INFLAMMATION

Prof R V Subramanyam

1

ACUTE INFLAMMATION
Transient and early response to injury that involves release of chemical mediators, causing
stereotypic vessel and leukocyte responses.
Signs of Acute Inflammation
Rubor (redness) and calor (heat)
Histamine-mediated vasodilation of arterioles
Tumor (swelling)
Histamine-mediated increase in permeability of venules
Dolor (pain)
Prostaglandin (PG) E2 sensitizes specialized nerve endings to the effects of bradykinin
and other pain mediators.
Functio laesa
Loss of function
Stimuli for acute inflammation
Infections (e.g., bacterial or viral infection)
Immune reactions (e.g., reaction to a bee sting)
Other stimuli
Tissue necrosis (e.g., acute myocardial infarction), trauma, radiation, burns
Sequential vascular events
Vasoconstriction of arterioles
Neurogenic reflex that lasts only seconds
Vasodilation of arterioles
Histamine and other vasodilators (e.g., nitric oxide) relax vascular smooth muscle,
causing increased blood flow.
Increased blood flow increases hydrostatic pressure.
Increased permeability of venules
Histamine and other mediators contract endothelial cells producing endothelial
gaps.
A transudate (protein and cell-poor fluid) moves into the interstitial tissue.
Swelling of tissue (edema)
Net outflow of fluid surpasses lymphatic ability to remove fluid.
Reduced blood flow
A decrease in hydrostatic pressure is caused by outflow of fluid into the interstitial
tissue.
Sequential cellular events
The events described will emphasize neutrophil events in acute inflammation due to a
bacterial infection (e.g., Staphylococcus aureus).
Neutrophils are the primary leukocytes in acute inflammation.
Margination
RBCs aggregate into rouleaux ("stacks of coins") in venules.
Neutrophils are pushed from the central axial column to the periphery
(margination).
Rolling
Due to activation of selectin adhesion molecules on the surface of neutrophils and
endothelial cells
Neutrophils loosely bind to selectins and "roll" along the endothelium.
Adhesion
Adhesion molecules firmly bind neutrophils to endothelial cells.
Neutrophil adhesion molecules
INFLAMMATION
Prof R V Subramanyam

2

2-Integrins (CD11a:CD18)
Adhesion molecule activation is mediated by C5a and leukotriene B4 (LTB4).
Catecholamines, corticosteroids, and lithium inhibit activation of adhesion
molecules.
This causes an increase in the peripheral blood neutrophil count
(neutrophilic leukocytosis).
Endotoxins enhance activation of adhesion molecules.
This causes a decrease in the peripheral blood neutrophil count
(neutropenia).
Endothelial cell adhesion molecules
Intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule
(VCAM) bind to integrins on the surface of neutrophils.
ICAM and VCAM activation is mediated by interleukin 1 (IL-1) and tumor
necrosis factor (TNF).
Leukocyte adhesion deficiency (LAD)
Autosomal recessive disorders
LAD type 1 is a deficiency of CD11a:CD18.
LAD type 2 is a deficiency of a selectin that binds neutrophils.
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
leucocytosis
Transmigration (diapedesis)
Neutrophils dissolve the basement membrane and enter interstitial tissue.
Fluid rich in proteins and cells (i.e., exudate) accumulates in interstitial tissue.
Functions of exudate
Dilute bacterial toxins
Provide opsonins (assist in phagocytosis), antibodies, and complement
Chemotaxis
Neutrophils follow chemical gradients that lead to the infection site.
Chemotactic mediators bind to neutrophil receptors.
Mediators include C5a, LTB4, bacterial products, and IL-8.
Binding causes the release of calcium, which increases neutrophil motility.
Phagocytosis
Multistep process:
Opsonization
Ingestion
Killing
Opsonization
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.
Opsonization enhances neutrophil recognition and attachment to bacteria.
Bruton's agammaglobulinemia is an opsonization defect.
Ingestion
Neutrophils engulf (phagocytose) and then trap bacteria in phagocytic
vacuoles.
INFLAMMATION
Prof R V Subramanyam

3

Primary lysosomes empty hydrolytic enzymes into phagocytic vacuoles
producing phagolysosomes.
In Chdiak-Higashi syndrome, a defect in membrane fusion prevents
phagolysosome formation.
Bacterial killing
O
2
-dependent myeloperoxidase (MPO) system (Fig. 1)
Only present in neutrophils and monocytes (not macrophages)
Production of superoxide free radicals (O
2
~
)
NADPH oxidase converts molecular O
2
to O
2
~
, which releases energy
called the respiratory, or oxidative, burst.
Production of peroxide (H
2
O
2
)
Superoxide dismutase converts O
2
~
to H
2
O
2
, which is neutralized by
glutathione peroxidase.
Production of bleach (HOCl)
MPO combines H
2
O
2
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 O
2
-dependent MPO system.
Deficiency of NADPH (e.g., glucose-6-phosphate dehydrogenase
deficiency) produces a microbicidal defect.
O
2
-independent system
Refers to bacterial killing from substances located in leukocyte granules
Examples-lactoferrin (binds iron necessary for bacterial reproduction) and
major basic protein (eosinophil product that is cytotoxic to helminths)

Figure 1. Oxygen-dependent myeloperoxidase system. A series of biochemical reactions occurs in the
phagolysosome, resulting in the production of hypochlorous free radicals (bleach; HOCl) that destroy bacteria. GSH,
reduced glutathione; G6-P, glucose 6-phosphate; GSSG, oxidized glutathione; H2O2, peroxide; MPO, myeloperoxidase;
NADP+, oxidized form of nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine
dinucleotide phosphate; 6PG, 6-phosphogluconate; SOD, superoxide dismutase.
INFLAMMATION
Prof R V Subramanyam

4

Table 1. Sources and Functions of Chemical Mediators
Mediator Source(s) Function(s)
Arachidonic Acid Metabolites
Prostaglandins Macrophages, endothelial cells,
platelets
PGH2: major precursor of PGs and
thromboxanes
PGE2: vasodilation, pain, fever
PGI2: vasodilation; inhibition of platelet
aggregation
Thromboxane
A2
Platelets
Converted from PGH2 by
thromboxane synthase
Vasoconstriction, platelet
aggregation, bronchoconstriction
Leukotrienes
(LTs)
Converted from arachidonic acid by
lipoxygenase-mediated hydroxylation
LTB4: chemotaxis and activation of
neutrophil adhesion molecules
LTC4, LTD4, LTE4: vasoconstriction,
increased vessel permeability,
bronchoconstriction
Bradykinin Product of kinin system activation by
activated factor XII
Vasodilation, increased vessel
permeability, pain,
bronchoconstriction
Chemokines Leukocytes, endothelial cells Activate neutrophil chemotaxis
Complement 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
Cytokines
IL-1, TNF Lymphocytes, macrophages,
endothelial cells
Initiate PGE2 synthesis in anterior
hypothalamus, leading to production
of fever
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
IL-6 Increase liver synthesis of acute phase
reactants
IL-8 Chemotaxis
Histamine Mast cells (primary cell), platelets,
enterochromaffin cells
Vasodilation, increased vessel
permeability
Nitric Oxide
(NO)
Macrophages, endothelial cells
Free radical gas released during
conversion of arginine to citrulline by
NO synthase
Vasodilation, bactericidal
Serotonin Mast cells, platelets Vasodilation, increased vessel
permeability
IL, interleukin; PG, prostaglandin; TNF, tumor necrosis factor.
INFLAMMATION
Prof R V Subramanyam

5


Figure 2 Arachidonic acid metabolism. Arachidonic acid is released from membrane phospholipids. It is converted
into prostaglandins (PGs), thromboxane A2 (TXA2), and leukotrienes (LTs).

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

Consequences of acute inflammation
Complete resolution
Occurs with mild injury to cells that have the capacity to enter the cell cycle (e.g., labile
and stable cells)
Examples-first-degree burn, bee sting
Tissue destruction and scar formation
Occurs with extensive injury or damage to permanent cells
INFLAMMATION
Prof R V Subramanyam

6

Example-third-degree burns
Progression to chronic inflammation

Types of acute inflammation
Location, cause, and duration of inflammation determine the morphology of an inflammatory
reaction.
Purulent (suppurative) inflammation
Localized proliferation of pus-forming organisms, such as Staphylococcus aureus
(e.g., skin abscess)
S. aureus contains coagulase, which cleaves fibrinogen into fibrin and traps
bacteria and neutrophils.
Fibrinous inflammation
Due to increased vessel permeability, with deposition of a fibrin-rich exudate
Example-fibrinous pericarditis
Pseudomembranous inflammation
Bacterial toxin-induced damage of the mucosal lining, producing a shaggy
membrane composed of necrotic tissue
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
Right-shifts oxygen-binding curve
More O
2
is available for the O
2
-dependent MPO system.
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
Infection
Examples-tuberculosis, leprosy, hepatitis C
Autoimmune disease
Examples-rheumatoid arthritis, systemic lupus erythematosus
Sterile agents
Examples-silica, uric acid, silicone in breast implants

Morphology
Cell types
Monocytes and macrophages, lymphocytes and plasma cells, eosinophils
Necrosis
Not as prominent a feature as in acute inflammation
Destruction of parenchyma
Loss of functional tissue, with repair by fibrosis
Formation of granulation tissue
Highly vascular tissue composed of newly formed blood vessels (i.e.,
angiogenesis) and activated fibroblasts
Essential for normal wound healing
INFLAMMATION
Prof R V Subramanyam

7

Converted into scar tissue
Fibronectin is required for granulation tissue formation.
Cell adhesion glycoprotein located in the extracellular matrix (ECM)
Binds to collagen, fibrin, and cell surface receptors (e.g., integrins)
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.
Granulomatous inflammation
Specialized type of chronic inflammation
Causes
Infections
Examples-tuberculosis 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 pathogens.
Noninfectious causes
Examples-sarcoidosis and Crohn's disease
Noncaseating (i.e., hard granulomas)
Morphology
Pale, white nodule with or without central caseation
Usually well-circumscribed
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
Pathogenesis of a tuberculous granuloma (Box 1)

BOX 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 T
H
1 class cells) and
IL-1 (causes fever; activates T
H
1 cells).
T
H
1 cells release IL-2 (stimulates T
H
1 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
Parenchymal cell regeneration
Repair by connective tissue (fibrosis)

INFLAMMATION
Prof R V Subramanyam

8

Table 2. Factors Involved in Tissue Repair
Factor Function(s)
Growth Factors
Vascular endothelial cell growth
factor (VEGF)
Stimulates angiogenesis
Basic fibroblast growth factor
(BFGF)
Stimulates angiogenesis
Epidermal growth factor (EGF) Stimulates keratinocyte migration
Stimulates granulation tissue formation
Platelet-derived growth factor
(PDGF)
Stimulates proliferation of smooth muscle, fibroblasts,
endothelial cells
Hormones
Insulin growth factor-1 (IGF-1) Stimulates synthesis of collagen
Promotes keratinocyte migration
Interleukins (IL)
IL-1 Chemotactic for neutrophils
Stimulates synthesis of metalloproteinases (i.e., trace metal
containing enzymes)
Stimulates synthesis and release of acute phase reactants
from the liver


Fig 3. Cell cycle. Refer to the description in the text

Depends on the ability of cells to replicate
Labile cells (e.g., stem cells in epidermis) and stable cells (e.g., fibroblasts) can
replicate (see Chapter 1).
Permanent cells cannot replicate.
Cardiac and striated muscle are replaced by scar tissue (fibrosis).
Depends on factors that stimulate parenchymal cell division and migration
INFLAMMATION
Prof R V Subramanyam

9

Stimulatory factors include loss of tissue and production of growth factors (Table
2-2).
CELL CYCLE (Fig. 3)
Phases of the cell cycle
G0 phase
Resting phase of stable parenchymal cells
G1 phase
Synthesis of RNA, protein, organelles, and cyclin D
S (synthesis) phase
Synthesis of DNA, RNA, protein
G2 phase
Synthesis of tubulin, which is necessary for formation of the mitotic spindle
M (mitotic) phase
Two daughter cells are produced.
Regulation of the G1 checkpoint (G1 to S phase)
Most critical phase of the cell cycle
Control proteins include cyclin-dependent kinase 4 (Cdk4) and cyclin D
Growth factors activate nuclear transcribing proto-oncogenes to produce
cyclin D and Cdk4.
Cyclin D binds to Cdk4, forming a complex causing the cell to enter the S
phase.
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.
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.
Restoration to normal
Requires preservation of the basement membrane
Requires a relatively intact extracellular matrix (ECM; i.e., collagen, adhesive
proteins)
Laminin, the key adhesion protein in the basement membrane, interacts with
type IV collagen, cell surface receptors, and components in the ECM.