Inflammation

and
Wound Healing
The response of living tissue to injury
 What is Inflammation?
• Response to injury (including infection)
• Complex protective reaction
• Caused by various endo- and exogenous
stimuli
• Reaction of blood vessels leads to:
– Accumulation of fluid and leukocytes in
extravascular tissues
• Destroys, dilutes, or walls off the injurious
agent
• Initiates the repair process
• Fundamentally a protective response
 What is inflammation?
• May be potentially harmful
– Hypersensitivity reactions to insect bites, drugs, contrast
media in radiology
– Chronic diseases: arthritis, atherosclerosis
– Disfiguring scars, visceral adhesions
• Consists of two general components
– Vascular reaction
– Cellular reaction
• Controlled by a variety of chemical mediators
– Derived from plasma proteins
– Derived from cells inside and outside of
blood vessels
 Terminology
• Greek root + -itis
• metritis, not uteritis
• kolpitis, not vaginitis
• nephritis, not renitis
 Historical Highlights
• Classical 5 symptoms (celsus 1st c. B.C.,
Virchow 19th c. A.D.):
– Rubor (erythema [redness]): vasodilatation,
increased blood flow
– Tumor (swelling): extravascular accumulation
of fluid
– Calor (heat): vasodilatation, increased blood
flow
– Dolor (pain)
– Functio laesa - loss (or impairment) of function
 The fluid definitions

• A TRANSUDATE has a low protein content,

usually caused by alterations in hydrostatic
or oncotic pressure.
Implies a hydrostatic (pressure) problem.

• An EXUDATE has a high protein content,

caused by increased vascular permeability.
Implies an inflammatory process.
 Mechanisms
• Local - in cases of mild injury
• Systemic
• 3 major:
– 1. Alteration
– 2. Exsudation - inflammatory exsudate
• Liquid (exsudate)
• Cellular (infiltrate)
– 3. Proliferation (formation of granulation and fibrous
tissue)
• Usualy - all 3 components - not the same
intensity
 Chemical Mediators of
Inflammation
• General principles of chemical mediators
– May be derived from plasma or cells
– Most bind to specific receptors on target cells
– Can stimulate release of mediators by target cells,
which may amplify or ameliorate the inflammatory
response
– May act on one or a few target cells, have
widespread targets, and may have differing effects
depending on cell and tissue types
– Usually short-lived
– Most have the potential to cause harmful effects
 What are the mechanisms?
CHEMICAL MEDIATORS.
Three phases:

1) Immediate early response (1/2 hr):

• HISTAMINE
– Released from mast cells, basophils and platelets, in
response to many stimuli: physical damage,
immunologic reactions, C3a, C5a, IL1, factors from
neutrophils and platelets

– Effects: Largely vascular. Pain. Not chemotactic.

2)Immediate sustained response:

(Not always seen. Due to direct

damage to endothelial cells.)
3)Delayed response: (Peaks about 3hrs):

• Many and varied chemical mediators,

interlinked and of varying importance
• Incompletely understood.

• IMPORTANT because of possibility of

therapeutic intervention
Mechanism of effect of chemical mediators -
see ‘Membranes and receptors’ module
Other inflammatory mediators:
• PRODUCTS FROM PLATELETS
– 5-hydroxy tryptamine, histamine, ADP...
– Platelet-derived growth factor, coagulation proteins...
• PRODUCTS FROM NEUTROPHILS
– Lysosomal constituents
– Products released on neutrophil death
• PRODUCTS FROM ENDOTHELIUM
– PGI2 (prostacyclin)
– Nitric oxide (EDRF: = NO)
– Endothelin
• Plasminogen activators / inhibitors
• OXYGEN DERIVED FREE RADICALS
– Endothelial damage, inactivation of antiproteases, injury to
other cells.
• One could continue.....
 Chemical Mediators of
Inflammation
• Vasoactive mediators
– Histamine
– Bradykinin
– Complement (C3a, C5a)
– Prostaglandins/leukotrienes
– Platelet activating factor
– Nitric oxide
• Chemotactic factors
– Complement (C5a)
– Leukotriene (B4)
– Platelet activating factor
– Cytokines (IL-1, TNF)
– Chemokines
– Nitric oxide
 Histamine
• Mast cells (also basophils and
platelets)
• Release mechanisms
– Binding of antigen (allergen) to
IgE on mast cells releases
histamine-containing granules
– Release by nonimmune
mechanisms such as cold, trauma,
or other chemical mediators
– Release by other mediators
• Dilates arterioles and increases
permeability of venules (wheal and
flare reaction)
 Complement
• Proteins found in greatest concentration in
the plasma
• Require activation
• Increase vascular permeability and cause
vasodilation
– Mainly by releasing histamine from mast cells
• Increase leukocyte adhesion, chemotaxis,
and activation
• C3b attaches to bacterial wall and enhances
phagocytosis by neutrophils & macrophages
 Bradykinin

• Small peptide released from plasma

precursors
• Increases vascular permeability
• Dilates blood vessels
• Causes pain
• Rapid inactivation
Arachidonic Acid Metabolites
• Prostaglandins
– Vasodilators: prostacyclin (PGI2), PGE1, PGE2, PGD2
– Vasoconstrictors: thromboxane A2
– Pain (PGE2 makes tissue hypersensitive to
bradykinin)
– Fever (PGE2)
– Production blocked by steroids and nonsteroidal
anti-inflammatory agents (NSAIDs)
• Leukotrienes
– Increase vascular permeability: leukotrienes C4, D4,
E4
– Vasoconstriction: leukotrienes C4, D4, E4
– Leukocyte adhesion & chemotaxis: leukotriene B4,
HETE, lipoxins
– Production blocked by steroids but not conventional
 Platelet Activating Factor
• Subclass of phospholipids
• Synthesized by stimulated platelets,
leukocytes, endothelium
• Inflammatory effects
– Stimulates platelet aggregation
– Vasoconstriction and bronchoconstriction
– Vasodilation and increased venular
permeability
– Increased leukocyte adhesion to
endothelium, chemotaxis, degranulation, and
oxidative burst
– Increases synthesis of arachidonic acid
metabolites by leukocytes and other cells
 Cytokines
• Proteins produced by many cell types
(principally activated lymphocytes &
macrophages)
• Modulate the function of other cell types
• Interleukin-1 (IL-1) and tumor necrosis factor
(TNF) are the major cytokines that mediate
inflammation
Figure 2-18 Robbins and Cotran Pathologic Basis of Disease, 7th
Ed.
 Chemokines
• Small proteins that act primarily as
chemoattractants for specific types of
leukocytes (approximately 40 known)
• Stimulate leukocyte recruitment in
inflammation
• Control the normal migration of cells
through tissues (organogenesis and
maintenance of tissue organization)
• Examples: IL-8, eotaxin, lymphotactin
 Nitric Oxide

Figure 2-19 Robbins and Cotran Pathologic Basis of Disease, 7th

Ed.
 Other Mediators
• Neutrophil granules:
– Cationic proteins increase vascular
permeability, immobilize neutrophils,
chemotactic for mononuclear phagocytes
– Neutral proteases generate other mediators and
degrade tissue
• Oxygen-Derived Free Radicals:
– Produced during phagocytosis by neutrophils
(“respiratory burst”)
– Tissue damage including endothelium
 Summary of Inflammatory
Mediators
• Vasodilation • Increased vascular
– Prostaglandins permeability
– Nitric oxide – Histamine, serotonin
– Histamine
– Complement (C3a, C5a)
– Bradykinin
– Leukotrienes (C4, D4, E4)
– Platelet Activating
Factor
– Substance P
 Summary of Inflammatory
Mediators

• Chemotaxis, • Fever
leukocyte – Interleukin-1
activation – Tumor necrosis
– Complement factor
(C5a) – Prostaglandins
– Leukotriene B4
– Chemokines
– IL-1, TNF
– Bacterial products
 Summary of Inflammatory
Mediators

• Pain • Tissue Damage

– Prostaglandins – Neutrophil and
– Bradykinin macrophage lysosomal
enzymes
– Oxygen metabolites
– Nitric oxide
 Classification
Several points of view
• Length:
– Acute × chronic (+ subacute, hyperacute)
• According to predominant component
– 1. Alterative (predominance of necrosis - diphtheria)
– 2. Exsudative (pleuritis)
– 3. Proliferative (cholecystitis - thickening of the wall
by fibrous tissue)
 Classification

• According to histological features

– Nonspecific (not possible to trace the etiology) -
vast majority
– Specific (e.G. Tb)

• According to causative agent

– Aseptic (sterile) - chemical substances,
congelation, radiation - inflammation has a
reparative character
– Septic (caused by living organisms) -
inflammation has a protective character
 Types of Inflammation
• Acute inflammation • Chronic inflammation
– Short duration
– Edema
– Longer duration
– Mainly neutrophils – Lymphocytes &
macrophages
• Granulomatous predominate
inflammation
– Distinctive pattern of
– Fibrosis
chronic inflammation – New blood vessels
– Activated macrophages (angiogenesis)
(epithelioid cells)
predominate
– +/- Multinucleated giant
cells
 Types of Inflammation:
Acute vs. Chronic

Types of repair:
Resolution vs. Organization (fibrosis)
Important role in inflammation has
microcirculation!

supply of white blood cells,

interleukins, fibrin, etc.
ACUTE INFLAMMATION
 Acute Inflammation
• Three major components:
– Increase in blood flow (redness & warmth)
– Edema results from increased hydrostatic
pressure (vasodilation) and lowered
intravascular osmotic pressure (protein leakage)
– Leukocytes emigrate from microcirculation and
accumulate in the focus of injury
• Stimuli: infections, trauma, physical or
chemical agents, foreign bodies, immune
reactions
Edema in inflammation
Edema is a general term for
swelling (usu. due to fluid)

Plasma proteins in blood

maintain a “colloid osmotic
pressure” to help draw fluid
that leaks out into tissue bed
via hydrostatic pressure

Dysregulation of hydrostatic
pressure (e.g. heart failure)
and/or colloid pressure
(decresased protein
synthesis/retention) pushes
out more fluid (transudate)
into tissue bed

Inflammation causes
endothelial cells to separate,
thus allowing fluid + protein
(exudate) to enter tissue bed.
Sequence of Events - Infection
 Sequence of Leukocyte
Emigration
• Neutrophils predominate during the
first 6 to 24 hours
• Monocytes in 24 to 48 hours
• Induction/activation of different
adhesion molecule pairs and specific
chemotactic factors in different
phases of inflammation
 Chemical mediators of acute
inflammation
• Proteases
– Kinins (Bradykinin and Kallekrein)
– Complement system
– Coagulation / fibrinolytic system
• Prostaglandins / Leukotrienes
– Numerous metabolites of arachidonic acid
– Synthesis blocked by NSAIDs, e.g. aspirin
• Cytokines / chemokines
– Many and varied! Interleukins, PAF, TNF
alpha, PDGF, TGF beta, MCP, ....
 Problems caused by acute
inflammation
• Local
– Swelling: Blockage of tubes, e.g. bile duct,
intestine
– Exudate: Compression e.g. cardiac tamponade
Loss of fluid e.g. burns
– Pain & loss of function - especially if prolonged
– ‘Bystander effect’ exacerbates damage, may
initiate autoimmunity
 Problems caused by acute
inflammation
• Systemic
– Acute phase response
– Spread of micro-organisms and toxins

–SHOCK
 Systemic effects of acute
inflammation
• Fever
– ‘Endogenous pyrogens’ produced: IL1 and TNFa
– IL1 - prostaglandins in hypothalamus
hence aspirin etc. reduce fever
• Leukocytosis
– IL1 and TNFa produce an accelerated release from
marrow
– Macrophages, T lymphocytes produce colony-
stimulating factors
– Bacterial infections - neutrophils, viral - lymphocytes
– Clinically useful
 Systemic effects of acute
inflammation
• Acute phase response
– Decreased appetite, altered sleep patterns and
changes in plasma concentrations of:
• Acute phase proteins:
– C-reactive protein (CRP) (Clinically useful)
– a1 antitrypsin
– Haptoglobin
– Fibrinogen
– Serum amyloid A protein
 Outcomes of acute inflammation
• 1. resolution - restoration to normal, limited
injury
– chemical substances neutralization
– normalization of vasc. permeability
– apoptosis of inflammatory cells
– lymphatic drainage
• 2. healing by scar
– tissue destruction
– fibrinous inflammtion
– purulent infl.  abscess formation (pus, pyogenic
membrane, resorption - pseudoxanthoma cells -
weeks to months)
• 3. progression into chronic inflammation
 Acute inflammation:
RESOLUTION
What may happen after the development of acute
inflammation?
1) Complete resolution.
2) Continued acute inflammation with chronic
inflammation; chronic suppuration.
3) Chronic inflammation and fibrous repair,
probably with tissue regeneration.
4) Death.
Resolution of acute inflammation
• Morphology
Changes gradually reverse.
Vascular changes stop:
– neutrophils no longer marginate
– vessel permeability returns to normal
– vessel calibre returns to normal.
Resolution of acute inflammation
• Therefore:
– Exudate drains to lymphatics
– Fibrin is degraded by plasmin and other proteases
– Neutrophils die, break up and are carried away or are
phagocytosed
– Damaged tissue might be able to regenerate.

– Note that if tissue architecture has been destroyed,

complete resolution is not possible.
Outcomes of Acute Inflammation
• Complete resolution
• Abscess formation
• Fibrosis
– After substantial tissue destruction
– In tissues that do not regenerate
– After abundant fibrin exudation,
especially in serous cavities (pleura,
peritoneum)
• Progression to chronic inflammation
Chronic inflammation
 Chronic inflammation
• Reasons:
– Persisting infection or prolonged exposure to
irritants (intracell. Surviving of agents - TBC)
– Repeated acute inflamations (otitis, rhinitis)
– Primary chronic inflammation - low virulence,
sterile inflammations (silicosis)
– Autoimmune reactions (rheumatoid arthritis,
glomerulonephritis, multiple sclerosis)
 Chronic Inflammation
• Inflammation of prolonged duration
(weeks or months)
– Active inflammation, tissue destruction, and
attempts at repair are proceeding
simultaneously
• May follow acute inflammation or begin
insidiously and often asymptomatically
– Persistent infections, exposure to toxic agents
such as silica (silicosis), or by autoimmunity
 Chronic Inflammation
• Persistent infections
– Treponema pallidum [syphilis], viruses, fungi,
parasites
• Exposure to toxic agents
– Exogenous: silica (silicosis)
– Endogenous: toxic plasma lipid components
(atherosclerosis)
• Autoimmunity
– Rheumatoid arthritis, systemic lupus
erythematosus
 Chronic Inflammation

• Histological features
– Infiltration with mononuclear cells
(macrophages, lymphocytes, and plasma
cells)
– Tissue destruction
(induced by the inflammatory cells)
– Healing by replacement of damaged tissue
by connective tissue (fibrosis)
and new blood vessels (angiogenesis)
 Chronic inflammation
• Chronic inflammatory cells ("round cell"
infiltrate)
– Lymphocytes
– Plasma cells
– Monocytes/macrophages activation of
macrophages by various mediators - fight against
invaders
• Lymphocytes  plasma cells, cytotoxic (NK)
cells, coordination with other parts of
immune system
• Plasma cells - production of ig
• Monocytes-macrophages-specialized cells
(siderophages, gitter cells, mucophages)
 Macrophages
• Monocytes begin to
emigrate into tissues early
in inflammation where
they transform into the
larger phagocytic cell
known as the macrophage
• Macrophages predominate
by 48 hours
– Recruitment (circulating
monocytes); division;
immobilization
• Activation results in
secretion of biologically
active products
 Other Cells in Chronic
Inflammation
• Lymphocytes
– Produce inflammatory mediators
– Participate in cell-mediated immune
reactions
– Plasma cells produce antibody
– Lymphocytes and macrophages interact in
a
bi-directional fashion
 Other Cells in Chronic
Inflammation
• Eosinophils
– Immune reactions mediated by IgE
– Parasitic infections
• Eosinophil granules contain a protein that is
toxic to parasites
• Mast cells
– Release mediators (histamine) and
cytokines
Granulomatous
inflammation
 Granulomatous inflammation
• Distinctive chronic inflammation type
• Cell mediated immune reaction (delayed)
• Aggregates of activated macrophages 
epithelioid cell  multinucleated giant
cells (of langhans type x of foreign body
type)
• NO agent elimination but walling off
• Intracellulary agents (TBC)
 Granulomatous inflammation
• 1. Bacteria
– TBC
– leprosy
– syphilis (3rd stage)
• 2. Parasites + Fungi
• 3. Inorganic metals or dust
– silicosis
– berylliosis
• 4. Foreign body
– suture (Schloffer „tumor“), breast prosthesis
• 5. Unknown - sarcoidosis
Wound Healing
 Wound Healing
• A complex but orderly process involving many of the
chemical mediators previously discussed, along with
many other growth factors and cell-matrix interactions.

• Occurs in the following steps:

1. Injury induces acute inflammation
2. Parenchymal cells regenerate
3. Both parenchymal and connective tissue cells migrate and
proliferate
4. Extracellular matrix is produced
5. Parenchyma and connective tissue matrix remodel
6. Increase in wound strength due to collagen deposition
Wound Healing Time Course
 Granulation Tissue

• Hallmark of healing
• Term comes from soft, pink, granular
appearance when viewed from the surface
of a wound
• Histology: Proliferation of small blood
vessels and fibroblasts; tissue often
edematous
Healing by 1st intention vs. 2nd intention

By 1st intention:
• “clean” incision
• limited scarring or
wound contraction

By 2nd intention:
• ulcers or
lacerations
• often scarring
and wound
contraction
 Resolution of Inflammation:
“Regeneration” vs. “Healing”
 Variables affecting repair
• Infection –prolongs inflammation, increases degree of tissue injury
• Nutrition –protein or vitamin deficiency can impair synthesis of new proteins
• Anti-inflammatory drugs –can impede fibrosis necessary for repair
• Mechanical variables –tension, pressure, or the presence of foreign bodies can affect repair
• Vascular disease –limits nutrient and oxygen supply required for repairing tissues
• Tissue type –only tissues capable of renewing will regenerate, otherwise healing is by fibrosis
• Degree of exudate removal –adequate removal of exudate allows RESOLUTION of the
injury (general restoration of the normal tissue architecture); inadequate removal results in
ORGANIZATION (abnormal, dysfunctional tissue architecture)
• Regulation of cell proliferation –abnormal proliferation of connective tissue may
inhibit re-epithelialization and/or raised scars (keloids)