Inflammation: Acute, Chronic and Systemic Mon.

08/23/10

Design a System
• Recognize injury promptly & properly
• Eliminate invaders & debris
• Communicate & continuously adjust to changing conditions
• Continue the response as long as needed
• Prepare for rebuilding

Sources of Injury
• Traumatic
• Infectious
• Chemical
• Immune reactions (hypersensitivity)
• Immune system response begins with platelets and
neutrophils or mast cells
• Neoplastic

Inflammation
• Every person, every disease
• Destroy, dilute or wall off the injurious agent
• A closely regulated protective reaction
• Relies on vascularized tissue

Learning Objectives
1. Acute and chronic inflammation features
2. 3 components of the inflammatory system
3. Steps of leukocyte emigration, chemotaxis and phagocytosis
4. Nine mediator classes
5. How inhibitors regulate & cytokines transition to chronic phase
6. Four causes of chronic inflammation
7. Cardinal signs of acute inflammation

1. Acute and chronic inflammation features:

Test q: Which of the following is a marker of chronic inflammation?
Capillary formation.
Acute vs Chronic Inflammation:
Acute Chronic
• Immediate • Gradual
• Transient (does not last long) • Prolonged (persistence of injury-causing agent)
• Edema • Fibrosis & vessels (change in architecture)
• Blood vessels derive from preexisting blood vessels (angiogenesis)
• Essential for normal wound healing
• Neutrophils • Mononuclear cells (monocytes, macrophages, lymphocytes, plasma cells)
• Fibrin • Collagen
• Necrosis (cell death cleaned up fast) • Resolution of necrosis (takes a long time to clean up debris)

FIGURE 2–7A Nature of

leukocyte infiltrates in
inflammatory reactions. The
photomicrographs are
representative of the early
(neutrophilic) (A) and later
(mononuclear) cellular
infiltrates (B) seen in an
inflammatory reaction in the
myocardium following
ischemic necrosis
(infarction). The kinetics of
edema and cellular
infiltration (C) are
approximations.
Test q: A 20y/o college student comes to your office w/vague complaints of fatigue and right upper quadrant “fullness”. His liver enzymes are elevated
and he has a family history of primary biliary cirrhosis, so you request a liver biopsy. When you review the slides w/the pathologist, he points out
prominent periportal lymphocytic infiltration w/germinal centers and scattered fibroblasts in the interlobular zone. The most likely pathologic diagnosis
is: chronic inflammation.

Figure: Histology of Acute Inflammation 

FIGURE 2–17A The characteristic histopathology of acute

inflammation. A, Normal lung shows thin (virtually invisible)
blood vessels in the alveolar walls and no cells in the
alveoli. B, The vascular component of acute inflammation is
manifested by congested blood vessels (packed with
erythrocytes), resulting from stasis. C, The cellular
component of the response is manifested by large numbers
of leukocytes (neutrophils) in the alveoli.

Acute inflammation- dilation of blood vessels, neutrophils

come in.

2. 3 Components of the Inflammatory System:

1. Vessels
• Arterioles
• Venules
• Lymphatics
2. Leukocytes
3. Soluble mediators: many produced by cell and effective in neighborhood around cell. Some in serum but only
activated in location of acute inflammatory response.
• Paracrine
• Serum enzyme
• Cytokines
• Proteins produced by many cell types (activated lymphocytes and macrophages; endothelial, epithelial,
connective tissue)
• TNF + IL-1: produced by macrophages (activated)
• Endothelial activation: endothelial adhesion; chemical mediators

Vascular and Cellular Responses

• Increased blood flow to tissue (vasodilation)
• Increased vascular permeability (leakage) – only certain vessels.
Arterioles dilate and let in more blood, venules become more
leaky.
• Migration of leukocytes out of the blood vessels (chemotaxis)

FIGURE 2–2 Formation of transudates and exudates. A, Normal

hydrostatic pressure (blue arrows) is about 32 mm Hg at the
arterial end of a capillary bed and 12 mm Hg at the venous end;
the mean colloid osmotic pressure of tissues is approximately 25
mm Hg (green arrows), which is equal to the mean capillary
pressure. Therefore, the net flow of fluid across the vascular bed
is almost nil. B, A transudate is formed when fluid leaks out
because of increased hydrostatic pressure or decreased osmotic
pressure. C, An exudate is formed in inflammation, because
vascular permeability increases as a result of increased interendothelial spaces.

• Normal: slight leakage out of vessel

• Congestive heart failure, fluid overload: increased hydrostatic pressure  fluid leaks out more.
• Transudate: fluid with low protein content, little or no cellular material, low specific gravity. Ultrafiltrate of blood
plasma that results from osmotic or hydrostatic imbalance across vessel wall without an increase in vascular
permeability.
• Exudate: escape of fluid, proteins, blood cells from vascular system into interstitial tissue or body cavities. Increase in
normal permeability of small blood vessels due to injury  inflammation. Blood flow slows down in acute
inflammatory vessels. Have extravascular fluid with high protein concentration, cellular debris, high specific gravity.
Test q: In acute inflammation, the most significant increase in vascular permeability occurs in: Post-capillary venules.
Figure: Capillaries dilate with increased pressure due to dilation of 
arterioles. Venules get leaky.

Vascular Changes:
• Transient Vasoconstriction
· Hemostasis: slow moving red cells (b/c vasodilation follows
transient vasoconstriction)
• Vasodilation (biggest effect)
· Mediated by prostaglandins and Nitric oxide
· Arteriole smooth muscle relaxes
· Relax vessels  allow more blood flow
• Increased Permeability (leakage)
· Transient, sustained or delayed

Above: Arrow = arteriole. Rabbit

Normal: Capillary has only 1 endothelial Injury: Stimulate endothelial cells to injected with carbon black
cell around vessel. Venules has ~3. contract and release tight junctions pigment. Histamine put in area.
bt cells  increased interendothelial Venules more leaky due to
spaces. dilated vessels. Contraction of
endothelial cells and increased
interendothelial spaces is elicited
3. Emigration, chemotaxis and phagocytosis: by histamine.
Leukocyte Extravasation
• Margination
– Leukocytes approach endothelium
– RBCs aggregate in venules
– Neutrophils pushed from central to periphery
• Rolling
– Mediated by selectin
– Weak bonding bt cell and endothelium
– Activation of selectin adhesion molecules on
surface of neutrophils and endothelial cells
– Neutrophils loosely bind selectins and “roll”
along endothelium
• Adhesion (pavementing)
– Tight integrin (β2) binding Test q: During acute inflammation, neutrophils
– Communication in cytoplasm, rearrangement of cytosol migrate through the walls of the venules. This
migration requires integrins and selectins.
– Adhesion molecules firmly bind neutrophils to endothelial cells
– Catecholamine, corticosteroids, and lithium inhibit activation of Test q: A 6y/o child has a history of recurrent
adhesion molecules infections w/pyogenic bacteria, including Staph
• Transmigration (Diapedesis) aureus and Strep pneumoniae. The infections are
accompanied by a neutrophilic leukocytosis.
– Integrin Microscopic exam of a biopsy specimen obtained
– Find a hole – neutrophils dissolve basement membrane and enter from an area of soft tissue necrosis shows
interstitial tissue microbial organisms but very few neutrophils. An
– Functions of exudate: (1) dilutes bacterial toxins (2) provides analysis of neutrophil function shows a defect in
rolling. This child’s increased susceptibility to
opsonins infection is most likely caused by a defect in which
• Chemotaxis of the following molecules? Selectins.
– Neutrophils follow chemical gradients that lead to the infection site
– Chemotactic mediators bind to neutrophil receptors; binding Test q: In the acute inflammatory reaction, the
principal function of selectins and integrins is to
causes release of calcium which increases neutrophil motility enhance leukocyte binding to the endothelium.
FIGURE 2–4 The multistep process
of leukocyte migration through blood
vessels, shown here for neutrophils.
The leukocytes first roll, then become
activated and adhere to endothelium,
then transmigrate across the
endothelium, pierce the basement
membrane, and migrate toward
chemoattractants emanating from the
source of injury. Different molecules
play predominant roles in different
steps of this process—selectins in
rolling; chemokines (usually
displayed bound to proteoglycans) in
activating the neutrophils to increase
avidity of integrins; integrins in firm
adhesion; and CD31 (PECAM-1) in
transmigration. Neutrophils express
low levels of L-selectin; they bind to
endothelial cells predominantly via P-
and E-selectins. ICAM-1, intercellular
adhesion molecule 1; TNF, tumor
necrosis factor.

TNF and IL-1--released by macrophages--act on

endothelial of post-capillary venules and induce
expression of adhesion molecules.
A
Adhesion Molecule Expression:

FIGURE 2–5: Regulation of expression of endothelial and

leukocyte adhesion molecules. A, Redistribution of P-
selectin from intracellular stores to the cell surface. B,
Increased surface expression of selectins and ligands for
integrins upon cytokine activation of endothelium. C,
Increased binding avidity of integrins induced by
chemokines. Clustering of integrins contributes to their
increased binding avidity (not shown). IL-1, interleukin-1;
TNF, tumor necrosis factor.

– Weibel-Palade bodies: endothelial granules that store P-selectin; redistribution of P-selectin in W-P bodies to
surface.
– Chemokines produced at injury site enter blood vessel and bind to endothelial cell proteoglycans; induced
expression of integrin ligands on endothelium and activation of integrins to high affinity state on leukocytes

Figure: Migration to extracellular space.  High

response of inflammatory substance at core of
inflammation. Chemotaxis attacts leukocyte by
having extracellular matrix attachment sites.
Chemotaxis: a family of 40 peptides that attract inflammatory cells.
Figure:
• Increasing chemical gradient
macrophage 
• Exogenous agents SEM. Scanning
– Bacterial N-formyl-methionine peptides electron
• Endogenous products micrograph of a
– Complement (C3a & C5a) moving leukocyte
– Lipoxygenase products (LTB4) in culture showing
– Cytokines (TNF, IL-1) a filopodium
- IL-1 is produced by macrophages. Macrophages (upper left) and a
release it once they’re at inflammatory site. trailing tail.
– Chemokines (IL-8, α,β,γ) Figure:
Pseudopod
Phagocytosis: toward attractant.
• Neutrophil has to recognize that material is foreign.  Project
• Recognition and attachment cytoplasm in
- Opsonins: IgG-Fc, C3b, iC3b, collectins direction that has
- attach to bacteria (or foreign bodies) most chemotaxis
- Neutrophils have receptors for IgG
and C3b Test q: A 10y/o boy suffers recurring infections due to Strep pneumoniae. He is
found to have an inherited disorder of a complement factor such that phagocytosis
- Enhances neutrophil recognition and is deficient. This factor is most likely: C3b.
attachment to foreign bodies
- Leukocyte receptors: FcγR, CR1/2 Test q: Phagocytosis of bacteria by neutrophils or other bactericidal cells is greatly
facilitated by coating the foreign organisms w/substances recognized by the
• Engulfment: phagocytose; phagocytic vacuoles phagocytes. These attachment-promoting substances, called opsonin, are
• Killing and degradation: present in the ECF of inflamed tissue. One example of an opsonin is: Fc
- Oxidative burst fragments of IgG. REPEATED TWICE (but on 2005 answer key, says answer is
- Enzyme digestion C5a even though “Fc fragments of IgG” is a choice…typo?)

Test q: The oxidative burst of

leukocytes produces a substance
which is the most potent bactericidal
Phagocytosis & Oxidative Burst: product of the cell. This substance
is called: Hypochlorous acid
FIGURE 2–9 Phagocytosis and intracellular (HOCl). (Other choices: Bacterial
destruction of microbes. Phagocytosis of a particle permeability increasing protein
(e.g., bacterium) involves binding to receptors on the (BPI); Major basic protein (MBP);
leukocyte membrane, engulfment, and fusion of Lactoferrin; Lysozyme)
lysosomes with phagocytic vacuoles. This is followed
by destruction of ingested particles within the
phagolysosomes by lysosomal enzymes and by
reactive oxygen and nitrogen species. The microbicidal
products generated from superoxide are hypochlorite
(HOCl•) and hydroxyl radical (•OH), and from nitric
oxide (NO) it is peroxynitrite (OONO•). During
phagocytosis, granule contents may be released into
extracellular tissues (not shown). MPO,
myeloperoxidase; iNOS, inducible NO synthase.

Reactive Oxygen Species:

• Respiratory burst: oxidizes NADPH and in
process, reduces oxygen superoxide anion, which is converted to H2O2
• Occurs in lysosome
• H2O2 not able to efficiently kill microbes; enzyme myeloperoxidase in
neutrophil granules converts H2O2 to hypochlorite.

Neutrophil Granules
• Specific (secondary)
– Smaller, fuse with plasmalemma
– Lysozyme: hydrolyzes muramic acid-N-acetylglucosamine bond, found
in glycopeptide coat of all bacteria
– Collagenase IV
• Azurophil (primary)
– Fusion with phagosome
– Myeloperoxidase, NADPH oxidase
– Acid & neutral protease
 4. Nine mediator classes:
Test q: A clever pharmaceutical rep is telling you about how his company’s
amazing drug counteracts all of the soluble mediators of acute inflammation. He
Soluble Factor Overview describes how this drug counteracts the effects of plasma protease products,
• Paracrine cell products arachidonic acid metabolites, histamine, platelet activating factor, and even
– Nitric Oxide (NO) neuropeptides. You, however, know something about acute inflammatory
mediators. Noticing that he has left something out, you ask him what his drug
– Vasoactive amines (Histamine) does for: Nitric oxide.
– Arachidonic acid metabolites (COX,LOX)
– Platelet Activating Factor (PAF)
– Neuropeptides (SP)
• Plasma protease systems
– Bradykinin, Kallekrein
– Complement cascade
– Clotting products and enzymes

Nitric Oxide
• Vasodilates
• Produced by endothelium and macrophages
• From L-arginine, O2, NADPH, cofactors
– NO synthesized from L-arginine via nitric oxide synthase (NOS) Nitric Oxide Synthase
– Endothelial, neuronal, inducible on macrophages
• Inhibits rolling, adhesion of leukocytes (thought to control inflammatory response)
• Three types of NOS: eNOS (endothelial), nNOS (neuronal), iNOS (inducible)
• Antimicrobial free radicals released (NO is microbicidal)

Vasoactive Amines
• Histamine
– Stored in granules of mast cells and basophils
– Granules released into surrounding inflammatory tissue by allergen binding multiple IgE molecules on mast cell
Test q: In acute inflammation, arterioles dilate and venules become more permeable (leaky). These changes occur when mast cells release Histamine.
Test q: A woman who is allergic to cats visits a neighbor who has several cats. During the visit, she inhales cat dander and within minutes, she
develops nasal congestion w/abundant nasal secretions. Which of the following substances is most likely to produce these findings? Histamine.
Test q: A man w/a mold allergy returns to his recently flooded home in New Orleans. During the visit, he develops nasal congestion w/abundant nasal
secretions. Which of the following substances is most likely to produce these findings? Histamine.
Test q: Of those listed, the earliest chemical mediator of inflammation is: histamine. (Other choices: Hageman factor, Bradykinin, serotonin, Kallikrein)
• Serotonin (5-HT)
– Stored in granules of platelets and enterochromaffin cells
– Released when platelets aggregate
• Vasodilate and increase permeability

FIGURE 2–11 
Generation of arachidonic acid metabolites
and their roles in inflammation. The molecular
targets of action of some anti-inflammatory
drugs are indicated by a red X. Not shown are
agents that inhibit leukotriene production by
inhibition of 5-lipoxygenase (e.g., Zileuton) or
block leukotriene receptors (e.g.,
Montelukast). COX, cyclooxygenase; HETE,
hydroxyeicosatetraenoic acid; HPETE,
hydroperoxyeicosatetraenoic acid.

Arachidonic acid
- when inflammatory stimulation, may
be further metabolised by
Cycloxygenase pathway or
Lipoxygenase pathway (produce
lipoxins- inhibitors of inflammatory
response and also chemotaxins
important in asthma response)
Cyclooxygenase pathway
- balance between prostacyclin and thromboxane
Test q: We now believe that many of the anti-inflammatory effects of glucocorticoid hormone-related drugs are caused by boosting of cytoplasmic
calcium-dependent phospholipid-binding proteins called lipocortin. Since lipcortin-1 inhibits phospholipase A2, glucocorticoid indirectly decreases the
level of free arachidonic acid by cells receiving inflammatory stimuli. One consequence of decreased free arachidonic acid is decreased vasodilation by
products of: the cyclooxygenase pathway.
 Simplified AA Metabolism:
Membrane
Phopholipase A2: primary enzyme that releases
Phospholipids arachidonic acid from membrane phospholipids.
Phospholipase A 2
AA-derived mediators--aka eicosanoids--synthesized
Arachidonic by two major classes of enzymes:
Acid
Cyclooxygenase Lipoxygenase 1. Cyclooxygenase: generate prostaglandins
Pathway Pathway
2. Lipoxygenase: Leukotriense and lipoxins

Prostaglandins vasodil Leukotrienes incr perm

Lipoxins oppose inflam
Thromboxane clot
Prostacyclin unclot

Platelet Activating Factor (PAF) – paracrine substance produced at inflammation site

• Vasodilates and increases permeability
– 100 to10,000 times more potent than histamine
– also adhesion, chemotaxis, oxidative burst
• Fatty acid on middle C of PC replaced
– “by product” of phospholipase A2
• From endothelial cells, platelets
– Synthesized at site of inflammation
– PAF-specific acetylhydrolase inactivates
– Test q: The major sources of PAF are: Platelets and endothelium.

Neuropeptides
• Substance P (most widely known neuropeptide) is the prototype
– Tachykinin family of peptides
• CNS & PNS
• Multiple effects
– Vasodilate
– Increase permeability
– Pain mediation (most important function)
• Capsaicin in hot peppers

Hageman Factor XII: protein synthesized by liver

that circulates in inactive form. Inflammation and
blood clotting are intertwined, with each promoting
the other. Anytime clotting promoted, you also get
fibrinolysis. Deposition and degradation balance.

- Plasmin: activates fibrinolysis and complement.

- Kallikrein: enzyme that cleaves precursor to
bradykinin
- Bradykinin:
• Increase permeability
• Contraction of smooth muscle
• Vasodilation
• Pain

Fibrin clot formation also occurs with fibrinolysis

(cleaves fibrin, solubilize clot)

Plasmin also cleaves complement protein C3 to

produce C3 fragment
• C3a + C5a: increase vascular permeability
• C5a: chemotaxis
FIGURE 2–14 
The activation and functions of the complement
system. Activation of complement by different
pathways leads to cleavage of C3. The functions
of the complement system are mediated by
breakdown products of C3 and other complement
proteins, and by the membrane attack complex
(MAC).

Test q: A 20y/o male presents w/acute abdominal pain.

Phys exam reveals “rebound tenderness” indicating
peritonitis. The discomfort experienced by the young
patient is mediated primarily by: Bradykinin.

Mediator Functions:

Nitric oxide Vasodilates, inflammation control, defense Test q: Nitric oxide is an important mediatior
of: vasodilation. REPEATED TWICE.
Histamine Vasodilation, ↑permeability

Serotonin Vasodilation, ↑permeability

Cyclooxygenase Prostaglandins: vasodilation

Thromboxane: clot
Prostacylin: unclot

Lipoxygenase Leukotrienes: ↑permeability

Lipoxygenase: X inflammation

PAF Vasodilation, ↑permeability

Vasodilate
Neuropeptide Vasodilation, ↑permeability, pain
Substance P Increase Permeability
Bradykinin Vasodilation, ↑permeability, smooth muscle Chemotaxis
contraction, pain
Pain
Complement C3a: ↑permeability
C5a: ↑permeability, vasodilate

Clotting Vasodilate, cleave fibrin,solubilize clot

Clotting
5. How inhibitors regulate & cytokines transition to chronic phase Complement
Because of the destructive effects of lysosomal enzymes, the initial leukocytic infiltration – if unchecked – can potentiate
further inflammation and tissue damage. Harmful proteases are kept in check by antiproteases in serum and tissue fluids.
Kinins
Antiprotease Antioxidant Test q: If acute inflammatory responses were to proceed
• Found in serum
• α1 - antitrypsin
• Scavenge
•
– O2 , H2O2, HO
• -
•
Cyclooxygenase
} AA
w/o inhibition, they would cause considerable tissue
destruction and permanent loss of function of inflamed
organs. Once important regulator of acute inflammation
Lipoxygenase
– Inhibits neutrophil – NO2 , OONO , RSNO is the substance: alpha-1-antitrypsin.
elastase • Extracellular
Test q: Examples of two plasma proteins that limit,
– Alveoli rupture/coalesce – Ceruloplasmin Histamine
control, and regulate the potentially destructive products
pulmonary emphysema – Transferrin of the acute inflammatory response: α-1-antitrypsin
– No alpha-1-antitrypsin = • Intracellular
neutrophil elastase is not
Nitric Oxide
and ceruloplasmin.
– Superoxide dismutase
inhibited (sustained action – Catalase Test q: Which of the following cellular enzymes are
of leukocyte proteases) – Glutathione peroxidase
PAF
produced by polymorphonuclear cells in acute
inflammatory responses to protect against toxic
• α2 – macroglobulin byproducts? Superoxidase.
- In both serum and secretions Substance P
Test q: Which of the following is assoc’d w/prevention
of damage to human tissue by free radicals?
Glutathione peroxidase.
Cytokines: transition from acute to chronic/reparative response
• Interleukins
– – Monokines IL-1
– – Lymphokines IL-2
• Macrophage activators
– IFNγ (most important activator of macrophages), TNFα , TNFβ , IL-5, IL-10, IL-12
• Hematopoietic growth factors
– c-kit ligand, GMCSF, MCSF, G-CSF, stem cell factor
• Chemokines chemotactic – attract other inflammatory cells

Cytokines: Acute Inflammation:

Cytokine Principal Sources Principal Actions in Inflammation
TNF Macrophages, mast cells, T Stimulates expression of endothelial adhesion molecules and
lymphocytes secretion of other cytokines; systemic effects
IL-1 Macrophages, endothelial cells, Similar to TNF; greater role in fever
some epithelial cells
IL-6 Macrophages, other cells Systemic effects (acute-phase response)
Chemokines Macrophages, endothelial cells, Recruitment of leukocytes to sites of inflammation; migration
T lymphocytes, mast cells, other of cells to normal tissues
cell types

Cytokines: Chronic Inflammation:

Cytokine Principal Sources Principal Actions in Inflammation
IL-12 Dendritic cells, macrophages Increased production of IFN-γ

IFN-γ T lymphocytes, NK cells Activation of macrophages (increased ability to kill microbes and
tumor cells)

IL-17 T lymphocytes Recruitment of neutrophils and monocytes

FIGURE 2–25 Macrophage-lymphocyte interactions in chronic inflammation.

Activated T cells produce cytokines that recruit macrophages (TNF, IL-17,
chemokines) and others that activate macrophages (IFNγ). Different subsets
of T cells (called TH1 and TH17) may produce different sets of cytokines;
these are described in Chapter 6. Activated macrophages in turn stimulate T
cells by presenting antigens and via cytokines (such as IL-12).

IFN-γ activates more macrophages.

Outcome of Acute Inflammation:

• Resolution (regeneration)
– No functional or histologic change
• Progression
– Chronic inflammation
– Granuloma
• Abscess formation
– Abcess or granuloma – chronic inflammation response
• Healing (reconstitution)
– Collagen binder or filler
– Fibrosis (replacement by scar)
Acute versus Chronic Lung Inflammation
FIGURE 2–22A A, Chronic
inflammation in the lung,
showing all three characteristic
histologic features: (1) collection
of chronic inflammatory cells (*),
(2) destruction of parenchyma
(normal alveoli are replaced by
spaces lined by cuboidal
epithelium, arrowheads), and
(3) replacement by connective
tissue (fibrosis, arrows). B, By
contrast, in acute inflammation
of the lung (acute
bronchopneumonia), neutrophils
A fill the alveolar spaces and
blood vessels are congested.
Chronic inflammatory response- change in architecture

6. Four Causes of Chronic Inflammation: Serous Inflammation (skin blister):

• Persistent infection
• Persistent injurious agent
• Interference with healing
• Autoimmunity

• May begin with minimal acute phase

– Rheumatoid arthritis
– Atherosclerosis
– Tuberculosis

Serous & Fibrinous Inflammation (Figures)  Fibrinous Inflammation (fibrinous pericarditis):

FIGURE 2–18 Serous inflammation (top). Low-power view of a
cross-section of a skin blister showing the epidermis separated
from the dermis by a focal collection of serous effusion.
FIGURE 2–19A Fibrinous pericarditis (bottom). A, Deposits of
fibrin on the pericardium. B, A pink meshwork of fibrin exudate (F)
overlies the pericardial surface
(P).

Bread and butter pericarditis 

Test q: A 53y/o male develops pericarditis after a bacterial

pneumonia and dies. At autopsy, the pericardium is coated
w/acellular pink (smudgy) material. Fibroblasts and capillaries are
not present. The best description is: fibrinous pericarditis.

FIGURE 2–20A (left) Purulent inflammation. A, Multiple

bacterial abscesses in the lung, in a case of
bronchopneumonia. B, The abscess contains neutrophils and
cellular debris, and is surrounded by congested blood
vessels.

FIGURE 2–21A (right) The morphology of an ulcer. A, A

chronic duodenal ulcer. B, Low-power cross-section of a
duodenal ulcer crater with an acute inflammatory exudate in
the base.

Test q: A 75y/o female develops a cough and fever of 103F.

Chest x-ray shows a virtual “white-out” of the left upper lobe. If
the area of involvement were biopsied, you would expect to see:
Gram-positive diplococci and neutrophils. (indicating Strep
pneumo)
 FIGURE 2–23 Maturation of mononuclear phagocytes:
Test q: A 70y/o woman has worsening
shortness of breath. Her temp is 38.3*C.
On percussion, there is fullness over the left
lung fields. Thoracentesis yields 800mL of
cloudy yellow fluid from the left pleural
cavity. Analysis of the fluid reveals a WBC
count of 2500/mm3 w/98% neutrophils and
2% lymphocytes. A gram stain of the fluid
shows gram-positive cocci in clusters.
Which of the following terms best describes
the process occurring in the left pleural
cavity? Purulent exudates. (Other choices
were Abscess, Chronic inflammation,
Transudate, and Fibrinous inflammation)

Granuloma:
Disease Cause Tissue Reaction
Tuberculosis M. tuberculosis Caseating granuloma (tubercle)
Leprosy M. leprae Noncaseating granulomas Acid-fast
bacilli in macrophages
Test q: A chest radiograph of an
Syphilis Treponema pallidum Gumma: plasma cell infiltrate; central asymptomatic, 37y/o man showed
cells necrotic without loss of cellular a 3cm nodule in the middle lobe of
the right lung. The nodule was
outline excised w/a pulmonary wedge
resection, and sectioning showed
Cat-scratch disease Gram-negative bacillus Stellate granuloma with neutrophils; the nodule to be sharply
giant cells uncommon circumscribed with a soft, white
center. Culture of tissue from the
Sarcoidosis Unknown etiology Noncaseating granulomas with nodule grew Mycobacterium
abundant activated macrophages tuberculosis. Which of the
following pathologic processes
Crohn disease Intestinal bacteria, Noncaseating granulomas intestine has most likely occurred in this
self-antigens wall, transmural inflammatory infiltrate nodule? Necrotizing
granulomatous inflammation.
REPEATED TWICE (once w/o the
“necrotizing” in the answer)

Test q: A 20y/o African American male has

bilateral hilar adenopathy, and radiography
reveals densities in both lung fields. A
bronchoscopic biopsy reveals
granulomatous inflammation w/multiple giant
cells of the Langhans type and no evidence
of necrosis. Routine mycobacterial and
fungal cultures are negative. Which of the
following is the most likely diagnosis?
Sarcoidosis,

 FIGURE 2–13 Principal local and

systemic actions of tumor necrosis
factor (TNF) and interleukin-1 (IL-1).

Prolonged inflammation- cytokines can

have systemic effects.

Systemic illness: fever (mostly from IL-

1/TNF)
7. Cardinal Signs of Acute Inflammation:
– Heat- blood flow
– Redness- vasodilation
– Swelling- increased blood flow
– Pain- due to swelling
– Loss of function- directly related to core four (above)

Learning Objectives (w/answers):

1. Acute and chronic inflammation features
– AI=PMNs & exudate CI=mononucs & spindle cells
2. 3 components of the inflammatory system
– Vessels, leukocytes, soluble mediators
3. Steps of leukocyte emigration, chemotaxis and phagocytosis
– Margination, rolling, adhesion, transmigration, chemotaxis, phagocytosis, oxidative burst
4. Nine mediator classes
– NO, amines, COX, LOX, PAF, NP, Clot, comp, kinin
5. How inhibitors regulate and cytokines transition to chronic phase
– Antiprotease, antioxidant; Cyt mitogenic & activate macrophages, chemotactic to endothelial & fibrocytes
6. Four causes of chronic inflammation
– Persistent infection, insult, healing delay, autoimmune
7. Cardinal signs of acute inflammation
– ↑BF=rubor,calor (redness, heat), ↑ perm=tumor (swelling),↑ cells=dolor (pain), functio laesa (loss of function)
– Why are the above answers written in Latin…?

Repair: Regeneration, Replacement, or Fibrosis Tues. 08/24/10

Learning Objectives:
1. Regeneration versus replacement
2. 3 Surface receptor types
3. Cell cycle, 4 cyclins, 2 checkpoints
4. 2 unique basement membrane molecules
5. Collagen synthesis & structure
6. 5 Growth factors
7. Wound healing & maturation, zinc function

1. Regeneration versus replacement

• Depends on
– Matrix preservation
– Parenchymal cells able to regenerate
• Cells (stromal & epithelial) must
– Migrate chemotaxis
– Proliferate mitogenesis
– Differentiate angiogenesis,
collagen synthesis
• Intact matrix (BM+ECM) required for all 3

In the “interstitial fibrosis” (middle) picture, 

there are neutrophils in the alveoli – alveolar
lining cells have been able to multiply and
restore the normal architecture.

In the myocardial fibrosis pic (far right), 

instead of expanding, the fibrosis contracts
down. Myocardial scarring – never as big as
the original defect.
Replacement
• Matrix disrupted or permanent cells destroyed
• Granulation tissue early in process
– Angiogenesis (and edema)
– Fibroblasts
– Evolving inflammation
• Connective tissue scar end result
– Replaces granulation tissue by maturation

Granulation tissue – general term for tissue w/new vessels growing in it (no pericytes) – never stays the same. Matures
over time and changes its appearance. Looks different in every instance.

Wound Healing

 Can see overlap between inflammation and granulation tissue.

Usually, in MI, granulation tissue appears at day 3 (becomes histologically
recognizable).

 Figure: Cell Cycle.

There are two points at which the cell decides whether to proceed:
1. Before it makes the enzymes in G1 phase.
2. Just before the cell enters mitosis

2. 3 Surface receptor types

Cell Surface Receptors:

• Intrinsic kinase activity (IK)
– Transmembrane with binding and catalytic domains
– Either Tyrosine kinase or Serine/threonine kinase
– Mitogenic receptors
• Cytosol kinase-linked activity (CK)
– Transmembrane with extracellular and cytosolic enzyme binding
– Activates cytosoic tyrosine kinase
– Cytokine receptor superfamily
• G protein-linked (GPCR)
– Seven-spanning receptors (serpentine)
– Intracellular second messenger (cAMP or cGMP)
– Chemokines, epinephrine, glucagon, drug receptors
FIGURE 3–9 Overview of the main types of cell surface
receptors and their principal signal transduction pathways.
Shown are receptors with intrinsic tyrosine kinase activity,
seven transmembrane G protein–coupled receptors, and
receptors without intrinsic tyrosine kinase activity. cAMP,
cyclic adenosine monophosphate: IP3, inositol triphosphate;
JAK, Janus kinase; MAP kinase, mitogen-activated protein
kinase; PI3 kinase, phosphatidylinositol 3-kinase; PKB,
protein kinase B, also known as Akt; PLC-γ, phospholipase
C gamma; STATs, signal transducers and activators of
transcription.
Test q: Intrinsic kinase receptors may communicate w/the nucleus
by the PI3 kinase pathway, the MAP kinase pathway, or the IP3
pathway. A common ligand for this type of receptor is: Growth
factor.

Tissue Type Determines Regeneration Capacity

• Labile
– epithelia, bone marrow respond promptly
• Stable
– glands, mesenchyme G0 recruited to G1
• Permanent
– neurons, striate muscle don’t proliferate

3. Cell cycle, 4 cyclins, 2 checkpoints

Test q: The tumor suppressor
Regulation of Cell Division genes Rb and p53 are found in what
• Checkpoints  completion of molecular events cellular location? In the nucleus.
– G1 checkpoint
» Rb gene regulates
Test q: The nuclear proteins Rb and
– G2M checkpoint p53 are gene products for: Tumor
» p53 gene regulates suppressor genes. REPEATED
• Protein phosphorylation is Upregulated by cyclins TWICE.
– Cyclin D in early G1
– Cyclin E in late G1, early S
– Cyclin A in S, early G2
– Cyclin B in late G2, early M

Stem Cells
• Self renewal
• Asymmetric differentiation
– Stem cell
– Progenitor cell

Adult Stem Cells

• Bone Marrow
– Hematopoietic stem cells (HSC)
– Mesodermal progenitor cells
– Multipotent adult progenitor cells (MAPC)
• Developmental plasticity in culture
– MAPC similar to ES
• Tissue stem cell Niche locations
– Hair follicles, GI crypts, muscle satellite cell, canals of
Herring, corneal limbus

Figure: Adult Stem Cell Niches 

B. Small intestine stem cells located near the base of a crypt, above
Paneth cells (stem cells in the small intestine may also be located at
the bottom of the crypt). C. Liver stem (progenitor) cells, known as
oval cells, are located in the canals of Hering (thick arrow), structures
that connect bile ductules (thin arrow) with parenchymal hepatocytes
(bile duct and Hering canals are stained for cytokeratin 7). D. Corneal
stem cells are located in the limbus region, between the conjunctiva
and the cornea.
Embryonic Stem Cells
• Up to Blastocyst stage (32 cells)
• Developmental plasticity in culture
– Chimeras in all organs when reimplanted in another mouse blastocyst
– Human embryonic stem cells (HES) proliferative over 70 passages in vitro
– HES do not form teratomas in nude mice
• No therapeutic uses yet

Stem Cell Therapy:

FIGURE 3–6: Steps involved in stem cell therapy, using
embryonic stem (ES) cells or induced pluripotent stem (iPS)
cells. Left side, Therapeutic cloning using ES cells. The diploid
nucleus of an adult cell from a patient is introduced into an enucleated
oocyte. The oocyte is activated, and the zygote divides to
become a blastocyst that contains the donor DNA. The
blastocyst is dissociated to obtain ES cells. Right side, Stem cell
therapy using iPS cells. The cells of a patient are placed in
culture and transduced with genes encoding transcription factors, to
generate iPS cells. Both ES and iPS cells are capable of differentiating
into various cell types. The goal of stem cell therapy is to
repopulate damaged organs of a patient or to correct a genetic
defect, using the cells of the same patient to avoid
immunological rejection.

4. 2 unique basement membrane molecules

Extracellular Matrix (ECM)

• Scaffold and support for cell adherence, migration, proliferation
• Binds growth factors and factors for cell migration and differentiation
• Binds water and ions for turgor, mineralization and mechanical properties

• 3 major components
– Structural collagen, elastin (lung)
– Adhesive glycoproteins fibronectin, laminin
– Stabilizing gel proteoglycans, hyaluronan

Figure: ECM components 

FIGURE 3–12 Main components of

the extracellular matrix (ECM),
including collagens, proteoglycans,
and adhesive glycoproteins. Both
epithelial and mesenchymal cells
(e.g., fibroblasts) interact with ECM
via integrins. Basement membranes
and interstitial ECM have different
architecture and general
composition, although there is some
overlap in their constituents. For the
sake of simplification, many ECM
components (e.g., elastin, fibrillin,
hyaluronan, and syndecan) are not
included.

Collagen Type IV = BM
Basement Membrane (BM)
• Spreading of epithelial or endothelial cells
• Collagen type IV
• Laminin
– Links cells to BM matrix by collagen
IV & heparan
• Fibronectin
– Adheres to cells by RGD integrin-
binding motif
– Also attaches to heparan, collagen &
fibrin
• Heparan sulfate
– Ligand for both laminin and
fibronectin

Center portion of laminin attaches to base of

cell, other parts fold back into BM. Important
for attaching epithelial cells. There are also
release signals for when cells begin to divide.
See various binding domains for ECM
(heparan, fibrin, collagen, etc.)

5. Collagen synthesis & structure

Collagen Structure
• Tropocollagen is basic unit (monomer)
• 3 alpha chains in each unit
– Triple helix, left handed (DNA is right-
handed helix)
• 27 collagen types determined by
– 41 genes on 14 chromosomes
• Fibrillar collagens: I, II, III, V, IX
– Have 67 nm banding from linking
zones
– Present in tendon, scar, strong
connective tissue
– As a scar matures, type III  type I
• Nonfibrillary collagens: IV, others
– Amorphous (no banding pattern)
– Present in interstitium, submucosa,
BM

Lysine hydroxyl groups form very strong cross-links.

Test q: A 25y/o med student wrecks her bike in a construction zone, resulting in several abrasions to her arms and knees. In a few days, a scab forms
which contains: Type III collagen.
Test q: A 23y/o woman receiving corticosteroid therapy for an autoimmune disease has an abscess on her upper outer right arm. She undergoes minor
surgery to incise and drain the abscess, but the wound heals poorly over the next month. Which of the following aspects of wound healing is most likely
to be deficient in this patient? Collagen synthesis.

6. 5 Growth factors

Stages of Repair
• Angiogenesis
• Fibroblast invasion and proliferation
• Collagen and ECM synthesis
• Granulation tissue into scar
• Tissue Remodeling
Five key Growth Factors:
Symbol Source Functions
EGF Platelets, macrophages, saliva, urine, milk, Mitogenic: keratinocytes (aka squamous
plasma epithelial cells) and fibroblasts; ↑ keratinocyte
migration
TGF-β Platelets, T-cells, endoth., macrophages, sm Chemotactic inflam., FB, sm ms; ↑scar,
ms, FB angiogenic, ↓MMP, epith. prolif.
VEGF Many types of cells ↑ vascular permeability; mitogenic:
endothelial cells; angiogenic
PDGF Platelets, macrophages, endothelial cells, Chemotactic: phagocytes, fibroblasts, sm.ms;
keratinocytes, smooth muscle cells Activates: phagocytes, fibroblasts; Mitogenic:
fibroblasts, endothelial, sm.muscle cells;
↑MMPs, fibronectin, MPS, angiogenesis and
wound contraction
FGF Macrophages, mast cells, T lymphocytes, Chemotactic: fibroblasts; Mitogenic:
endothelial cells, fibroblasts fibroblasts, epith. cells; ↑keratinocyte
migration, angiogenesis, wound contraction,
and matrix deposition

Principal Mediators of Repair

Function
Monocyte chemotaxis
Fibroblast
migration/replication
Keratinocyte replication
Angiogenesis
Collagen synthesis
Collagenase secretion
TGF-β can be an off signal – inhibits secretion and remodeling of collagen in mature scars.
Growth Factors and Cytokines Test q: Basic Fibroblast
Growth Factor is known to
Chemokines, PDGF, FGF, TGF-β, TNF promote new vessel formation
in granulation tissue. Another
PDGF, EGF, FGF, TGF-β, TNF, IL-1 prominent growth factor
responsible for angiogenesis
is: VEGF.
HB-EGF, KGF, HGF, EGF
Test q: A 50y/o male is
VEGF, FGF, angiopoietins involved in a motor vehicle
accident w/liver and spleen
TGF-β, PDGF trauma. Surgery requires
splenectomy and partial
PDGF, FGF, TNF; TGF-β inhibits hepatectomy. Two years later
the liver has regenerated to
almost normal size. The
hepatocytes will end
regeneration with secretion of:
TGF-β.

 Figure: different signals for each stage/zone.

Angiogenic Factors:
• VEGF (vascular endothelial growth factor)
– Receptors have intrinsic tyrosine kinase activity
» VEGF-R2 for proliferation
» VEGF-R1 for tube formation
• bFGF also angiogenic
– Stimulates other non-endothelial mesenchymal cells, too
(ex: pericytes)
• Angiopoietins – turn off vascular proliferation
– Ang1 binds endothelial Tie2 receptor to recruit pericytes
• Endostatin (breakdown product)
– Collagen fragment that inhibits angiogenesis
Test q: Many researchers have produced anti-angiogenic cancer drugs. A
compound normally found in the body that inhibits angiogenesis is: Endostatin.
Fibroplasia Factors
• Fibrinogen, plasma fibronectin
– Chemotactic mediators from leaky new
vessels
• PDGF, EGF, FGF
– From platelets, epithelia & histiocytes
– Fibroblast migration & proliferation
• IL-1, TNF-α
– “Fibrogenic cytokines”
– Induce PDGF, bFGF, TGFβ from
macrophages
– Induce collagen and collagenase in
fibroblasts
• TGF-β most pleotrophic fibrogenic mediator
– All of the above plus inhibit collagenase
secretion (off signal)

Fibroblasts have some phagocytic capability – can

clean up debris as they migrate.

7. Wound healing & maturation, zinc function

Surgical Wound Healing

• A model for dealing with other wound types
• Primary intention
– Clean, closely approximated margins
– Minimal clot/granulation tissue, motion, bacteria
• Secondary intention
– Large tissue defect or reopened surgical wound
– Greater inflammation and granulation tissue
– Healing time depends on size of defect
– Wound contraction up to 95% at 6 weeks (Gpig, rabbit)
» Myofibroblasts
» Elastin remodeling

Fresh Wound (gray = clot w/inflammatory cells in it) 

• Clean incision
• Limit motion
• No infection
• Minimal foreign material
• Adequate nutrition and circulation

Granulation Tissue Replacement of Injury

• Collagen accumulation is dynamic
– Depends on both synthesis and degradation
• Metalloproteinases
– require zinc ions (so An important for a person with healing wounds)
• Serine proteases form leaky vessels
– Cause continual turnover of ECM in granulation tissue

Granulation Tissue 
• Thin wall vessels
• Edematous/disorganized stroma
• Fibroblasts
• Decreasing inflammation
• Type III collagen (wiggly lines)
• Reepithelialization
Test q: As granulation tissue matures, collage type III is
replaced by collagen type I, the wound contracts and blood
vessels appear to dissipate from the reparative tissue. This
process of wound tissue remodeling requires a special class
of protease that requires: Zinc.
Test q: A 58y/o physician experiences poor healing of a foot
laceration. He decides to take a supplement of __ to
enhance metalloproteinase activity. Zinc.