INFLAMMATION AND REPAIR

Ma. Christina C. Jovida-Castro, MD, FPSP

Anatomic and Clinical Pathologist
 In lammation - response of vascularized tissues that delivers leukocytes and
molecules of host defense from the circulation to the sites of infection and cell
damage in order to eliminate the offending agents.
- actually a protective response that is essential for survival.
- serves to rid the host of both the initial cause of cell injury (e.g., microbes,
toxins) and the consequences of such injury (e.g., necrotic cells and
tissues).
- The suf ix -itis after an organ denotes in lammation in that site, such as
appendicitis, conjunctivitis, or meningitis
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 The typical in lammatory reaction develops through a series of sequential
steps.
1) Recognition of the noxious agent that is the initiating stimulus for
in lammation.
2) Recruitment of leukocytes and plasma proteins into the tissues.
3) Removal of the stimulus for in lammation is accomplished mainly by
phagocytic cells, which ingest and destroy microbes and dead cells.
4) Regulation of the response is important for terminating the reaction when
it has accomplished its purpose.
5) Repair consists of a series of events that heal damaged tissue.
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 INFLAMMATION

Recognition of the noxious agent

Recruitment of leukocytes

Removal of the stimulus for in lammation/Phagocytosis

Termination of the reaction

Repair
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Fundamental properties of the in lammatory response:
•The major participants in the in lammatory reaction in tissues are
blood vessels and leukocytes
•Protective in lammatory reactions to infections are often
accompanied by local tissue damage and its associated signs and
symptoms (e.g., pain and functional impairment).
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 Fundamental properties of the in lammatory response:

- There are many diseases in which the in lammatory reaction is

misdirected (e.g., against self tissues in autoimmune diseases),
occurs against normally harmless environmental substances
(e.g., in allergies), or is inadequately controlled.
- Antiin lammatory drugs ideally control the harmful sequelae of
in lammation yet not interfere with its bene icial effects.
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 •The in lammation is largely con ined to the site of infection or
damage.
- In rare situations, the in lammatory reaction is systemic and
causes widespread pathologic abnormalities.
- This reaction has been called sepsis, which is one form of the
systemic in lammatory response syndrome.

•Microbes, necrotic cells (whatever the cause of cell death), and

even hypoxia can trigger the elaboration of in lammatory mediators
and thus elicit in lammation.
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•Acute in lammation is a rapid, often self-limited, response to offending agents
that are readily eliminated, such as many bacteria and fungi, and dead cells.
- typically develops within minutes or hours and is of short duration (several
hours to a few days).
- characterized by the exudation of luid and plasma proteins (edema) and the
emigration of leukocytes, predominantly neutrophils.
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•Chronic in lammation - may follow acute in lammation or arise de novo.
- It is a response to agents that are dif icult to eradicate, such as some
bacteria (e.g., tubercle bacilli) and other pathogens (such as viruses and
fungi).
- of longer duration and is associated with more tissue destruction and
scarring ( ibrosis).
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The cardinal signs/hallmarks of in lammation are:
• rubor (redness)
• tumor (swelling)
• calor (heat)
• dolor (pain)
• loss of function (functio laesa)
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 Causes of In lammation

•Infections (bacterial, viral, fungal, parasitic) and microbial

toxins - most common and medically important
•Tissue necrosis
•Foreign bodies (splinters, dirt, sutures)
•Immune reactions - directed against self-antigens, causing
autoimmune diseases, or may be inappropriate reactions
against environmental substances, as in allergies, or
against microbes
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 Cells express receptors
1. in the plasma membrane (for extracellular microbes)
2. endosomes (for ingested microbes)
3. the cytosol (for intracellular microbes).

The best de ined of these receptors belong to the family of Toll-

like receptors (TLRs)
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 Major components of Acute In lammation:
1. Dilation of small vessels leading to an increase in blood
low
2. Increased permeability of the microvasculature
enabling plasma proteins and leukocytes to leave the
circulation
3. Emigration of the leukocytes from the microcirculation,
their accumulation in the focus of injury, and their
activation to eliminate the offending agent
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REACTIONS OF BLOOD VESSELS IN ACUTE INFLAMMATION
- Initially there is vasodilation.
- Vasodilation is induced by the action of several mediators,
notably histamine, on vascular smooth muscle.
- Result is increased blood low, which is the cause of heat and
redness (erythema) at the site of in lammation.
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REACTIONS OF BLOOD VESSELS IN ACUTE INFLAMMATION

Vasodilation is quickly followed by increased permeability of the

microvasculature, with the outpouring of protein-rich luid into the
extravascular tissues.

The escape of luid, proteins, and blood cells from the vascular
system is known as exudation.
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An exudate - an extravascular luid that has a high protein
concentration and contains cellular debris.
- Its presence implies the existence of an in lammatory process.

Transudate - a luid with low protein content (most of which is

albumin), little or no cellular material, and low speci ic gravity.
- produced as a result of osmotic or hydrostatic imbalance across
the vessel wall.
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Mechanisms of Increased Vascular Permeability (Vascular Leakage)

•Contraction of endothelial cells resulting in increased interendothelial

gaps - most common mechanism of vascular leakage.
- elicited by histamine, bradykinin, and leukotrienes
-It is called the immediate transient response because it occurs
rapidly after exposure to the mediator and is usually short-lived
(15 to 30 minutes).

•Endothelial injury - results in endothelial cell necrosis and

detachment (burns, microbial toxins)
- In most instances leakage starts immediately after injury and is
sustained for several hours.
 In addition to blood vessels, lymphatic vessels also participate
in acute in lammation.

The presence of red streaks near a skin wound is a telltale sign

of bacterial infection.

The streaks represent in lamed lymphatic channels and are

diagnostic of lymphangitis.
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LEUKOCYTE RECRUITMENT TO SITES OF INFLAMMATION
-The changes in blood low and vascular permeability are
quickly followed by an in lux of leukocytes into the tissue.
-These leukocytes perform the key function of eliminating
the offending agents.
-The most important leukocytes are the ones capable of
phagocytosis, namely neutrophils and macrophages.
Macrophages also produce growth factors that aid in repair.
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Phases of the journey of leukocytes from the vessel lumen to the tissue:
1. In the lumen: margination, rolling, and adhesion to endothelium.
-In Margination, more white cells assume a peripheral position along the
endothelial surface.
- Leukocytes adhere transiently to the endothelium, detach and bind again,
thus rolling on the vessel wall.
- The initial rolling interactions are mediated by a family of proteins called
SELECTINS.
o expressed on leukocytes ( selectin)
o on endothelium ( selectin)
o in platelets and on endothelium ( selectin)
- The ligands for selectins are sialylated oligosaccharides bound to mucin-
like glycoproteins
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 - After rolling, the cells inally come to rest at some point
where they adhere irmly to the endothelium.
- Firm adhesion is mediated by a family of
heterodimeric leukocyte surface proteins called
INTEGRINS.
- TNF and I 1 induce endothelial expression of ligands
for integrins, mainly VCA 1, (the ligand for the
integrin VL 4) and ICA 1 (the ligand for the integrins
LF 1 and Ma 1).
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 2. Migration across the endothelium and vessel wall
- transmigration or diapedesis
- immunoglobulin superfamily called CD31 or PECAM-1

3. Chemotaxis of leukocytes
- After exiting the circulation, leukocytes move in the tissues toward the
site of injury.
- de ined as locomotion along a chemical gradient.
- most common exogenous agents are bacterial products
- Endogenous chemoattractants include several chemical mediators:
o cytokines (e.g., I 8)
o components of the complement system, particularly C5a
o arachidonic acid (AA) metabolites, mainly leukotriene B4 (LTB4)
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 The nature of the leukocyte in iltrate varies with the age of the
in lammatory response and the type of stimulus.

In most forms of acute in lammation, neutrophils predominate in the

in lammatory in iltrate during the irst 6 to 24 hours and are replaced
by monocytes in 24 to 48 hours.

Monocytes not only survive longer but may also proliferate in the
tissues, and thus they become the dominant population in prolonged
in lammatory reactions.
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Some exceptions do occur.
•Pseudomonas bacteria—the cellular in iltrate is dominated by
continuously recruited neutrophils for several days
•in viral infections - lymphocytes may be the irst cells to arrive
• in helminthic infections and allergic reactions - eosinophils

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Phagocytosis and Clearance of the Offending Agent

Once leukocytes (particularly neutrophils and monocytes) are

recruited to a site of infection or cell death, they must be activated
to perform their functions.
Phagocytosis involves sequential steps:
1) Recognition and attachment of the particle to be
ingested by the leukocyte;
2) Engulfment, with subsequent formation of a
phagocytic vacuole
3) Killing of the microbe and degradation of the ingested
material.
 PHAGOCYTOSIS

The ef iciency of phagocytosis is greatly enhanced when microbes are

coated with opsonins for which the phagocytes express high-af inity
receptors.
The major opsonins:
1.immunoglobulin G (IgG) antibodies
2.C3b breakdown product of complement
3.certain plasma lectins, notably mannose-binding lectin and
collectins.
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PHAGOCYTOSIS

After a particle is bound to phagocyte receptors, extensions of the

cytoplasm low around it, and the plasma membrane pinches off to form
a vesicle (phagosome) that encloses the particle.
The phagosome then fuses with a lysosomal granule, which discharges its
contents into the phagolysosome.
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Killing of microbes is accomplished by reactive oxygen species (ROS) and reactive
nitrogen species (mainly derived from nitric oxide, NO), as well as lysosomal
enzymes. This is the inal step in the elimination of infectious agents and necrotic
cells.

Reactive oxygen species (ROS) are produced by the activation of NADPH oxidase (also
called phagocyte oxidase).

In neutrophils, this oxidative reaction accompanies phagocytosis and is called the

respiratory burst.
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Respiratory burst

In the process, it reduces oxygen to superoxide anion (O2-) which is then converted
into hydrogen peroxide (H2O2).

H2O2 is not able to ef iciently kill microbes by itself. However, the azurophilic
granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the
presence of a halide such as Cl- converts H2O2 to hypochlorite, the active ingredient
in household bleach.

Hypochlorite is a potent antimicrobial agent that destroys microbes by

halogenation. The H2O2-MPO-halide system is the most potent bactericidal system
of neutrophils.
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 Oxygen derived radicals may be released extracellularly from
leukocytes and may lead to tissue damage accompanying
in lammation.

- Antioxidants that protect against potentially harmful

oxyge derived radicals include:
o the enzyme superoxide dismutase
o the enzyme catalase - detoxi ies H2O2
o glutathione peroxidase - another powerful H2O2 detoxi ier
o the coppe -containing serum protein ceruloplasmin
o the iro -free fraction of serum transferrin

Inherited de iciencies of components of phagocyte oxidase cause an

immunode iciency disease called chronic granulomatous disease
(CGD).
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•Nitric Oxide, NO - a soluble gas produced from arginine by
the action of nitric oxide synthase (NOS).
-Inducible (iNOS) is the type that is involved in microbial
killing.
-In macrophages, NO reacts with superoxide to generate
the highly reactive free radical peroxynitrite.
Lysosomal Enzymes and Other Lysosomal Proteins.

Two main types of granules of neutrophils:

•The smaller speci ic (or secondary) granules - contain
lysozyme, collagenase, gelatinase, lactoferrin, plasminogen
activator, histaminase, and alkaline phosphatase.
•The larger azurophil (or primary) granules - contain
myeloperoxidase, bactericidal factors (lysozyme,
defensins), acid hydrolases, and a variety of neutral
proteases (elastase, cathepsin G, nonspeci ic collagenases,
proteinase 3)
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These harmful proteases are normally controlled by a
system of antiproteases in the serum and tissue luids:
1. α1antitrypsin - the major inhibitor of neutrophil
elastase
2. α2Macroglobulin

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MEDIATORS OF INFLAMMATION

Cell-derived mediators are normally sequestered in

intracellular granules and can be rapidly secreted by granule
exocytosis (e.g., histamine in mast cell granules) or are
synthesized de novo (e.g., prostaglandins and leukotrienes,
cytokines).

Plasma-derived mediators (e.g., complement proteins) are

produced mainly in the liver and are present in the circulation
as inactive precursors that must be activated.
 MEDIATORS OF INFLAMMATION
1. Vasoactive Amines
a. Histamine - causes dilation of arterioles and increases
the permeability of venules
-the principal mediator of the immediate transient
phase of increased vascular permeability.
b. Serotonin ( hydroxytryptamine) - vasoconstrictor
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MEDIATORS OF INFLAMMATION

2. Arachidonic Acid Metabolites - The lipid mediators

prostaglandins and leukotrienes are produced from arachidonic
acid (AA) present in membrane phospholipids.
- The prostaglandins are generated by the actions of two
cyclooxygenases called COX-1 and COX-2.
- COX-1 is constitutively expressed in most tissues, where it may
serve various homeostatic functions (e.g., luid and electrolyte
balance in the kidneys, cytoprotection in the gastrointestinal
tract), and is also induced by in lammatory stimuli.
- COX-2 expression is mainly con ined to cells that are
participating in in lammatory reactions.
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 Arachidonic Acid Metabolites

•The most important prostaglandins in in lammation are PGE2,

PGD2, PGF2a, PGI2 (prostacyclin), and TxA2 (thromboxane
A2).
o TxA 2 - a potent platele aggregating agent and
vasoconstrictor.
o Prostacyclin - a vasodilator and a potent inhibitor of
platelet aggregation.
o In addition to their local effects, the prostaglandins are
involved in the pathogenesis of pain and fever in
in lammation. PGE2 is hyperalgesic and makes the skin
hypersensitive to painful stimuli.
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Arachidonic Acid Metabolites

•Leukotrienes are produced by leukocytes and mast cells by

the action of lipoxygenase.
o LTB4 - a potent chemotactic agent and activator of
neutrophils.
o LTC4, LTD4, and LTE4 - cause intense vasoconstriction,
and bronchospasm (important in asthma)
o Leukotrienes are more potent than is histamine in
increasing vascular permeability and causing
bronchospasm.
 Arachidonic Acid Metabolites

•Lipoxins are also generated from AA by the lipoxygenase

pathway.
- suppress in lammation by inhibiting neutrophil
chemotaxis
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 Pharmacologic Inhibitors of Prostaglandins and Leukotrienes

Antiin lammatory drugs:

¬ Cyclooxygenase inhibitors - include aspirin and other

nonsteroidal anti-in lammatory drugs (NSAIDs) such as ibuprofen
•inhibit both COX-1 and COX-2 and thus inhibit prostaglandin
synthesis, (hence their ef icacy in treating pain and fever)
- However, COX-1 is involved in both in lammation and
physiologic protective functions, whereas COX-2 generates
prostaglandins that are involved only in in lammatory reactions.
- Selective COX-2 inhibitors should be antiin lammatory without
having the toxicities of the nonselective inhibitors, such as
gastric ulceration.
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¬ Lipoxygenase inhibitors - in the treatment of asthma
¬ Corticosteroids - broa spectrum antiin lammatory agents
that reduce the transcription of genes encoding CO 2,
phospholipase A2, proin lammatory cytokines (e.g., I 1 and
TNF), and iNOS
¬ Leukotriene receptor antagonists - useful in the treatment
of asthma.
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 MEDIATORS OF INFLAMMATION
3. Cytokines and Chemokines

•The cytokines TNF and IL-1 serve critical roles in leukocyte

recruitment by promoting adhesion of leukocytes to endothelium
and their migration through vessels.
- TNF antagonists have been remarkably effective in the
treatment of chronic in lammatory diseases, particularly
rheumatoid arthritis, psoriasis, and some types of
in lammatory bowel disease.

•Chemokines act primarily as chemoattractants for speci ic types

of leukocytes.
- Examples are IL-8 for chemotaxis of neutrophils (now called
CXCL8), eotaxin (CCL11) and lymphotactin (XCL1).
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Complement System - consists of more than 20 proteins, some of
which are numbered C1 through C9.

¬ Complement proteins are present in inactive forms in the

plasma.
¬ The critical step in complement activation is the
proteolysis of the third (and most abundant) component,
C3.
 ¬ Cleavage of C3 can occur by one of three pathways:

1. The classical pathway - triggered by ixation of C1 to

antibody-antibody complex (IgM or IgG)
2. The alternative pathway - triggered by microbial surface
molecules (e.g., endotoxin, or LPS) in the absence of antibody
3. The lectin pathway - plasma mannos binding lectin binds
to carbohydrates on microbes and directly activates C1
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All three pathways of complement activation lead to the
formation of an active enzyme called the C3 convertase, which
splits C3 into two functionally distinct fragments, C3a and C3b.

¬ Ultimately, the membrane attack complex MAC is formed

composed of multiple C9 molecules.
 The complement system has three main functions:

1. In lammation - C3a, C5a, stimulate histamine release from

mast cells and thereby increase vascular permeability and
cause vasodilation (anaphylatoxins).
¬ C5a is also a chemotactic agent for neutrophils,
monocytes, eosinophils, and basophils.

2. Opsonization and phagocytosis - C3b and its cleavage

product iC3b (inactive C3b), act as opsonins and promote
phagocytosis by neutrophils and macrophages.
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Complement system functions:

3. Cell lysis - The deposition of the MAC on cells makes these

cells permeable to water and ions and results in death (lysis)
of the cells.
¬ This role of complement is important mainly for the
killing of microbes with thin cell walls, such as Neisseria
bacteria.
 Regulatory proteins that tightly control the activation of complement:

1. C1 inhibitor (C1 INH) - blocks the activation of C1, the irst protein of
the classical complement pathway.
- Inherited de iciency of this inhibitor is the cause of hereditary
angioedema.

2. Decay accelerating factor (DAF) and CD59 – DAF prevents formation

of C3 convertases and CD59 inhibits formation of the MAC.
¬ De iciency leads to a disease called Paroxysmal Nocturnal
Hemoglobinuria (PNH).

3. Complement Factor H - inhibits the alternative pathway of

complement activation by promoting the cleavage and destruction
of C3b.
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SPECIAL MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION:

1. Serous in lammation - marked by the exudation of cell-poor luid into

spaces created by cell injury or into body cavities lined by the
peritoneum, pleura, or pericardium.
Effusion - accumulation of luid in these cavities
The skin blister represents accumulation of serous luid within or
immediately beneath the damaged epidermis of the skin
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 SPECIAL MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION:

2. Fibrinous In lammation - With greater increase in vascular

permeability, large molecules such as ibrinogen pass out of the blood,
and ibrin is formed and deposited in the extracellular space.
¬ characteristic of in lammation in the lining of body cavities, such as
the meninges, pericardium, and pleura
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 SPECIAL MORPHOLOGIC PATTERNS OF ACUTE
INFLAMMATION:

3. (Suppurative) In lammation - characterized by the

production of pus, an exudate consisting of neutrophils, the
lique ied debris of necrotic cells, and edema luid
-The most frequent cause is infection with bacteria that cause
liquefactive tissue necrosis, such as staphylococci.
- The pathogens are referred to as pyogenic (pus-producing)
bacteria.
- Abscesses are localized collections of purulent
in lammatory tissue caused by suppuration buried in a
tissue, an organ, or a con ined space.
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 SPECIAL MORPHOLOGIC PATTERNS OF ACUTE
INFLAMMATION:

4. An ulcer - a local defect, or excavation, of the surface of an

organ or tissue that is produced by the sloughing (shedding)
of in lamed necrotic tissue.
¬ eg. peptic ulcer of the stomach or duodenum
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 Outcomes of Acute In lammation
1. Complete resolution – the usual outcome when the injury is limited
or shor -lived or when there has been little tissue destruction
-the damaged parenchymal cells can regenerate

2. Healing by connective tissue replacement (scarring, or ibrosis) -

occurs after substantial tissue destruction, or when in lammation
involves tissues that are incapable of regeneration

3. Chronic in lammation - occurs when the acute in lammatory

response cannot be resolved
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CHRONIC INFLAMMATION - a response of prolonged duration
(weeks or months) in which in lammation, tissue injury and
attempts at repair coexist.
It arises in the following settings:
1) Persistent infections by microorganisms that are dif icult to
eradicate, such as mycobacteria and certain viruses, fungi,
and parasites;
2) Hypersensitivity diseases
3) Prolonged exposure to potentially toxic agents, like silica.

Morphologic features include in iltration with mononuclear

cells (macrophages, lymphocytes, and plasma cells), tissue
destruction, and attempts at healing accomplished by
angiogenesis and, in particular, ibrosis.
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 Cells and Mediators of Chronic In lammation:
1. Macrophages – They are the dominant cells in most chronic
in lammatory reactions
-secrete cytokines and growth factors that destroy foreign invaders,
and activate other cells.
- Circulating cells of this lineage are known as monocytes.
- normally diffusely scattered in most connective tissues
- found in speci ic locations in organs:
✓ liver (Kupffer cells)
✓ spleen and lymph nodes (sinus histiocytes)
✓ central nervous system (microglial cells)
✓ lungs (alveolar macrophages)
-Together, these cells comprise the mononuclear phagocyte system,
also known by the older (and inaccurate) name reticuloendothelial
system.
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Cells and Mediators of Chronic In lammation:

Macrophages

a. Macrophages, like the neutrophils, ingest and eliminate microbes and

dead tissues.
b. Macrophages initiate the process of tissue repair and are involved in
scar formation and ibrosis.
c. Macrophages also display antigens to T lymphocytes (APC).
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Cells and Mediators of Chronic In lammation:

2. T and B lymphocytes
•CD4+ T lymphocytes - secrete cytokines
✓IFN-G from TH1 - activate macrophages by the classical pathway
✓IL-4, IL-5 and IL-13 from TH2 - recruit and activate eosinophils
and neutrophils.
✓IL-17 from TH17 - recruit neutrophils
•Activated B lymphocytes and antibody-producing plasma cells - often
present at sites of chronic in lammation
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Cells and Mediators of Chronic Inflammation:

3. Eosinophils - abundant in immune reactions mediated by IgE and in

parasitic infections.
- have granules that contain major basic protein that is toxic to
parasites
4. Mast cells - widely distributed in connective tissues and participate in
both acute and chronic in lammatory reactions.
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Granulomatous in lammation - a form of chronic in lammation
characterized by collections of activated macrophages often with
T lymphocytes, and sometimes associated with central necrosis.
¬ The activated macrophages may develop abundant
cytoplasm and begin to resemble epithelial cells, and are
called epithelioid cells.
¬ Epithelioid cells may fuse, forming multinucleate giant
cells called Langhans giant cells.
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Granulomatous in lammation

Foreign body granulomas form around materials such as talc and sutures.
They are not immunogenic.

Immune granulomas are associated with a persistent T cell–mediated

immune response such as when the inciting agent is dif icult to eradicate,
such as a persistent microbe.

In granulomas associated with Mycobacterium tuberculosis, there is a central

zone of necrosis is called caseous necrosis. The granuloma is referred to as a
tubercle.

The granulomas in Crohn disease, sarcoidosis, and foreign body reactions

tend to not have necrotic centers and are said to be noncaseating.
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SYSTEMIC EFFECTS OF INFLAMMATION (Acute-phase response)

1. Fever - characterized by an elevation of body temperature,

usually by 1° to 4°C.
•Exogenous pyrogens (Bacterial products, such as LPS) -
stimulate leukocytes to release cytokines such as IL-1 and
TNF.
•Endogenous pyrogens (IL-1 and TNF) - increase the enzymes
(cyclooxygenases) that convert AA into prostaglandins.
•In the hypothalamus, the prostaglandins, especially PGE2,
stimulate the production of neurotransmitters that reset the
temperature set point at a higher level.
SYSTEMIC EFFECTS OF INFLAMMATION (Acute-phase response)

2. Acute-phase proteins - plasma proteins, mostly synthesized

in the liver, whose plasma concentrations may increase as part
of the response to in lammatory stimuli.
- eg. C-reactive protein (CRP), ibrinogen, and serum
amyloid A (SAA) protein.
- CRP have been proposed as a marker for increased risk of
myocardial infarction in patients with coronary artery
disease.
Fibrinogen binds to red cells and causes them to form
stacks (rouleaux) that sediment more rapidly at unit
gravity than do individual red cells. This is the basis for
measuring the erythrocyte sedimentation rate.
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SYSTEMIC EFFECTS OF INFLAMMATION (Acute-phase response)

3. Leukocytosis - a common feature of in lammatory reactions,

especially those induced by bacterial infections.
- The leukocyte count usually climbs to 15,000 or 20,000 cells/
mL.
- Extraordinarily high levels of 40,000 to 100,000 cells/mL are
sometimes called leukemoid reactions.
- However, certain infections (typhoid fever) are associated
with a decreased number of circulating white cells
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SYSTEMIC EFFECTS OF INFLAMMATION (Acute-phase response)

4. In severe bacterial infections (sepsis) there is production of

enormous quantities of TNF and I 1 leading to septic shock
(clinical triad of DIC, hypotensive shock, and hyperglycemia).
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TISSUE REPAIR. Repair, sometimes called healing, refers to the restoration
of tissue architecture and function after an injury.

2 processes:
1. Regeneration - Some tissues are able to replace the damaged
components and essentially return to a normal state.
2. Connective tissue deposition (scar formation) - happens if the injured
tissues are incapable of complete restitution, or if the supporting
structures of the tissue are severely damaged.
The ability of tissues to repair themselves is determined, in part, by their
intrinsic proliferative capacit and the presence of tissue stem cells.

Based on this criterion, the tissues of the body are divided into three
groups:
1. Labile (continuously dividing) tissues - are continuously being lost
and replaced.
- hematopoietic cells in the bone marrow and the majority of surface
epithelia
 2. Stable tissues - Cells of these tissues are quiescent (in the G0 stage of
the cell cycle) and have only minimal proliferative activity in their
normal state
- capable of dividing in response to injury or loss of tissue mass
- eg. parenchyma of the liver, kidney, and pancreas and endothelial cells,
ibroblasts, and smooth muscle cells

3. Permanent tissues - terminally differentiated and nonproliferative in

postnatal life.
- eg. neurons and cardiac muscle cells
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REPAIR BY CONNECTIVE TISSUE DEPOSITION
•Angiogenesis is the process of new blood vessel development
from existing vessels.
- VEGFs, mainly VEGF-A, stimulate both migration and
proliferation of endothelial cells.
REPAIR BY CONNECTIVE TISSUE DEPOSITION
•Laying down of connective tissue
- TGF-β produced by activated macrophages is the most important
cytokine involved. It stimulates ibroblast migration and proliferation
and increases synthesis of collagen and ibronectin.
- Migration and proliferation of ibroblasts and deposition of loose
connective tissue, together with the vessels and interspersed
mononuclear leukocytes, form granulation tissue.
- Granulation tissue is progressively replaced by deposition of collagen.
•Remodeling of Connective Tissue - accomplished by a family of matrix
metalloproteinases (MMPs), so called because they are dependent on
metal ions (e.g., zinc) for their activity.
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 Factors that delay healing include:
•infection
•dabetes
•protein de iciency and vitamin C de iciency
•glucocorticoids
•mechanical factors such as increased local pressure
•poor perfusion
•foreign bodies.
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 Healing by First Intention - When the injury involves only the
epithelial layer, the principal mechanism of repair is epithelial
regeneration.
- also called primary union or healing by irst intention
- eg. healing of a clean, uninfected surgical incision
approximated by surgical sutures
- Carefully sutured wounds have approximately 70% of the
strength of normal skin, largely because of the placement of
sutures.
- Wound strength reaches approximately 70% to 80% of
normal by 3 months.

Healing by Second Intention occurs in wounds causing large tissue

de icits.
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 Fibrosis - excessive deposition of collagen and other ECM
components in a tissue.
- include liver cirrhosis, systemic sclerosis (scleroderma),
ibrosing diseases of the lung, and constrictive pericarditis.
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Abnormalities in Tissue Repair:

1.Defects in Healing: Chronic Wounds include Venous leg ulcers,

Diabetic ulcers and Pressure sores.
-When a surgical incision reopens internally or externally it is
called wound dehiscence.
Abnormalities in Tissue Repair:

2. Excessive formation of the components of the repair process can give

rise to hypertrophic scars and keloids.
✓hypertrophic scars - accumulation of excessive amounts of collagen
that give rise to a raised scar
✓keloid - if the scar tissue grows beyond the boundaries of the
original wound and does not regress
Abnormalities in Tissue Repair:

3. Exuberant granulation (proud lesh) - formation of

excessive amounts of granulation tissue, which protrudes
above the level of the surrounding skin and blocks
reepithelialization

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Abnormalities in Tissue Repair:

4. Contraction in the size of a wound

- An exaggeration of the healing process gives rise to
contracture and results in deformities of the wound and the
surrounding tissues.
- commonly occur in the palms, the soles, and the anterior
thorax
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