2 Inflammation and Repair

Acute Inflammation

Transient and early response to injury that involves release of chemical

mediators, causing stereotypic vessel and leukocyte responses

Acute
Inflammation

Transient and early response to injury that involves release of chemical

mediators, causing stereotypic vessel and leukocyte responses

Cardinal
signs of
inflammation
1. Rubor (redness) and calor (heat)
o Histamine-mediated vasodilation of arterioles
2. Tumor (swelling)
o Histamine-mediated increase in permeability of venules
3. Dolor (pain)
o

Prostaglandin (PG) E2 sensitizes specialized nerve endings to the

effects of bradykinin and other pain mediators.

Stimuli for
acute
inflammation
1. Infections (e.g., bacterial or viral infection)
2. Immune reactions (e.g., reaction to a bee sting)
3. Other stimuli
o

Tissue necrosis (e.g., acute myocardial infarction), trauma, radiation,

burns

Sequential
vascular
events
1. Vasoconstriction of arterioles
o Neurogenic reflex that lasts only seconds
2. Vasodilation of arterioles
a. Histamine and other vasodilators (e.g., nitric oxide) relax vascular
smooth muscle, causing increased blood flow.
b. Increased blood flow increases hydrostatic pressure.
2. Increased permeability of venules
a. Histamine and other mediators contract endothelial cells producing
endothelial gaps.
b. A transudate (protein and cell-poor fluid) moves into the interstitial
tissue.
3. Swelling of tissue (edema)
o

Net outflow of fluid surpasses lymphatic ability to remove fluid.

3. Reduced blood flow

o

A decrease in hydrostatic pressure is caused by outflow of fluid into

the interstitial tissue.

Sequential
cellular
events

Chronic granulomatous disease (CGD), an X-linked recessive

disorder, is characterized by deficient NADPH oxidase in the cell
membranes of neutrophils and monocytes. The reduced production
of
results in an absent respiratory burst. Catalase-positive organisms
that produce H2O2 (e.g., Staphylococcus aureus) are ingested but
not killed, because the catalase degrades H2O2. Myeloperoxidase is
present, but HOCl is not synthesized because of the absence of
H2O2. Catalase-negative organisms (e.g., Streptococcus species)
are ingested and killed when myeloperoxidase combines H2O2 with
Cl- to form HOCl. The classic screening test for CGD is the nitroblue
tetrazolium test (NBT). In this test, leukocytes are incubated with a
colorless NBT dye, which is converted to a blue color if the
respiratory burst is intact. This test has been replaced by other more
sensitive tests.
Myeloperoxidase (MPO) deficiency, an autosomal recessive
disorder, differs from CGD in that both
and H2O2 are produced (normal respiratory burst). The absence of
MPO prevents synthesis of HOCl.

The events described will emphasize neutrophil events in acute inflammation

due to a bacterial infection (e.g., Staphylococcus aureus).

1. Neutrophils are the primary leukocytes in acute inflammation

2. Margination
a. RBCs aggregate into rouleaux ("stacks of coins") in venules.
b. Neutrophils are pushed from the central axial column to the periphery
(margination).
3. Rolling
a. Due to activation of selectin adhesion molecules on the surface of
neutrophils and endothelial cells
b. Neutrophils loosely bind to selectins and "roll" along the endothelium.
4. Adhesion
a. Adhesion molecules firmly bind neutrophils to endothelial cells.
b. Neutrophil adhesion molecules
i.
2-Integrins (CD11a:CD18)
ii.
Adhesion molecule activation is mediated by C5a and
leukotriene B4 (LTB4).
iii.
Catecholamines, corticosteroids, and lithium inhibit activation
of adhesion molecules.
This causes an increase in the peripheral blood
neutrophil count (neutrophilic leukocytosis).
iv.
Endotoxins enhance activation of adhesion molecules.
This causes a decrease in the peripheral blood
neutrophil count (neutropenia).
c. Endothelial cell adhesion molecules

i.

Intercellular adhesion molecule (ICAM) and vascular cell

adhesion molecule (VCAM) bind to integrins on the surface of
neutrophils.
ii.
ICAM and VCAM activation is mediated by interleukin 1 (IL-1)
and tumor necrosis factor (TNF).
d. Leukocyte adhesion deficiency (LAD)
i.
Autosomal recessive disorders
ii.
LAD type 1 is a deficiency of CD11a:CD18.
iii.
LAD type 2 is a deficiency of a selectin that binds neutrophils.
iv.
Clinical findings
Delayed separation of the umbilical cord (>1 month)
Neutrophil enzymes are important in cord
separation.
Severe gingivitis, poor wound healing, peripheral
blood neutrophilic leukocytosis
5. Transmigration (diapedesis)
a. Neutrophils dissolve the basement membrane and enter interstitial
tissue.
b. Fluid rich in proteins and cells (i.e., exudate) accumulates in
interstitial tissue.
c. Functions of exudate
i.
Dilute bacterial toxins
ii.
Provide opsonins (assist in phagocytosis), antibodies, and
complement
6. Chemotaxis
a. Neutrophils follow chemical gradients that lead to the infection site.
b. Chemotactic mediators bind to neutrophil receptors.

22

Mediators include C5a, LTB4, bacterial products, and IL-8.

b. Binding causes the release of calcium, which increases neutrophil
motility.
Phagocytosis
a. Multistep process:
i.
Opsonization
ii.
Ingestion
iii.
Killing
b. Opsonization
i.
Opsonins attach to bacteria.
Opsonins include IgG, C3b fragment of complement,
and other proteins (e.g., C-reactive protein).
Neutrophils have membrane receptors for IgG and
C3b.
ii.
Opsonization enhances neutrophil recognition and
attachment to bacteria.
iii.
Bruton's agammaglobulinemia is an opsonization defect.
c. Ingestion
i.
Neutrophils engulf (phagocytose) and then trap bacteria in
phagocytic vacuoles.
ii.
Primary lysosomes empty hydrolytic enzymes into phagocytic
vacuoles producing phagolysosomes.
In Chdiak-Higashi syndrome (see a defect in
membrane fusion prevents phagolysosome
formation.
d. Bacterial killing
i.
O2-dependent myeloperoxidase (MPO) system
Only present in neutrophils and monocytes (not
macrophages)

Production of superoxide free radicals

NADPH oxidase converts molecular O2 to

, which releases energy called the
respiratory, or oxidative, burst.
Production of peroxide (H2O2)
Superoxide dismutase converts
to H2O2, which is neutralized by glutathione
peroxidase.
Production of bleach (HOCl)
MPO combines H2O2 with chloride (Cl-) to
form hypochlorous free radicals (HOCl),
which kill bacteria.
Chronic granulomatous disease and MPO deficiency
are examples of diseases that have a defect in the
O2-dependent MPO system.
Deficiency of NADPH (e.g., glucose-6-phosphate
dehydrogenase deficiency) produces a microbicidal
defect.
O2-independent system
Refers to bacterial killing from substances located in
leukocyte granules

ii.

Examples-lactoferrin (binds iron necessary for

bacterial reproduction) and major basic protein
(eosinophil product that is cytotoxic to helminths)

Chemical
mediators

Table 2-1. Sources and Functions of Chemical Mediators

Mediator

Source(s)

Arachidonic Acid
Metabolites
Prostaglandins
Macrophages, endothelial cells,
platelets
PGH2: major precursor of PGs
and thromboxanes
Thromboxane A2 Platelets
Converted from PGH2 by
thromboxane synthase
Leukotrienes (LTs) Converted from arachidonic
acid by lipoxygenase-mediated
hydroxylation

Bradykinin
Chemokines
Complement

Cytokines
IL-1, TNF

Function(s)
PGE2: vasodilation, pain, fever
PGI2: vasodilation; inhibition of platelet
aggregation
Vasoconstriction, platelet aggregation,
bronchoconstriction

LTB4: chemotaxis and activation of

neutrophil adhesion molecules
LTC4, LTD4, LTE4: vasoconstriction,
increased vessel permeability,
bronchoconstriction
Product of kinin system
Vasodilation, increased vessel permeability,
activation by activated factor XII pain, bronchoconstriction
Leukocytes, endothelial cells
Activate neutrophil chemotaxis
Synthesized in liver
C3a, C5a (anaphylatoxins): stimulate mast
cell release of histamine
C3b: opsonization
C5a: activation of neutrophil adhesion
molecules, chemotaxis
C5-C9 (membrane attack complex): cell
lysis
Lymphocytes, macrophages,
endothelial cells

Initiate PGE2 synthesis in anterior

hypothalamus, leading to production of
fever

IL-6
IL-8
Histamine

Activate endothelial cell adhesion molecules

Increase liver synthesis of acute-phase
reactants, such as ferritin, coagulation
factors (e.g., fibrinogen), and C-reactive
protein
Increase release of neutrophils from bone
marrow
Increase liver synthesis of acute phase
reactants
Chemotaxis
Vasodilation, increased vessel permeability

Mast cells (primary cell),

platelets, enterochromaffin cells
Nitric Oxide (NO) Macrophages, endothelial cells Vasodilation, bactericidal
Free radical gas released
during conversion of arginine to
citrulline by NO synthase
Serotonin
Mast cells, platelets
Vasodilation, increased vessel permeability

IL, interleukin; PG, prostaglandin; TNF, tumor necrosis factor.

1. They derive from plasma, leukocytes, local tissue, bacterial products.

o Example-arachidonic acid mediators are released from membrane
phospholipids in macrophages, endothelial cells, and platelets
2. They have short lives (e.g., seconds to minutes).
3. They may have local and systemic effects.
o Example-histamine may produce local signs of itching or systemic
signs of anaphylaxis.
4. They have diverse functions.
a. Vasodilation
Examples-histamine, nitric oxide, PGI2
b. Vasoconstriction
Example-thromboxane A2 (TXA2)
c. Increase vessel permeability
Examples-histamine, bradykinin, LTC4-D4-E4, C3a and C5a
(anaphylatoxins)
d. Produce pain
Examples-PGE2, bradykinin
e. Produce fever
Examples-PGE2, IL-1, TNF
f. Chemotactic
Examples-C5a, LTB4, IL-8

Consequences of acute inflammation

1. Complete resolution
a. Occurs with mild injury to cells that have the capacity to enter the cell
cycle (e.g., labile and stable cells)
b. Examples-first-degree burn, bee sting
2. Tissue destruction and scar formation
a. Occurs with extensive injury or damage to permanent cells
b. Example-third-degree burns
3. Progression to chronic inflammation

Types of acute inflammation

Location, cause, and duration of inflammation determine the morphology of

an inflammatory reaction.

1. Purulent (suppurative) inflammation

a. Localized proliferation of pus-forming organisms, such as

Staphylococcus aureus (e.g., skin abscess;
b. S. aureus contains coagulase, which cleaves fibrinogen into fibrin
and traps bacteria and neutrophils.
2. Fibrinous inflammation
a. Due to increased vessel permeability, with deposition of a fibrin-rich
exudate
b. Example-fibrinous pericarditis
3. Pseudomembranous inflammation
a. Bacterial toxin-induced damage of the mucosal lining, producing a
shaggy membrane composed of necrotic tissue
b. Example-pseudomembranes associated with Clostridium difficile in
pseudomembranous colitis
Corynebacterium diphtheriae produces a toxin causing
pseudomembrane formation in the pharynx and trachea.

Role of fever in inflammation

1. Right-shifts oxygen-binding curve
o More O2 is available for the O2-dependent MPO system.
2. Provides a hostile environment for bacterial and viral reproduction

Chronic
Inflammation

Inflammation of prolonged duration (weeks to years) that most often results

from persistence of an injury-causing agent

Causes of
chronic
inflammation
1. Infection
o Examples-tuberculosis, leprosy, hepatitis C
2. Autoimmune disease
o Examples-rheumatoid arthritis, systemic lupus erythematosus
3. Sterile agents
o

Examples-silica, uric acid, silicone in breast implants

Morphology
1. Cell types
o Monocytes and macrophages,
lymphocytes and plasma cells,
eosinophils
2. Necrosis
o Not as prominent a feature as in
acute inflammation
3. Destruction of parenchyma
o Loss of functional tissue, with
repair by fibrosis
4. Formation of granulation tissue
a. Highly vascular tissue composed
of newly formed blood vessels
(i.e., angiogenesis) and activated
fibroblasts

i.

Essential for normal

wound healing
ii.
Converted into scar tissue
b. Fibronectin is required for
granulation tissue formation.
i.
Cell adhesion glycoprotein
located in the extracellular
matrix (ECM)
Binds to collagen,
fibrin, and cell
surface receptors
(e.g., integrins)
ii.
Chemotactic factor that
attracts fibroblasts
(synthesize collagen) and
endothelial cells (form new
blood vessels,
angiogenesis)
Vascular
endothelial growth
factor (VEGF) and
basic fibroblast
growth factor
(FGF) are
important in
angiogenesis.
2. Granulomatous inflammation
o

Specialized type of chronic

inflammation

a. Causes
i.
Infections
Examplestuberculosis and
systemic fungal
infection (e.g.,
histoplasmosis)
Usually
associated with
caseous necrosis
(i.e., soft
granulomas)
Caseation
is due to
lipid
released
from the
cell wall of
dead
pathogen
s.
ii.
Noninfectious causes
Examplessarcoidosis and
Crohn's disease
Noncaseating
(i.e., hard

granulomas)
b. Morphology
i.
Pale, white nodule with or
without central caseation
ii.
Usually well-circumscribed
iii.
Cell types
Epithelioid cells
(activated
macrophages),
mononuclear
(round cell)
infiltrate (CD4
helper T cells, or
TH cells of the TH1
type)
Multinucleated
giant cells formed
by fusion of
epithelioid cells
Nuclei
usually
located at
the
periphery
iv.

Pathogenesis of a
tuberculous granuloma

BOX 2-1 SEQUENCE OF FORMATION OF A TUBERCULOUS

GRANULOMA
The tubercle bacillus Mycobacterium tuberculosis
undergoes phagocytosis by alveolar macrophages
(processing of bacterial antigen).
Macrophages present antigen to CD4 T cells in association
with class II antigen sites.
Macrophages release interleukin (IL) 12 (stimulates
formation of TH1 class cells) and IL-1 (causes fever;
activates TH1 cells).
TH1 cells release IL-2 (stimulates TH1 proliferation), interferon (activates macrophages to kill tubercle bacillus;
epithelioid cells), and migration inhibitory factor (causes
macrophages to accumulate).
Lipids from killed tubercle bacillus lead to caseous necrosis.

Activated macrophages fuse and become multinucleated

giant cells.

Tissue
Repair
Factors involved in tissue repair
1. Parenchymal cell regeneration
2. Repair by connective tissue (fibrosis)

Factors
involved

in tissue
repair
1. Parenchymal cell regeneration
2. Repair by connective tissue (fibrosis)

Parenchymal
cell
regeneration

Table 2-2. Factors Involved in Tissue Repair

Factor

Function(s)

Growth Factors
Vascular endothelial cell growth
factor (VEGF)
Basic fibroblast growth factor
(BFGF)
Epidermal growth factor (EGF)
Platelet-derived growth factor
(PDGF)
Hormones
Insulin growth factor-1 (IGF-1)
Interleukins (IL)
IL-1

Stimulates angiogenesis
Stimulates angiogenesis
Stimulates keratinocyte migration
Stimulates granulation tissue formation
Stimulates proliferation of smooth muscle, fibroblasts,
endothelial cells
Stimulates synthesis of collagen
Promotes keratinocyte migration
Chemotactic for neutrophils
Stimulates synthesis of metalloproteinases (i.e., trace metal
containing enzymes)
Stimulates synthesis and release of acute phase reactants
from the liver

1. Depends on the ability of cells to replicate

a. Labile cells (e.g., stem cells in epidermis) and stable cells (e.g.,
fibroblasts) can replicate (see
b. Permanent cells cannot replicate.
Cardiac and striated muscle are replaced by scar tissue
(fibrosis).
2. Depends on factors that stimulate parenchymal cell division and migration
o

Stimulatory factors include loss of tissue and production of growth

factors
2. Cell cycle (
a. Phases of the cell cycle
G0 phase
Resting phase of stable parenchymal cells
222
G1 phase
Synthesis of RNA, protein, organelles, and cyclin D
2222
S (synthesis) phase
Synthesis of DNA, RNA, protein
2v2
G2 phase
Synthesis of tubulin, which is necessary for formation
of the mitotic spindle
v2
M (mitotic) phase
Two daughter cells are produced.
b. Regulation of the G1 checkpoint (G1 to S phase)
22

Most critical phase of the cell cycle

Control proteins include cyclin-dependent kinase 4 (Cdk4)
and cyclin D
Growth factors activate nuclear transcribing protooncogenes to produce cyclin D and Cdk4.
Cyclin D binds to Cdk4, forming a complex causing
the cell to enter the S phase.
2222
RB (retinoblastoma) suppressor gene
RB protein product arrests the cell in the G1 phase.
Cdk4 phosphorylates the RB protein causing the cell
to enter the S phase.
2v2
TP53 suppressor gene
TP53 protein product arrests the cell in the G1 phase
by inhibiting Cdk4.
Prevents RB protein phosphorylation and, if
necessary, provides time for repair of DNA in
the cell
In the event that there is excessive DNA damage,
the BAX gene is activated.
BAX gene inhibits the BCL2 antiapoptosis
gene (Chapter 1) causing release of
cytochrome c from the mitochondria and
apoptosis of the cell.
2. Restoration to normal
a. Requires preservation of the basement membrane
b. Requires a relatively intact extracellular matrix (ECM; i.e., collagen,
adhesive proteins)
22
222

Laminin, the key adhesion protein in the basement

membrane, interacts with type IV collagen, cell surface
receptors, and components in the ECM.

Repair by connective tissue (fibrosis)

page 34
page 35

Ehlers-Danlos syndrome (EDS) consists of a group of mendelian

disorders characterized by defects of type I and type III collagen
synthesis and structure. Clinical findings include hypermobile joints,
aortic dissection (most common cause of death), bleeding into the
skin (ecchymoses), and poor wound healing
BOX 2-2
WOUND
HEALING BY
PRIMARY
AND
SECONDARY
INTENTION
Primary Intention
Day 1: fibrin clot (hematoma) develops. Neutrophils infiltrate
the wound margins. There is increased mitotic activity of
basal cells of squamous epithelium in the apposing wound
margins.
Day 2: squamous cells from apposing basal cell layers
migrate under the fibrin clot and seal off the wound after 48
hours. Macrophages emigrate into the wound.
Day 3: granulation tissue begins to form. Initial deposition of

type III collagen begins but does not bridge the incision site.
Macrophages replace neutrophils.
Days 4-6: granulation tissue formation peaks, and collagen
bridges the incision site.
Week 2: collagen compresses blood vessels in fibrous
tissue, resulting in reduced blood flow. Tensile strength is
10%.
Month 1: collagenase remodeling of the wound occurs, with
replacement of type III collagen by type I collagen. Tensile
strength increases, reaching 80% within 3 months. Scar
tissue is devoid of adnexal structures (e.g., hair, sweat
glands) and inflammatory cells.
Secondary Intention
Typically, these wounds heal differently from primary
intention:
More intense inflammatory reaction than primary healing
Increased amount of granulation tissue formation than in
primary healing
Wound contraction caused by increased numbers of
myofibroblasts

1. Occurs when injury is severe or persistent

o Tissue in a third-degree burn cannot be restored to normal owing to
loss of skin, basement membrane, and connective tissue
infrastructure.
2. Steps in repair
a. Requires neutrophil transmigration to liquefy injured tissue and then
macrophage transmigration to remove the debris
b. Requires formation of granulation tissue
Accumulates in the ECM and eventually produces dense
fibrotic tissue (scar)
c. Requires the initial production of type III collagen
Collagen is the major fibrous component of connective tissue.
It is a triple helix of cross-linked -chains.
Lysyl oxidase cross-links points of hydroxylation
(vitamin C-mediated) on adjacent -chains.
2222
Cross-linking increases the tensile strength of collagen.
Type I collagen in skin, bone, and tendons has the
greatest tensile strength.
b. Dense scar tissue produced from granulation tissue must be
remodeled.
22
Remodeling increases the tensile strength of scar tissue.
222
Metalloproteinases (collagenases) replace type III collagen
with type I collagen, increasing tensile strength to
approximately 80% of the original.
2. Primary and secondary intention wound healing
a. Healing by primary intention
22
Approximation of wound edges by sutures
222
Used for clean surgical wounds
b. Healing by secondary intention
22
222

22
222

Wound remains open

Used for gaping or infected wounds

Factors
that
impair
healing
page 35
page 36

1. Persistent infection
a. Most common cause of impaired wound healing
b. Staphylococcus aureus is the most common pathogen.
2. Metabolic disorders
o

Example-diabetes mellitus increases susceptibility to infection by

decreasing blood flow to tissue and increasing tissue levels of
glucose.
2. Nutritional deficiencies
a. Decreased protein (e.g., malnutrition)
b. Vitamin C deficiency
Decreased hydroxylation of proline and lysine causes
decreased tensile strength in collagen owing to loss of
linkage sites between -chains.
c. Trace metal deficiency
22
222

Copper deficiency leads to decreased cross-linking of chains in collagen.

Zinc deficiency leads to defects in removal of type III collagen
in wound remodeling.

2. Glucocorticoids
a. Interfere with collagen formation and decrease tensile strength
b. Occasionally used along with antibiotics to prevent scar formation
(e.g., bacterial meningitis)
page 36
page 37

Keloids, the raised scars caused by excessive synthesis of type III

collagen, are common in African Americans and may occur as the
result of third-degree burns. Microscopically, keloids appear as
irregular, thick collagen bundles that extend beyond the confines of
the original injury

Repair
in other
tissues
page 37
page 38

1. Liver
a. Mild injury (e.g., hepatitis A)
i.
Regeneration of hepatocytes
ii.
Restoration to normal is possible if cytoarchitecture is intact.
b. Severe or persistent injury (e.g., hepatitis C)
i.
Regenerative nodules develop that lack sinusoids and portal

ii.

triads.
Increased fibrosis occurs around regenerative nodules.
Potential for cirrhosis

2. Lung
a. Type II pneumocytes are the key repair cells of the lung.
b. They replace damaged type I and type II pneumocytes.
3. Brain
a. Astrocytes proliferate in response to an injury (e.g., brain infarction).

22

This is called gliosis.

b. Microglial cells (macrophages) are scavenger cells that remove
debris (e.g., myelin).
Peripheral nerve transection
a. Distal degeneration of the axon (called wallerian degeneration) and
myelin sheath
b. Proximal axonal degeneration up to the next node of Ranvier
c. Macrophages and Schwann cells phagocytose axonal/myelin debris.
d. Muscle undergoes atrophy in 15 days.
e. Nerve cell body undergoes central chromatolysis.
i.
ii.

Nerve cell body swells.

Nissl bodies (composed of rough endoplasmic reticulum and
free ribosomes) disappear centrally.
iii.
Nucleus is peripheralized.
b. Schwann cells proliferate in the distal stump.
c. Axonal sprouts develop in the proximal stump and extend distally
using Schwann cells for guidance.
d. Regenerated axon grows 2 to 3mm/day.
e. Axon becomes remyelinated.
f. Muscle is eventually reinnervated.
4. Heart
g. Cardiac muscle is permanent tissue.
h. Damaged muscle is replaced by noncontractile scar tissue.

Laboratory
Findings
Associated
with
Inflammation
Leukocytes
page 38
page 39

Table 2-3. Cells in Inflammation

Cell

Characteristics

Neutrophil

Key cell in acute inflammation

Receptors for IgG and C3b: important in phagocytosis of opsonized bacteria
Bone marrow neutrophil pools
Mitotic pool: myeloblasts, promyelocytes, myelocytes
Postmitotic pool: metamyelocytes, band neutrophils (stabs), segmented
neutrophils

Peripheral blood neutrophil pools

Marginating pool: adherent to the endothelium (account for 50% of
peripheral blood pool)
Circulating pool: measured in complete blood cell count (CBC)
Causes neutrophilic leukocytosis
Infections (e.g., acute appendicitis)
Sterile inflammation with necrosis (e.g., acute myocardial infarction)
Drugs inhibiting neutrophil adhesion molecules: corticosteroids,
catecholamines, lithium
Monocytes and
Key cells in chronic inflammation
macrophages
Receptors for IgG and C3b
Monocytes become macrophages: fixed (e.g., macrophages in red pulp),
wandering (e.g., alveolar macrophages)
Functions: phagocytosis, process antigen, enhance host immunologic
response (secrete cytokines like IL-1, TNF)
Causes of monocytosis: chronic inflammation, autoimmune disease,
malignancy
B cells and T cells Peripheral blood lymphocyte count: T cells 60-70%, B cells 10-20% of the
total
B cell function: become plasma cells when antigenically stimulated
T cell functions: cellular immunity (type IV HSR), cytokines regulate B cells,
defense against intracellular pathogens (e.g., tuberculosis)
Causes of B/T lymphocytosis: viral infections
Plasma cells
Antibody-producing cells derived from B cells
Morphology: well-developed rough endoplasmic reticulum (site of protein
synthesis); bright blue cytoplasm under Wright-Giemsa stain; nucleus
eccentrically located and has perinuclear clearing
Mast cells and
Release mediators in acute inflammation and allergic reactions (type I HSR)
basophils
Receptors for IgE
Early release reaction: release of preformed mediators (i.e., histamine,
chemotactic factors, proteases)
Late phase reaction: new synthesis and release of PGs and LTs, which
enhance and prolong the acute inflammatory process
Eosinophils
Receptors for IgE
Red granules contain crystalline material; become Charcot-Leyden crystals in
the sputum of asthmatics
Preformed chemical mediators in granules
Major basic protein (MBP) kills invasive helminths
Histaminase neutralizes histamine
Arylsulfatase neutralizes leukotrienes
Functions
Modulate type I HSR by neutralizing histamine and leukotrienes
Destruction of invasive helminths: IgE receptors interact with IgE coating the
surface of invasive helminths antibody-dependent cytotoxicity reaction (type
II HSR) causes the release of MBP kills helminth
Causes of eosinophilia
Type I HSR reactions: allergic rhinitis, bronchial asthma
Invasive helminthic infections excluding pinworms and adult worms in
ascariasis, which are not invasive

HSR, hypersensitivity reaction; IL, interleukin; PG, prostaglandin; LT, leukotriene; TNF, tumor necrosis factor.

1. Acute inflammation (e.g., bacterial infection)

a. Absolute neutrophilic leukocytosis
i.
Accelerated release of neutrophils from the bone marrow
ii.
Mediated by IL-1 and TNF
b. Left shift
Defined as greater than 10% band (stab) neutrophils or the
presence of earlier precursors (e.g., metamyelocytes)
b. Toxic granulation
Prominence of azurophilic granules (primary lysosomes) in
neutrophils

c.

Increase in serum IgM

i.
ii.

Peaks in 7 to 10 days
Isotype switching ( heavy chain replaced by heavy chain)
in plasma cells to produce IgG peaks in 12 to 14 days.

2. Chronic inflammation (e.g., tuberculosis)

b. Absolute monocytosis
c. Increase in serum IgG
3. summarizes cells involved in inflammation.
4. Peripheral blood effects of corticosteroid therapy
d. Absolute neutrophilic leukocytosis

Inhibits activation of neutrophil adhesion molecules

b. Lymphopenia
i.
Sequesters B and T lymphocytes in lymph nodes
ii.
Signal for apoptosis of lymphocytes
e. Eosinopenia

Sequesters eosinophils in lymph nodes

Leukocytes
page 39

Table 2-3. Cells in Inflammation

Cell
Neutrophil

Characteristics

Key cell in acute inflammation

Receptors for IgG and C3b: important in phagocytosis of opsonized bacteria
Bone marrow neutrophil pools
Mitotic pool: myeloblasts, promyelocytes, myelocytes
Postmitotic pool: metamyelocytes, band neutrophils (stabs), segmented
neutrophils
Peripheral blood neutrophil pools
Marginating pool: adherent to the endothelium (account for 50% of
peripheral blood pool)
Circulating pool: measured in complete blood cell count (CBC)
Causes neutrophilic leukocytosis
Infections (e.g., acute appendicitis)
Sterile inflammation with necrosis (e.g., acute myocardial infarction)
Drugs inhibiting neutrophil adhesion molecules: corticosteroids,
catecholamines, lithium
Monocytes and
Key cells in chronic inflammation
macrophages
Receptors for IgG and C3b
Monocytes become macrophages: fixed (e.g., macrophages in red pulp),
wandering (e.g., alveolar macrophages)
Functions: phagocytosis, process antigen, enhance host immunologic
response (secrete cytokines like IL-1, TNF)
Causes of monocytosis: chronic inflammation, autoimmune disease,
malignancy
B cells and T cells Peripheral blood lymphocyte count: T cells 60-70%, B cells 10-20% of the
total
B cell function: become plasma cells when antigenically stimulated
T cell functions: cellular immunity (type IV HSR), cytokines regulate B cells,
defense against intracellular pathogens (e.g., tuberculosis)
Causes of B/T lymphocytosis: viral infections

Plasma cells

Mast cells and

basophils

Eosinophils

Antibody-producing cells derived from B cells

Morphology: well-developed rough endoplasmic reticulum (site of protein
synthesis); bright blue cytoplasm under Wright-Giemsa stain; nucleus
eccentrically located and has perinuclear clearing
Release mediators in acute inflammation and allergic reactions (type I HSR)
Receptors for IgE
Early release reaction: release of preformed mediators (i.e., histamine,
chemotactic factors, proteases)
Late phase reaction: new synthesis and release of PGs and LTs, which
enhance and prolong the acute inflammatory process
Receptors for IgE
Red granules contain crystalline material; become Charcot-Leyden crystals in
the sputum of asthmatics
Preformed chemical mediators in granules
Major basic protein (MBP) kills invasive helminths
Histaminase neutralizes histamine
Arylsulfatase neutralizes leukotrienes
Functions
Modulate type I HSR by neutralizing histamine and leukotrienes
Destruction of invasive helminths: IgE receptors interact with IgE coating the
surface of invasive helminths antibody-dependent cytotoxicity reaction (type
II HSR) causes the release of MBP kills helminth
Causes of eosinophilia
Type I HSR reactions: allergic rhinitis, bronchial asthma
Invasive helminthic infections excluding pinworms and adult worms in
ascariasis, which are not invasive

HSR, hypersensitivity reaction; IL, interleukin; PG, prostaglandin; LT, leukotriene; TNF, tumor necrosis factor.

1. Acute inflammation (e.g., bacterial infection)

a. Absolute neutrophilic leukocytosis
i.
Accelerated release of neutrophils from the bone marrow
ii.
Mediated by IL-1 and TNF
b. Left shift
Defined as greater than 10% band (stab) neutrophils or the
presence of earlier precursors (e.g., metamyelocytes)
b. Toxic granulation
Prominence of azurophilic granules (primary lysosomes) in
neutrophils
c. Increase in serum IgM
i.
ii.

Peaks in 7 to 10 days
Isotype switching ( heavy chain replaced by heavy chain)
in plasma cells to produce IgG peaks in 12 to 14 days.

2. Chronic inflammation (e.g., tuberculosis)

b. Absolute monocytosis
c. Increase in serum IgG
3. summarizes cells involved in inflammation.
4. Peripheral blood effects of corticosteroid therapy
d. Absolute neutrophilic leukocytosis

Inhibits activation of neutrophil adhesion molecules

b. Lymphopenia
i.

Sequesters B and T lymphocytes in lymph nodes

ii.
Signal for apoptosis of lymphocytes
e. Eosinopenia

Sequesters eosinophils in lymph nodes

Erythrocyte
sedimentation
rate (ESR)

ESR is the rate (mm/hour) of settling of RBCs in a vertical tube.

1. ESR is increased in acute and chronic inflammation (e.g., rheumatoid

arthritis).
2. Plasma factor or RBC factors that promote rouleaux formation increase the
ESR.
a. Increase in fibrinogen (acute-phase reactant) in plasma decreases
negative charge in RBCs, promoting rouleaux formation.
b. Anemia promotes rouleaux formation.

Abnormally shaped RBCs (e.g., sickle cells) do not produce

rouleaux.

Creactive
protein
(CRP)
1. Acute-phase reactant
2. Clinical usefulness
a. Sensitive indicator of necrosis associated with acute inflammation
CRP is increased in inflammatory (disrupted) atherosclerotic
plaques and bacterial infections.
b. Excellent monitor of disease activity (e.g., rheumatoid arthritis)

Serum protein electrophoresis in inflammation

Clinical correlation: Proteins in serum are separated into individual
fractions by serum protein electrophoresis (SPE). Charged proteins
placed in a buffered electrolyte solution will migrate toward one or
the other electrode when a current is run through the solution.
Proteins with the most negative charges (e.g., albumin) migrate to
the positive pole, or anode, and those with the most positive
charges (e.g., -globulins) remain at the negatively charged pole, or
cathode. Beginning at the anode, proteins separate into five major
peaks on cellulose acetate-albumin, followed by 1-, 2-, -, and globulins. The -globulins in decreasing order of concentration are
IgG, IgA, and IgM (IgD and IgE are in very low concentration).
1. Acute inflammation
a. Slight decrease in serum albumin
i.
Catabolic effect of inflammation
ii.
Amino acids are used by the liver to synthesize acute phase
reactants.
b. Normal -globulin peak

22

Serum IgM is increased in acute inflammation; however, it

does not alter the configuration of the -globulin peak.
Chronic inflammation (see

a. Greater decrease in serum albumin than in acute inflammation

b. Increase in -globulins due to increase in IgG
Diffuse increase in the -globulin peak is due to many clones
of benign plasma cells producing IgG (i.e., polyclonal
gammopathy).