `` red blood cells
`` Serum,
`` tissue fluids,
`` and host cells possess various antioxidants
`` `` superoxide dismutase,
`` `` catalase,
`` `` glutathione peroxidase,
`` `` ceruloplasmin,
`` `` transferrin
`` that protect the host against these potentially harmful oxygen-derived radicals

Front 112

CHEMICAL MEDIATORS OF INFLAMMATION

Back 112

Many inflammatory mediators have been identified,
`` and how they function in a coordinated manner is still not fully understood

Once activated and released from the cell,
`` most of these mediators are
`` ``short-lived

They quickly decay
`` `` arachidonic acid metabolites
`` or are inactivated by enzymes
`` `` kininase inactivates bradykinin
`` or they are otherwise scavenged
`` `` antioxidants scavenge toxic oxygen metabolites
`` or inhibited
`` `` complement regulatory proteins
`` `` `` break up and
`` `` `` degrade
`` `` `` `` activated complement components

There is thus a system of
`` checks and balances
`` in the regulation of mediator actions,
`` because most mediators have the potential to
`` `` cause harmful effects

A relatively small number of current drugs target
`` certain inflammatory mediators
`` `` or groups of mediators

Front 113

Plasma-derived mediators

Back 113

Plasma-derived mediators
`` `` kinins,
`` `` complement and
`` `` coagulation proteins
`` are present in plasma in precursor forms that
`` `` must be activated,
`` `` usually by a series of proteolytic cleavages,
`` to acquire their biologic properties

Front 114

Complement system

The complement system consists of

Back 114

proteins
`` `` (and their cleavage products)
`` produced by
`` `` liver
`` and secreted into plasma

This system functions in both
`` `` innate and
`` `` adaptive
`` immunity for defense against microbial agents

Front 115

Complement system

In the process of complement activation 4

Back 115

a number of complement components are elaborated
`` that cause
`` `` increased vascular permeability,
`` `` chemotaxis,
`` `` opsonization, and
`` `` lysis of cells

Front 116

Complement System

Complement proteins are present as

Back 116

inactive forms in
`` plasma and
`` are numbered C1 through C9

Front 117

Complement System

Many of these proteins are activated to become

Back 117

proteolytic enzymes that
`` degrade other complement proteins,
`` `` thus forming a cascade capable of
`` `` `` tremendous enzymatic amplification

Front 118

Complement System

The critical step in the elaboration of the biologic functions of complement is

Back 118

the activation of the third
`` `` (and most abundant) `` component,
`` `` C3

Front 119

Complement System

Cleavage of C3 can occur by one of three pathways:

Back 119

the classical pathway,
`` which is triggered by
`` `` fixation of C1 to
`` `` `` antibody
`` `` `` `` IgM
`` `` `` `` IgG
`` combined with antigen;

the alternative pathway,
`` which can be triggered by
`` `` microbial surface molecules
`` `` `` endotoxin, or
`` `` `` LPS
`` in the absence of antibody;

the lectin pathway,
`` in which plasma mannose-binding lectin binds to
`` `` carbohydrates on microbes
`` and directly activates C1.

Front 120

Complement System

Whichever pathway is involved

in the early steps of complement activation,

they all lead to

Back 120

the formation of an active enzyme
`` `` called the C3 convertase,
`` which splits C3 into two functionally distinct fragments,
`` `` C3a and
`` `` C3b

C3a is released
`` and C3b becomes covalently attached to
`` `` the cell or molecule where
`` `` `` complement is being activated

C3b then binds to the
`` previously generated fragments to form
`` `` C5 convertase,
`` `` `` which cleaves C5 to
`` `` `` `` release C5a

The remaining C5b binds
`` the late components
`` `` C6-C9
`` culminating in the formation of
`` `` the membrane attack complex
`` `` `` MAC,
`` `` `` `` composed of multiple C9 molecules

Front 121

Complement System

The biologic functions of the complement system

fall into four general categories:

Back 121

Vascular phenomena:
`` C3a and C5a components stimulate
`` `` histamine release from mast cells
`` and thereby increase
`` `` vascular permeability and
`` `` cause vasodilation
`` They are called anaphylatoxins because
`` `` they have effects similar to those of
`` `` `` mast cell mediators that are involved in the reaction called anaphylaxis

Chemotaxis:
`` C5a is a powerful chemotactic agent for
`` `` neutrophils,
`` `` monocytes,
`` `` eosinophils, and
`` `` basophils

Phagocytosis:
`` C3b, when fixed to the bacterial cell wall,
`` `` act as opsonins and
`` `` favor phagocytosis by
`` `` `` neutrophils and
`` `` `` macrophages,
`` which bear cell surface receptors for these complement fragments

Cell lysis:
`` MAC
`` `` (polymerized C9)
`` forms a channel in lipid membranes which
`` `` allows fluid and ions to enter and
`` `` `` causes cell lysis

Front 122

Complement System

The activation of complement is

Back 122

tightly controlled by regulatory proteins

`` These proteins are generally absent from microbes;
`` accordingly, complement is activated by and functions against microorganisms

The presence of these inhibitors in host cell membranes
`` protects the host from inappropriate damage during
`` `` protective reactions against patholgens

These regulatory mechanisms include:
`` Regulation of C3 and C5 Convertases
`` C1 inhibitor
`` MAC formation inhibition

Front 123

Complement System

Regulation of C3 and C5 convertases

Back 123

Since the formation of C3 convertase
`` and the generation of C3b are
`` `` the central features of all complement pathways,
`` it is not surprising that many of the regulatory proteins are
`` `` directed at controlling these activities

These regulators function by
`` enhancing the dissociation
`` ``` (decay acceleration)
`` of the convertase complex
`` `` decay-accelerating factor [DAF]
`` or by
`` `` proteolytically cleaving C3b
`` `` factor I

Front 124

Complement System

Activation of C1

Back 124

by an immune complex is
`` blocked by C1 inhibitor

Front 125

Complement System

Excessive complement activation is also prevented by

Back 125

a number of proteins that act to
`` inhibit MAC formation
`` `` CD59,
`` `` `` also called membrane inhibitor of reactive lysis

Front 126

Kinin system

Activation of the kinin system results in

Back 126

the release of the vasoactive bradykinin

Bradykinin causes
`` `` dilation of blood vessels,
`` `` increased vascular permeability
`` `` and pain
`` when injected into the skin

These effects are similar to those of
`` histamine

The cascade that eventually produces kinins is triggered
`` by activation of
`` `` Hageman factor
`` `` `` factor XII of the intrinsic clotting pathway
`` upon contact with negatively charged surfaces
`` `` LPS,
`` `` collagen

Acitvated factor XII
`` `` (XIIa = prekallikrein activator)
`` converts plasma prekallikrein into
`` `` kallikrein,
`` `` `` which cleaves high-molecular-weight kininogen,
`` to produce bradykinin

Kallikrein itself is a potent activator of
`` `` Hageman factor,
`` allowing for autocatalytic amplification of
`` `` the initial stimulus

Front 127

Clotting system and Inflamation

The clotting system and inflammation are

Back 127

intimately connected processes

The clotting system is divided into
`` two pathways that
`` `` converge,
`` culminating in the activation of
`` `` thrombin and
`` `` `` the formation of fibrin

Front 128

Clotting system and Inflammation

The intrinsic clotting pathway is

Back 128

a series of plasma proteins that
`` can be activated by Hageman factor
`` `` (factor XII),
`` a protein synthesized by
`` `` the liver
`` that circulates in an inactive form until
`` `` it encounters negatively charged surfaces
`` `` `` LPS,
`` `` `` collagen,
`` `` `` activated platelets

Front 129

Clotting system and Inflammation

Activated factor XII activates four mediator systems:

Back 129

Kinin system,
`` which produces vasoactive bradykinin

Clotting system,
`` which induces formation of thrombin and fibrin
`` Thrombin provides
`` `` the main link between the coagulation system and
`` `` inflammation
`` It induces mobilization of
`` `` P-selectin,
`` `` production of chemokines, and
`` `` expression of endothelial adhesion molecules;
`` `` induction of cyclooxygenase-2;
`` `` and production of nitric oxide

Fibrinolytic system,
`` which produces
`` `` plasmin and
`` `` degrades the fibrin

Complement system,
`` which produces anaphylatoxins
`` `` (C3a)

Front 130

Clotting System and Inflammation

Acute inflammation, by activating or damaging the endothelium, can

Back 130

trigger coagulation
`` and induce thrombus formation

Front 131

Clotting System and Inflammation

Conversely, the coagulation cascade induces

Back 131

inflammation,
`` primarily via
`` `` the actions of thrombin

Front 132

Cell-derived mediators

Cell-derived mediators are normally

Back 132

sequestered in intracellular granules that
`` need to be secreted
`` `` histamine in mast cell granules
`` or are synthesized de novo
`` `` prostaglandins,
`` `` cytokines
`` in response to a stimulus

Front 133

Cell-derived mediators

The major cellular sources

Back 133

are
`` `` platelets,
`` `` neutrophils,
`` `` monocytes-macrophages,
`` `` and mast cells,
`` but mesenchymal cells
`` `` endothelium,
`` `` smooth muscle,
`` `` fibroblasts
`` and most epithelia
`` can also be induced to
`` `` elaborate some of the mediators

Front 134

Vasoactive Amines

Histamine

Back 134

Preformed histamine is
`` present in granules of mast cell

It is also found in
`` `` blood basophils and
`` `` platelets

Since it is preformed and stored in granules,
`` histamine is among the
`` `` first mediators to be released during
`` `` `` inflammation

Front 135

Vasoactive Amines

Histamine is released by

Back 135

mast cell degranulation in response to
`` a variety of stimuli:

physical injury such as
`` `` trauma,
`` `` cold, or
`` `` heat

immune reactions involving
`` binding of antibodies to mast cells

fragments of complement called
`` anaphylatoxins
`` `` C3a and
`` `` C5a

cytokines
`` `` IL-1,
`` `` IL-8

Front 136

Vasoactive Amines

Histamine causes

Back 136

dilation of the arterioles
`` and increases the permeability of venules

Front 137

Vasoactive Amines

Histamine is considered to be

Back 137

the principal mediator of
`` the immediate transient phase of
`` `` increased vascular permeability,
`` `` causing endothelial gaps

Front 138

Vasoactive Amines

Serotonin is a

Back 138

preformed vasoactive mediator
`` with actions similar to those of histamine

It is present in
`` `` platelets and
`` `` in mast cells of
`` rodents
`` `` but not humans

Front 139

Arachidonic acid metabolites

Back 139

When cells are activated by diverse stimuli,
`` their membrane lipids are rapidly remodeled to
`` generate biologically active lipid mediators
`` that serve as
`` `` intracellular or
`` `` extracellular
`` signals to affect a variety of biologic processes,
`` `` including
`` `` inflammation and
`` `` hemostasis

Front 140

Arachidonic acid metabolites

Arachidonic acid (AA) is released from

Back 140

membrane phospholipids
`` through the action of
`` `` cellular phospholipase
`` `` `` A2,
`` `` which is activated by
`` `` `` mechanical,
`` `` `` chemical, and
`` `` `` physical stimuli
`` `` or by other mediators
`` `` `` C5a

Front 141

Arachidonic acid metabolites

AA metabolites,

also called eicosanoids,

are

Back 141

synthesized by two major classes of enzymes:

cyclooxygenases
`` `` prostaglandins and
`` `` thromboxanes

lipoxygenases
`` `` leukotrienes and
`` `` lipoxins

Front 142

Arachidonic acid metabolites

Eicosanoids bind to

Back 142

many cell types
`` and can mediate
`` `` virtually every step of
`` `` `` inflammation

Front 143

Anti-inflammatory therapy

can be directed at many targets along the

eicosanoid biosynthetic pathways: 3

Back 143

Cyclooxygenase Inhibitors

Lipooxygenase Inhibitors

Glucocorticoids

Front 144

Cyclooxygenase inhibitors include 3

Back 144

aspirin and other
`` nonsteroidal anti-inflammatory drugs
`` `` NSAIDs

Aspirin irreversibly inhibits
`` `` cyclooxygenase
`` by acetylation

COX-2 inhibitors are a newer class of these drugs

The finding that COX-2
`` is inducibly expressed only
`` `` in response to inflammatory stimuli
`` was the impetus for developing
`` `` antagonists against this enzyme to
`` `` `` reduce inflammation without
`` `` `` `` interfering with the physiologic functions of
`` `` `` `` `` AA metabolites mediated by COX-1
`` `` `` `` `` `` fluid and electrolyte balance in the kidneys,
`` `` `` `` `` `` cytoprotection in the gastrointestinal tract

Front 145

Lipoxygenase inhibitors:

Back 145

5-lipoxygenase
`` is not affected by NSAIDs,
`` and many new inhibitors of this enzyme pathway
`` `` have been developed for human medicine

Pharmacologic agents that
`` inhibit leukotriene production
`` or block leukotriene receptors
`` have been found useful
`` `` in the treatment of asthma

Front 146

Broad-spectrum Inflammation inhibitors include

Back 146

glucocorticoids

These powerful anti-inflammatory agents
`` may act by
`` `` down-regulating the expression of specific target genes,
`` `` `` including the genes encoding
`` `` `` `` COX-2,
`` `` `` ` phospholipase A2,
`` `` `` `` proinflammatory cytokines
`` `` `` `` `` such as IL-1 and
`` `` `` `` `` TNF
`` `` `` `` and nitric oxide synthase
`` `` `` `` `` iNOS

Glucocorticoids also
`` up-regulate genes that encode
`` `` potent anti-inflammatory proteins,
`` `` `` such as lipocortin 1

Lipocortin 1 inhibits release of
`` AA from membrane phospholipids

Front 147

Cytokines

Cytokines are

Back 147

proteins produced by
`` many cell types
`` `` principally activated
`` `` `` lymphocytes and
`` `` `` macrophages,
`` `` but also
`` `` `` endothelium,
`` `` `` epithelium, and
`` `` `` connective tissue cells
`` that modulate the functions of
`` `` other cell types

Front 148

Cytokines

TNF and IL-1 are two of the

Back 148

major cytokines that
`` mediate inflammation

They are produced mainly by
`` macrophages
`` `` activated by
`` `` `` endotoxin (LPS),
`` `` `` immune complexes,
`` `` `` physical injury,
`` `` `` and a variety of inflammatory stimuli

Front 149

Cytokines

TNF and IL-1

Their most important actions in inflammation are

Back 149

their effects on
`` `` endothelium,
`` `` leukocytes, and
`` `` fibroblasts

induction of systemic acute-phase reactions.

Front 150

TNF and IL-1

In endothelium, 3

Back 150

they induce the synthesis of
`` endothelial adhesion molecules
`` and chemical mediators,
`` `` including other
`` `` `` cytokines,
`` `` `` chemokines,
`` `` `` eicosanoids, and
`` `` `` nitric oxide (NO

they increases the surface thrombogenicity
`` of the endothelium.

Front 151

TNF and IL-1

They induce secretion of

Back 151

cytokines by
`` leukocytes

TNF also induces priming of
`` neutrophils,

leading to augmented responses of these cells
`` to other mediators.

Front 152

TNF and IL-1

They induce 3

Back 152

fibroblastic proliferation,

collagen synthesis

production of proteases

Front 153

TNF and IL-1

as well as IL-6

induce the systemic

Back 153

acute-phase responses
`` associated with
`` `` infection or
`` `` injury

Front 154

Chemokines

Chemokines are a family of 3

Back 154

small
`` `` (8 to 10 kD)
`` cytokines that act
`` `` primarily as chemoattractants
`` `` `` for specific types of leukocytes

IL-8 is secreted predominantly by
`` `` activated macrophages and
`` `` endothelial cells
`` and causes
`` `` activation and
`` `` chemotaxis
`` of neutrophils,
`` with limited activity on
`` `` monocytes and
`` `` eosinophils

Macrophage inflammatory protein-1α
`` `` (MIP-1α)
`` generally attracts
`` `` monocytes,
`` `` eosinophils,
`` `` basophils, and
`` `` lymphocytes
`` but not neutrophils

Eotaxin selectively recruits
`` eosinophils

Front 155

Nitric oxide (NO) 7

Back 155

Inducible nitric oxide synthase
`` `` (iNOS)
`` is induced when
`` `` macrophages and
`` `` other cells
`` are activated by
`` `` cytokines
`` `` `` TNF

NO causes
`` vasodilation by
`` `` relaxing vascular smooth muscle

NO free radicals are toxic to
`` `` microbial and
`` `` mammalian cells

In addition, NO reduces
`` platelet aggregation and
`` adhesion,
`` inhibits several features of
`` mast cell-induced inflammation,
`` and serves as an
`` `` endogenous regulator of
`` `` `` leukocyte recruitment

Blocking NO production under normal conditions
`` promotes leukocyte
`` `` rolling and
`` `` adhesion
`` in postcapillary venules

delivery of exogenous NO
`` `` reduces leukocyte recruitment

Thus, production of NO is an
`` endogenous compensatory mechanism that
`` `` reduces inflammatory responses

Front 156

mediators of acute inflammation 11

Back 156

Histamine and serotonin

Bradykinin

C3a

C5a

Prostaglandins

Leukotriene
`` B4

Leukotriene
`` C4,
`` D4,
`` E4

Oxygen metabolites

IL-1 and TNF

Chemokines

Nitric oxyde

Front 157

Histamine and serotonin

Source

Vascular leakage

Chemotaxis

Other

Back 157

Mast cells,

platelets

+

-

Front 158

Bradykinin

Source

Vascular leakage

Chemotaxis

Other

Back 158

Plasma substrate

+

-

Pain

Front 159

C3a

Source

Vascular leakage

Chemotaxis

Other

Back 159

Plasma protein via liver
+

-

Opsonic fragment (C3b)

Front 160

C5a

Source

Vascular leakage

Chemotaxis

Other

Back 160

Plasma protein via liver
+

+

Leukocyte adhesion, activation

Front 161

Prostaglandins

Source

Vascular leakage

Chemotaxis

Other

Back 161

Mast cells, from membrane phospholipids

Potentiate other mediators

-

Vasodilation, pain, fever

Front 162

Leukotriene B4

Source

Vascular leakage

Chemotaxis

Other

Back 162

Leukocytes

-

+

Leukocyte adhesion, activation

Front 163

Leukotriene C4, D4, E4

Source

Vascular leakage

Chemotaxis

Other

Back 163

Leukocytes, mast cells

+

-

Bronchoconstriction, vasoconstriction

Front 164

Oxygen metabolites

Source

Vascular leakage

Chemotaxis

Other

Back 164

Leukocytes

+

-

Endothelial damage, tissue damage

Front 165

IL-1 and TNF

Source

Vascular leakage

Chemotaxis

Other

Back 165

Macrophages, other

-

+

Acute-phase reactions, endothelial activation

Front 166

Chemokines

Source

Vascular leakage

Chemotaxis

Other

Back 166

Leukocytes, others

-

+

Leukocyte activation

Front 167

Nitric oxyde

Source

Vascular leakage

Chemotaxis

Other

Back 167

Macrophages, endothelium
+

+

Vasodilation, cytotoxicity

Front 168

OUTCOMES OF ACUTE INFLAMMATION

3

Back 168

Complete Resolution

Healing by connective tissue replacement
`` fibrosis

Progression of tissue response to chronic inflammantion

Front 169

OUTCOMES OF ACUTE INFLAMMATION

Complete resolution

Back 169

Complete resolution is the outcome when
`` the injury is limited
`` and the damaged parenchymal cells can
`` `` regenerate

Resolution involves
`` `` neutralization or
`` `` spontaneous decay of
`` the chemical mediators,
`` return of normal vascular permeability,
`` cessation of leukocytic infiltration,
`` apoptosis of neutrophils,
`` and finally removal of
`` `` edema fluid and
`` `` proteins,
`` `` leukocytes,
`` `` foreign agents, and
`` `` necrotic debris
`` from the site

Phagocytes and lymphatics play
`` a major role in these events

Front 170

OUTCOMES OF ACUTE INFLAMMATION

Healing by connective tissue replacement (fibrosis)

Back 170

This occurs after
`` `` substantial tissue destruction,
`` `` when the inflammatory injury involves
`` `` `` tissues that are incapable of regeneration,
`` `` or when there is abundant
`` `` `` necrotic tissue or
`` `` fibrin exudation

When the fibrinous exudate in
`` `` tissue or
`` `` serous cavities
`` `` `` pleura,
`` `` `` peritoneum
`` cannot be adequately cleared,
`` granulation tissue grows into the area of exudate,
`` converting it into a mass of fibrous tissue
`` a process also called
`` `` organization

In many pyogenic infections
`` there may be intense
`` `` neutrophil infiltration and
`` `` liquefaction of tissues,
`` `` leading to pus formation

The destroyed tissue is
`` resorbed
`` and eventually replaced by
`` `` fibrosis

Front 171

OUTCOMES OF ACUTE INFLAMMATION

Progression of the tissue response to chronic inflammation

Back 171

This may
`` follow acute inflammation,
`` or the response may be chronic
`` `` almost from the onset

Acute to chronic transition occurs
`` when the acute inflammatory response
`` ` cannot be resolved
`` owing either to
`` `` the persistence of the injurious agent
`` `` or to some interference with the normal process of healing

For example,
`` bacterial infection of the lung
`` `` may begin as a focus of acute inflammation
`` `` `` pneumonia
`` but its failure to resolve may
`` `` lead to extensive tissue destruction
`` `` and formation of a cavity
`` `` `` in which the inflammation continues to smolder,
`` `` `` leading eventually to a chronic lung abscess

Front 172

SUMMARY OF ACUTE INFLAMMATION

Back 172

When a host encounters for example a pathogen,
`` phagocytes that reside in all tissues
`` `` try to get rid of these agents

At the same time,
`` `` phagocytes,
`` `` mast cells
`` `` and other host cells
`` react to the presence of the “foreigner” by
`` `` liberating
`` `` `` cytokines,
`` `` `` lipid messengers,
`` `` and the various other mediators of inflammation

Histamine and others act on the adjacent vasculature
`` `` inducing arteriolar
dilation,
`` `` increased blood flow and
`` `` opening of capillary beds
`` `` `` (redness = rubor; warmth = calor)
`` in the injured area

Increased vascular permeability results in
`` the accumulation of protein-rich extravascular fluid
`` `` (edemaswelling = tumor)
`` `` `` Immediate and transient
`` `` `` `` histamine, etc
`` `` ``` and delayed
`` `` `` `` IL-1, TNF
`` vascular permeability

Plasma proteins
`` leave the vessels,
`` `` most commonly through widened interendothelial cell junctions
`` `` `` (gaps)

Circulating leukocytes,
`` `` initially predominantly neutrophils,
`` adhere to the endothelium
`` `` margination,
`` `` rolling,
`` `` firm adhesion
`` via adhesion molecules
`` transmigrate across the endothelium
`` and migrate to the site of injury
`` under the influence of chemotactic agents
`` `` (chemotaxis)

Leukocytes that are activated
`` try to remove the offending agent by
`` `` phagocytosis

During phagocytosis,
`` `` toxic metabolites and
`` `` proteases
`` may be released extracellularly
`` and cause tissue damage

As the injurious agent is eliminated,
`` the inflammatory process disappears
`` and the host returns to a normal state of health

If the injurious agent cannot be quickly eliminated,
`` the result may be chronic inflammation

Front 173

CHRONIC INFLAMMATION

Chronic inflammation is considered to be

Back 173

inflammation of prolonged duration
`` `` (weeks or months)
`` in which
`` `` active inflammation,
`` `` tissue destruction,
`` `` and attempts at repair
`` are proceeding simultaneously

Front 174

CHRONIC INFLAMMATION

Chronic inflammation may

Back 174

follow acute inflammation

or it begins as low-grade subclinical process
`` progressing to clinically apparent chronic inflammatory diseases
`` with tissue damage and fibrosis (
`` `` sarcoptic mange,
`` `` rheumatoid arthritis,
`` `` atherosclerosis,
`` `` tuberculosis,
`` `` chronic lung diseases

Front 175

Chronic Inflammation

Morphologic features

Back 175

In contrast to acute inflammation,
`` which is manifested by
`` `` vascular changes,
`` `` edema,
`` `` fibrin, and
`` `` predominantly neutrophilic infiltration,
`` chronic inflammation is characterized by:

Mononuclear infiltration
`` consisting of
`` `` macrophages,
`` `` lymphocytes,
`` `` and plasma cells

Tissue destruction
`` induced by
`` `` the persistent offending agent
`` `` or by the inflammation

Front 176

Tissue repair:

Morphologic features

Back 176

proliferation of
`` small blood vessels
`` `` (angiogenesis)

and fibrosis

Front 177

Macrophage

The macrophage is the

Back 177

dominant cellular player in chronic inflammation

Front 178

Macrophage

Macrophages originate from

Back 178

blood monocytes

and from tissue macrophages
`` liver
`` `` (Kupffer cells),
`` spleen and
`` lymph nodes
`` `` (sinus histiocytes),
`` and lungs (
`` `` alveolar macrophages)]

Blood monocytes
`` migrate into various tissues
`` `` and differentiate into macrophages

Front 179

Macrophage

The half-life of

Back 179

blood monocytes is about
`` 1 day,

whereas the life span of tissue macrophages is
`` several months
`` or years

Front 180

Macrophage

Monocytes begin to emigrate

Back 180

into extravascular tissues
`` quite early
`` `` in acute inflammation,
`` and within
`` `` 48 hours
`` they may constitute the predominant cell type

Front 181

Macrophage

When the monocyte reaches the extravascular tissue

Back 181

it undergoes transformation
`` into a larger phagocytic cell
`` `` the macrophage

Front 182

Macrophage

In short-lived inflammation

Back 182

if the irritant is eliminated,
`` macrophages eventually disappear
`` `` either dying off or
`` `` making their way into
`` `` `` the lymphatics and
`` `` `` lymph nodes

Front 183

Macrophage

In chronic inflammation

Back 183

macrophage accumulation persists

Front 184

Macrophage

Macrophages are powerful host “defenders” 3

Back 184

using an impressive arsenal of “weapons”:

Lysosomal
`` `` oxygen-dependent and
`` `` oxygen-independent
`` toxic products

Secretion of
`` `` cytokines and
`` `` chemokines
`` causing influx of inflammatory cells

Secretion of
`` `` growth factors
`` causing
`` `` angiogenesis and
`` `` fibrosis

These products of activated macrophages serve to
`` eliminate injurious agents
`` and to initiate the process of repair of damaged tissue

Front 185

Lymphocytes are mobilized

Back 185

in both
`` `` antibody-mediated and
`` `` cell-mediated
`` immune reactions.

Front 186

Lymphocytes and macrophages interact in a

Back 186

bidirectional way,

and these reactions play an important role in
`` chronic inflammation

Macrophages present antigens to
`` `` T cells
`` and produce cytokines
`` `` IL-12
`` that stimulate
`` `` T-cell responses

Front 187

Activated T lymphocytes produce

Back 187

cytokines
`` `` (IFN-γ)
`` that stimulate macrophages

Front 188

Plasma cells develop

Back 188

from activated B lymphocytes
`` and produce antibody directed
`` `` either against persistent antigen in
`` `` `` the inflammatory site
`` `` or against
`` `` `` altered tissue components

Front 189

Lympho-plasmacytic inflammation has

Back 189

little diagnostic specificity,
`` because almost all inflammatory diseases will,
`` `` sooner or later,
`` become dominated by
`` `` long-lived mononuclear cells

Front 190

Granulomatous inflammation

Granulomatous inflammation is

Back 190

a distinctive pattern of
`` chronic inflammatory reaction characterized by
`` `` focal accumulations of
`` `` `` activated macrophages,
`` `` which often develop an
`` `` `` epithelioid appearance

Front 191

Granulomatous inflammation

A granuloma is

Back 191

a focus of
`` chronic inflammation
`` `` consisting of an
`` `` `` aggregation of epithelioid macrophages
`` `` `` often with giant cells
`` `` `` surrounded by
`` `` `` `` lymphocytes,
`` `` `` `` occasionally plasma cells
`` `` `` and intermingling fibroblasts

Front 192

Granulomatous inflammation

pyogranulomatous

Back 192

Depending on the causative agent,
`` some granulomas may contain
`` `` substantial amounts of neutrophils
`` `` forming
`` `` `` purulent exudate

therefore, such processes is called pyogranulomatous

Front 193

Granulomatous inflammation

The macroscopic appearance of a granuloma is often

Back 193

indistinguishable from a neoplasm,
`` because it is usually
`` `` a nodular
`` `` grey-white
`` `` mass

Front 194

Granulomatous inflammation

Microscopically, granulomatous inflammation should always

Back 194

be examined with special stains to
`` identify potential causative agents

In veterinary medicine,
`` `` foreign body,
`` `` fungal, and
`` `` mycobacterial
`` granulomas are most common

Front 195

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

Homeostasis

Back 195

Homeostatic mechanisms are designated to
`` maintain an optimal internal environment in
`` the face of a constantly changing external environment

During a particularly strong challenge to this homeostasis
`` an acute phase response might
`` `` take priority over this internal optimal balance
`` `` `` in order to defend the host from
`` `` `` `` a potentially life-threatening homeostatic disturbance

Front 196

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

The acute phase response is

Back 196

an adaptive component of
`` innate defence
`` and consists of numerous
`` `` predetermined and
`` `` well-orchestrated
`` `` `` local and
`` `` `` systemic
`` `` physiological reactions to
`` the acute phase stimuli

Front 197

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

Is mediated predominantly by

the following three cytokines:

Back 197

IL-1,

TNF

IL-6

Front 198

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

The acute phase response consists of 5

Back 198

several
`` clinical and
`` pathologic changes:

fever,

anorexia,

somnolence,

acute phase proteins,

leukocytosis

etc

Front 199

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

Fever

Fever is

Back 199

one of the most prominent manifestations of
`` the acute phase response,
`` especially when
`` `` inflammation is associated
`` `` `` with infection

Front 200

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

Fever

Fever is produced in response

Back 200

to substances called
`` pyrogens
`` `` exogenous
`` `` `` (LPS)
`` ``endogenous
`` ``` `` IL-1,
`` `` `` TNF
`` that induce production of
`` `` prostaglandins
`` `` `` (especially PGE2)
`` `` from arachidonic acid by
`` `` `` cyclooxygenases in
`` `` `` the vascular and
`` `` `` perivascular cells
`` `` of the
`` `` `` hypothalamus

Front 201

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

Fever

PGE2 stimulates production of

Back 201

neurotransmitters
`` `` (cyclic AMP),
`` which function to reset
`` `` the temperature set-point at
`` `` `` a higher level

Front 202

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

Fever

An elevated body temperature

Back 202

has been shown to help amphibians
`` to fight off microbial infections,
``and it is assumed that
`` fever does the same
`` `` for mammals,
`` `` `` although the mechanism is unknown

Front 203

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

Fever

One hypothesis is that fever

Back 203

may induce
`` `` heat shock proteins
`` that enhance
`` `` lymphocyte responses to
`` `` `` microbial antigens

Front 204

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE Proteins

Acute phase proteins are

Back 204

proteins produced by
`` `` the liver
`` whose plasma concentrations are
`` `` altered by
`` `` `` 25% or more
`` `` during the acute phase response

Positive acute phase proteins
`` `` increase
`` and
`` negative acute phase proteins
`` `` decrease
`` in concentration during
`` `` the acute phase response

Front 205

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE Proteins

Most of the positive acute phase proteins have

Back 205

important host protective
`` `` anti-inflammatory or
`` `` antimicrobial functions,

whereas
`` the function of
`` `` negative acute phase proteins is
`` associated with
`` `` maintenance of homeostasis

Front 206

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE Proteins

Reactivity of acute phase proteins

Back 206

varies tremendously among species

Front 207

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE Proteins

classification based on their function or structure: 4

Back 207

Opsonins:
`` C-reactive protein,
`` serum amyloid A,
`` mannose binding lectin

Proteinase inhibitors:
`` `` alpha2 macroglobulin
`` They regulate
`` `` complement,
`` `` coagulation and
`` `` fibrinolytic cascades
`` and inactivate
`` `` proteinases
`` `` `` released from leukocytes

Metal binding proteins:
`` transferrin
`` `` (binds iron),
`` haptoglobin
`` `` (binds hemoglobin),
`` ceruloplasmin
`` `` (binds copper)
`` Iron and copper are
`` `` essential elements of
`` `` `` numerous enzymes and
`` `` `` metabolic mechanisms
`` for
`` `` many prokaryotic and
`` `` all eukaryotic
`` organisms
`` Vertebrates have
`` `` various
`` `` `` metal binding proteins and
`` `` `` mechanisms to prevent cation mediated toxicity
`` `` `` and to sequestrate microelements from
`` `` `` `` invading pathogens

Coagulation and complement proteins:
`` fibrinogen,
`` C3,
`` C4

Front 208

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE Proteins

Clinical importance:

Back 208

concentration of fibrinogen is
`` used to determine if
`` `` ruminants and
`` `` horses
`` are in acute phase response

The other acute phase proteins are
`` not commonly used in veterinary medicine
`` `` presently,
`` `` but they will be in the near future

Acute phase proteins are common diagnostic tools used in human medicine

Front 209

Leukocytosis is a common

Back 209

feature of inflammatory reactions,
`` especially those
`` `` induced by bacterial infection

Front 210

SYSTEMIC EFFECTS OF INFLAMMATION

Leukocytosis

leukocytosis occurs initially

Back 210

because of
`` accelerated release of
`` `` cells from the
`` `` `` bone marrow
`` `` `` `` postmitotic reserve pool
`` `` caused by
`` `` `` IL-1 and
`` `` `` TNF

therefore leukocytosis is associated with
`` a rise in the number of
`` `` more immature neutrophils
`` `` `` in the blood
`` `` `` `` (shift to the left

Front 211

SYSTEMIC EFFECTS OF INFLAMMATION

Leukocytosis

Prolonged infection

Back 211

also induces
`` proliferation of precursors
`` `` in the bone marrow,

thus, the bone marrow output
`` of leukocytes is
`` `` increased to compensate for
`` `` `` the loss of these cells
`` `` `` `` in the inflammatory reaction

Front 212

SYSTEMIC EFFECTS OF INFLAMMATION

ACUTE PHASE RESPONSE

Other manifestations 4

Back 212

Rigors
`` (shivering),

chills
`` (search for warmth),

anorexia

somnolence

probably because of
`` the actions of cytokines
`` `` on brain

Front 213

SHOCK

Shock is

Back 213

(cardiovascular collapse)

a circulatory
`` `` dyshomeostasis
`` associated with
`` `` loss of circulating blood volume,
`` `` reduced cardiac output,
`` `` and/or inappropriate peripheral vascular resistance

Hypotension results in
`` impaired tissue perfusion and
`` cellular hypoxia
`` and a shift to anaerobic metabolism by cells,
`` cellular degeneration,
`` and death

Front 214

SHOCK

Shock is rapidly progressive and life threatening

Back 214

when
`` compensatory responses are
`` `` inadequate

Front 215

Shock

Cardiogenic shock results from

Back 215

failure of the heart to
`` adequately pump blood
`` `` which leads to
`` `` `` stagnation of blood and
`` `` `` progressive tissue hypoperfusion

Front 216

Shock

Hypovolemic shock arises from

Back 216

reduced circulating blood volume
`` due to blood loss caused by
`` `` hemorrhage,
`` or due to fluid loss
`` `` secondary to
`` `` `` vomiting,
`` `` `` diarrhea, or
`` `` `` burns

Reduced circulating blood volume leads to
`` decreased vascular pressure and
`` tissue hypoperfusion

Front 217

Shock

Hypovolemic shock

Immediate compensatory mechanisms 2 act

Back 217

peripheral vasoconstriction

fluid movement into the plasma

act to
`` increase vascular pressure
`` and maintain blood flow to
`` `` critical tissues, such as the
`` `` heart,
`` `` brain, and
`` `` kidney

Front 218

Shock

Blood maldistribution

is characterized by

Back 218

decreased peripheral vascular resistance

pooling of blood in peripheral tissues

Systemic vasodilation results in
`` a dramatically increased
`` `` microvascular area,
`` and although the blood volume is normal,
`` `` the effective circulating blood volume is
`` `` `` decreased

Front 219

Shock

The three major types of shock

due to blood maldistribution are

Back 219

anaphylactic,

neurogenic,

septic shock

Front 220

Shock

Anaphylactic shock is

Back 220

a generalized type I hypersensitivity

Front 221

Shock

Anaphylactic shock

Common causes 3

Back 221

exposure to
`` insects,
`` plants,
`` or drugs

Front 222

Shock

Anaphylactic shock

Mechanism

Back 222

The interaction of
`` `` the inciting allergen with
`` `` immunoglobulin E
`` `` `` bound to mast cells
`` results in
`` `` widespread mast cell degranulation
`` `` and the release of
`` `` `` histamine and
`` `` `` other vasoactive mediators

Subsequently,
`` there is
`` `` systemic vasodilation and
`` `` increased vascular permeability,
`` causing
`` `` hypotension and
`` `` tissue hypoperfusion

Front 223

Shock

Neurogenic shock

4 Ways and the Means

Back 223

may be induced by
`` trauma,
`` electrocution,
`` lightning,
`` emotional stress

The autonomic nervous system induces
`` `` peripheral vasodilation,
`` `` followed by
`` `` `` tissue hypoperfusion

Front 224

Septic Shock

Septic shock is

Back 224

the most common type of shock
`` associated with blood maldistribution

Front 225

Shock

Septic shock

In septic shock

Back 225

peripheral vasodilation is
`` caused by the release of
`` `` excessive amounts of
`` `` `` vascular and
`` `` `` inflammatory
`` `` mediators
`` induced by
`` `` bacterial components
`` `` `` endotoxin (LPS)
`` `` `` `` gram-negative
`` `` `` or peptidoglycans
`` `` `` and lipoteichoic acids
`` `` `` `` gram-positive

Front 226

Shock

Septic shock

Local release of LPS

Where and 4 Effects

Back 226

from degenerating bacteria
`` is a potent stimulus for
`` `` many of the host responses that are
`` `` `` necessary for defense against bacteria

LPS activates:

monocytes/macrophages
`` which release
`` `` TNF,
`` `` IL-l and
`` `` IL-6

endothelium
`` which decrease production of
`` `` anticoagulant substances

factor XII
`` to initiate
`` `` intrinsic coagulation
`` `` and other pathways
`` `` `` kinins,
`` `` `` fibrinolysis,
`` `` `` complement

directly alternative complement pathway

These events are important for enhancing
`` the inflammatory response
`` `` to control
`` `` `` localized infections associated with
`` `` `` `` relatively low concentrations of LPS

However, they can be
`` `` detrimental
`` if the response becomes
`` `` more pronounced due to
`` `` `` overwhelming bacterial infections
`` `` `` `` generating large concentrations of LPS
`` `` `` `` which induces increased production of
`` `` `` `` `` TNF,
`` `` `` `` `` IL-l and
`` `` `` `` `` other cytokines

Front 227

Shock

Septic shock

If cytokine activation cascade is not controlled

1 Consequence

6 Actions

Back 227

septic shock will follow

TNF and/or IL-l are
`` central mediators of septic shock

They:

induce
`` tissue factor expression
`` and endothelial activation of
`` `` extrinsic coagulation

enhance expression of
`` endothelial leukocyte adhesion molecules

mediate delayed endothelial leakage

stimulate arachidonic acid metabolite production

induce nitric oxide production
`` (vasodilation)

activate neutrophils
`` and enhance their adhesion to
`` endothelium,
`` `` which further interferes with
`` `` `` blood flow through the microvasculature

The end result of the activation of these myriad
`` `` vascular,
`` `` proinflammatory, and
`` `` procoagulant alterations
`` is the profound systemic
`` `` vasodilation,
`` `` hypotension, and
`` `` tissue hypoperfusion

Front 228

Shock

Septic shock

Morphologic changes: 5

Back 228

Septicemic animals may have any combination of the following changes:

Congested
`` `` skin and
`` `` peripheral organs,
`` due to
`` `` vasodilation

petechiation
`` `` Serosal,
`` `` mucosal and/or
`` `` parenchymal
`` due to
`` `` endothelial damage and
`` `` DIC

Diffuse
`` `` pulmonary edema and
`` `` congestion
`` due to
`` `` endothelial leakage and
`` `` vasodilation

Mild
`` `` fibrinous polyserositis and
`` `` polyarthritis
`` due to
`` `` endothelial leakage/damage

Enlarged
`` `` spleen and
`` `` lymph nodes
`` due to
`` `` activation of residual tissue macrophages

Front 229

Bacteremia –

Back 229

presence of bacteria in the blood

Front 230

Septicemia –

Back 230

presence of bacteria in the blood
`` that cause systemic disease

Front 231

Endotoxemia –

Back 231

presence of endotoxin (LPS) in the blood
`` that causes systemic disease

Front 232

Stages and progression of shock

3

Back 232

Regardless of the underlying cause,
`` shock generally progresses through
`` `` three different stages

Nonprogressive Stage

Progressive Stage

Irreversible Stage

Front 233

Shock

Nonprogressive stage is characterized by

3 and outcome

Back 233

the following compensatory mechanisms
`` that counteract
`` `` reduced functional circulating blood volume
`` `` and decreased vascular pressure:

epinephrine/norepinephrine
`` increases cardiac output
`` and causes arteriolar vasoconstriction
`` `` (increased peripheral resistance)
`` in most tissues
`` `` (except vital organs)
`` in an attempt to
`` `` raise vascular pressure;

ADH and renin-angiotensin system
`` `` (aldosterone)
`` increase plasma volume
`` `` water retention,
`` `` sodium retention,
`` `` vasoconstriction

decreased microvascular pressure
`` results in a shift in
`` `` fluid movement from
`` `` `` the interstitium into
`` `` `` `` the plasma
`` to also help increase
`` `` blood volume

This compensation results in
`` `` increased heart rate,
`` `` cardiac output, and
`` `` vascular pressure

Front 234

Shock

Progressive stage

5 and Outcome

Back 234

follows if compensatory mechanisms are inadequate

Cellular metabolism becomes
`` less efficient
`` and shifts from
`` `` aerobic to
`` `` anaerobic with
`` `` `` pyruvate converted to
`` `` `` `` lactate without entering the Krebs cycle

The deficient production of ATP
`` and overproduction of lactic acid
`` inhibits
`` `` normal cell functions
`` `` `` and results in
`` `` `` `` cellular and
`` `` `` `` systemic
`` `` `` `` `` acidosis

Local
`` `` hypoxia and
`` `` accumulation of metabolic products
`` eventually result in
`` `` arteriolar
`` `` `` relaxation and
`` `` ` dilation

Once these local influences
`` `` override
`` `` `` centrally mediated vasoconstriction
`` `` `` `` widespread peripheral vasodilation
`` `` `` `` `` decreases vascular pressure even more
`` and it is unlikely that
`` `` shock will be reversed

Oxygen and energy stores of the cell are
`` depleted and
`` `` cell necrosis occurs

Front 235

Shock

Irreversible stage is generally assured

Back 235

when shock progresses into
`` the syndrome of multiple organ dysfunction

Vicious cycles occur in which
`` the failing function of one organ
`` `` contributes to the failure of another

e.g., decreased cardiac output causes
`` renal ischemia;
`` `` electrolyte imbalances caused by renal ischemia then
`` `` `` result in cardiac arrhythmias