Inflammation and Repair

By:

Dr. Suhair Alkilani Alghazal

Reference: Robbins basic pathology 9th ed

Sirte Dental School

2021-2022
 Objectives:
 To master the concept of inflammation.

 To know the importance of inflammation.

 To know its classification: acute and chronic.

 To know cardinal signs of inflammation.

 To learn about how inflammation develop: vascular

and cellular events.
  Inflammation: “In-flame” to set fire

 Inflammation is:
“ dynamic response of vascularised tissue to injury”

 a protective response
 eliminate the initial cause of cell injury
 eliminate the necrotic cells
 bring defense & healing materials to the injured site
 External manifsetation of inflammation = cardinal signs
A roman writer cornelius Celsius (1st century) described the first 4 cardinal
signs of inflammation and Virchow described the 5th one:

Calor Rubor Tumor Dolor Functio laesa

Heat Redness Swelling Pain Loss of function

Inflammation is divided into two basic patterns:
Acute and chronic inflammation
Acute inflammation:

 Short duration: few minutes to a few days

 Vascular changes: exudates formation
 Main inflammatory cells: Neutrophils
Chronic inflammation:

 Weeks to months or years

 Vascular proliferation
 Fibrosis – Scarring
 Lymphocytes ,macrophages, plasma cells, fibroblasts.
 Acute inflammation
 The immediate and early response to injury

 Delivers leukocytes: to clear any invading agents

 Starts the breakdown of necrotic tissues

Events of acute inflammation:

A. Vascular events
integrated by
chemical mediators
B. Cellular events
 A. Vascular events:
 Changes in vascular caliber and flow

 Change in vascular permeability

Changes in vascular caliber and flow

1. Transient vasoconstriction of arterioles

2. Vasodilation & increase blood fluid: causing erythema and warmth

3. Slowing of the circulation (stasis)

4. After stasis occurs, leukocytes (Neutrophils) migrate to the

extracellular tissues (more details in cellular events)
 These changes are reflected microscopically by numerous dilated small
vessels packed with red cells…this process called stasis.
 Change in vascular permeability

A transudate is formed when fluid leaks out because of increased

hydrostatic pressure or decreased osmotic pressure

An exudate is formed in inflammation because vascular permeability

increases as a result of the increase in interendothelial spaces
Interstitial protein-rich fluid

An increase in interstitial
osmotic pressure

Outflow of water & ions into the

extravascular tissues oedema
 Advantages of exudate

 Dilution of toxins.

 Bring globulins for protective mechanisms.

 Fibrin deposition helps to limit spread of bacteria.

 Bring many factors that promoting healing.

 Cellular events

The events of extravasations of leukocytes from vascular

lumen are divided into :

1. Margination & rolling.

2. Adhesion & transmigration between endothelial cells.
3. Emigration towards chemotactic stimulus.
4. Phagocytosis and degranulation.
 1. Margination & rolling
 Leukocytes leave the central axial column (where they normally flow)

 They accumulate at the periphery of vessels (margination)

 Leukocytes transiently stick along the way (rolling)

Stasis

Margination

Oedema
 The loose & transient leukocyte adhesions in rolling are
mediated by adhesive molecules :selectin

Selectins: Receptors expressed on leukocytes and endothelium

Selectins include:
E-selectin (CD62E): Expressed in endothelium
L-selectin (CD62L): Expressed on most leukocytes
P-selectin (CD62P): Expressed in endothelium & platelets
 2. Adhesion and transmigration
Adhesion:

 Leukocytes firmly stick to endothelial surfaces

 This adhesion is mediated by integrins
 Integrins are expressed on leukocyte cell surfaces
 Integrins interact with their ligands on endothelial cells

Transmigration (Diapedesis):
 Leukocytes crawl between endothelial cells and through the
basement membrane into extravascular space.
 This is mediated by a cell adhesion molecule: PECAM-1
(platelet endothelial cell adhesion molecule 1)
 3. Emigration: Chemotaxis and activation
Chemotaxis:
The directional movement of leukocytes toward sites of injury
under the guidance of specific chemicals (chemotactics)

Many exogenous and endogenous substances act as chemotactic, e.g.,:

 cytokines.

 soluble bacterial products.

 components of the complement system (C5a).

 products of the lipoxygenase pathway of arachidonic acid

metabolism.
 4. Phagocytosis

1. Recognition and attachment of the particle to the leukocyte:

 enhanced by opsonins (serum proteins): - IgG

- C3b and iC3b

2. Engulfment and phagocytic vacuoles formation:

phagosome + lysosome = phagolysosome

3. Killing and degradation:

oxygen-dependent killing: oxidative or respiratory burst

oxygen-independent killing
 Oxygen-dependent killing: oxidative or respiratory burst

Phagocytosis induces an oxidative burst

• a sudden increase in oxygen consumption

• glycogen catabolism

• increased glucose oxidation

An oxidative burst:
 Lead to generation of reactive oxygen species (ROS)
 ROS potent antimicrobial: e.g.,

 O2ˉ superoxide ions

 H2O2 (Hydrogen peroxide)
 Oxygen-dependent killing: oxidative or respiratory burst

 The amount of H2O2 produced generally are insufficient to kill most bacteria

 Primary (azurophilic) granules of neutrophils:

Myeloperoxidase (MPO): powerful enzyme

 Needs halid (Cl•) and hydrogen peroxide
 Produces Hypochlorous radical (HOCl•)
(powerful oxidant and antimicrobial agent)

Oxygen-independent killing
 Lysozyme
 Elastase
 Defensins: kill microbes by creating holes in their membranes
 Lactoferrin: chelates iron required for bacterial growth
 Neutrophil Extracellular Traps (NETs)

Recently discovered: 1996, 2004

 They are extracellular fibrillar networks that are produced by neutrophils

 Induced by:
= infectious pathogens (mainly bacteria and fungi)
= inflammatory mediators
 Contains framework of nuclear chromatin with antimicrobial proteins
 Provide a high amount of antimicrobial proteins at sites of infection
 Prevent the spread of the microbes by trapping them in the fibrils
 NETs may have role in causing autoimmune disease
Summary
 Outcomes of acute inflammation

1. Resolution:
It occurs when:
 The injury is limited or short-lived
 There is no or minimal tissue damage
 Outcomes of acute inflammation

2. Scarring or fibrosis
It occurs when:
 There is massive tissue damage.
 Inflammation occurs in tissues that do not regenerate.

3. Progression to chronic inflammation:

 Chronic inflammation may follow acute inflammation.

 Signs of chronic inflammation may be present at the onset of injury

as in viral infection, autoimmune diseases.

 Chronic inflammation whether lead to regeneration of structure and

function or followed by scarring.
 1

3 2
Morphology of acute inflammation

Chronic inflammation
 Morphology (classification )of acute inflammation
Non suppurative:
 Serous: e.g.,
= blister of skin burns
= vesicles of herpes simplex
 Fibrinous: e.g.,
= fibrinous pericarditis
= pneumonia
 Haemorrhagic: e.g.,
= haemolytic streptococcal infection
 Catarrhal: e.g.,
= rhinitis, common cold
 Membranous & pseudomembranous: e.g.,
= diphtheria & bacillary dysentery
Suppurative:
 Localised: e.g.,
= abscess:focal collection of pus
= furuncle:small abscess related to
hair follicle, sebaceous or sweat
gland.
= carbuncle: focal abscess mainly
common in diabetic patients
 Diffuse: e.g.,
= cellulitis:Caused by
streptococcus haemolytics
Epidermis

Serous
exudate

Dermis

Serous inflammation: Skin blister

 Central necrotic
area

Neutrophils

Dilated vessels &

fibroblasts

Renal abscess
 Complications of abscess

1. Toxemia, septicemia and pyaemia

2. Sinus, fistula, ulcer and keloid

Sinus: it is an abnormal passage leading from a

suppurating cavity to the body surface. sinus

Fistula: it is an abnormal tract connecting two cavities

or between the hollow viscera and the surface.

Types of fistula:
 congenital: e.g., thyroglossal fistula. Fistula

 inflammatory: e.g., appendicular fistula

complicating acute suppurative appendicitis.
 malignancy: e.g., vesicovaginal fistula.
Hollow organ
Ulceration:
Ulcer is a local (discontinuity) defect in an epithelial surface
caused by the shedding of dead epithelial cells.

 Common in epithelial surfaces: skin, gastric epithelium, colonic

mucosa…others.

Duodenal ulcer
 Chronic inflammation
Chronic inflammation is characterised by:
 Chronic inflammatory cell:
 macrophages
 lymphocytes
 plasma cells
 New vessel proliferation (angiogenesis)
 Tissue destruction
 Fibrosis (Repair)

Chronic inflammation may follow acute inflammation:

Acute inflammation can not be resolved either because of
a. The persistence of injurious agent
b. The interference in the normal process of healing
 What does induce Chronic inflammation?

1. Certain viruses and fungi

2. Persistent microbial infections:

 Mycobacteria (tubercle bacilli)

 Treponema pallidum (syphilis)

3. Prolonged exposure to potentially toxic agents:

 exogenous : silica causing silicosis in lung

 endogenous : cholesterol crystals causing

atherosclerosis.

4. Autoimmune diseases:
 Rheumatoid arthritis
 Inflammatory bowel disease
 Psoriasis.
 Chronic inflammatory cells
 Macrophages: the critical cell type in chronic inflammation

 Lymphocytes: activate macrophage

Lymphocytes are not always a sign of chronic inflammation, they are

also present in acute viral infections.

 Plasma cells: produce antibodies

 Eosinophils: common in parasitic infections and allergic reactions.

 Mast cells: in both acute and chronic inflammation

“Although neutrophils are the hallmarks of acute inflammation,

many chronic conditions show extensive neutrophilic infilterates
where it is called acute on chronic inflammation”
 Chronic inflammation

 Chronic inflammatory cells (asterisk)

 Destruction of parenchyma
 Normal alveoli spaces lined by
cuboidal epithelium (arrowheads)
 Fibrosis

Lung tissue

Acute inflammation

 Neutrophils fill the alveolar spaces

 Congested blood vessels
 Chronic
inflammation
Chronic specific Chronic non-specific

Caused by one specific agent such Caused by more than one causative
as; TB, syphilis & bilharziasis. agents. E.g., pyelonephritis may be
caused by E.coli, klebsiella or others.

Granulomatous inflammation:

It is a distinctive pattern of chronic inflammation characterized by aggregation

of activated macrophages (epithelioid cells) with scattered lymphocytes.

Epithelioid cells: activated macrophages that have a similar appearance

(large, flat ,pink) of squamous cells. Epithelioid cells may have more
secretory role rather than phagocytic role.
Few pathological conditions can form granulomas:
A. Infective granuloma:

 Bacterial: TB, leprosy, syphilis

 Parasites: Schistosomiasis

 Some fungi

B. Non-infective granuloma:

 Foreign body granuloma & silicosis.

C. Unknown cause:

 Sarcoidosis

 Crohn’s disease.

Granuloma consists of:

Epithelioid cells, lymphocytes, fibroblasts, connective tissue,
some with giant cells and some with central necrosis
 Giant cells

Caseous
necrosis

Lymphocytes
 Systemic effects of inflammation
Acute-phase reactions

Fever, anorexia, hypotension, accelerated degradation of skeletal muscle

proteins, increase hepatic synthesis of many proteins (e.g., complement
and coagulation proteins) and alternation in white blood cell count

1. Fever: induced by cytokines: IL-1 and TNF

2. High erythrocyte sedimentation rate (ESR):
IL-6 induces synthesis of hepatic proteins such as fibrinogen.
Elevated fibrinogen stimulates RBCs to agglutinate more readily
causing high ESR

3. High level of C-reactive protein:

synthesized by liver and is induced by IL-1, IL-6 &TNF
4. Leukocytosis: increased white blood cell count

 It’s a common feature of inflammatory reactions ( bacterial infection)

 Leukocytosis : Induction of cells from the bone marrow by IL-1 and TNF

 Bacterial infections induce an increase in neutrophils (neutrophilia)

 Parasitic infections and allergic responses induce eosinophilia

 Certain viral infections (e.g., mumps, rubella) induce lymphocytosis.

 most viral infections, rickettsial, and typhoid fever induce a decrease in

leukocytes (leukopenia)
Chemical Mediators of Inflammation
 Chemical mediators

Plasma protein-derived Cell-derived

mediators mediators

Circulating in the plasma Locally produced by cells at

(typically synthesised by the liver) the site of inflammation

 Some bind to specific receptors on target cells.

 Others have direct enzymatic activities.

 Mediator function is tightly regulated as most of them have the

potential to cause harmful effects.

 Once they activated and released from the cell, most mediators rapidly
decay, inactivated, eliminated or inhibited.
 Important points of systemic mediators

 Bradykinin, C3a and C5a :

major mediators of increased vascular permeability.

 C5a is a major mediator of chemotaxis.

 Thrombin has multiple effects including leukocyte adhesion, vascular

permeability and chemotaxis.
 Cell-derived mediators:

1. Vasoactive amines: histamine, serotonin

2. Arachidonic acid metabolites: prostaglandins, leukotrienes

3. Cytokines: TNF and IL-1 induce fever, Chemokines.

4. Reactive oxygen species: killing microbes, tissue damage

5. Nitric oxide: vasodilation, killing microbes. tissue damage

6. Lysosomal enzymes: tissue damage, killing microbes

 Tissue Repair:
Cell Regeneration and Fibrosis
 Objectives

 To master he concept of tissue repair.

 To know the processes of repair: regeneration and fibrosis.

 To learn about granulation tissue and its importance.

 To identify the processes of repair by fibrosis.

 Studying cutaneous wound healing as an example of healing

by regeneration and fibrosis.

 To identify the phases of cutaneous wound healing.

 To know the repair of cutaneous wound healing by first

and second intention and the main differences between
them.

 To study the factors that delay repair.

Repair: Replacement of damaged tissue with healthy one.

 The repair begins very early in the process of inflammation and involves
two processes:

1. Regeneration of injured tissue by parenchymal cells of the same type.

2. Replacement by connective tissue (fibrosis) resulting in a scar.

Regeneration

Regeneration depends on:

A. Cell type

B. State of the supporting framework (stroma)

A. The cells of the body are divided into three groups according to
their regenerative capacity:

1. Labile cells: continuously dividing cells, high potential for regeneration:

 Skin, GIT
 Haematopoietic cells
 Respiratory cells, Genito-urinary cells
2. Stable cells: low or no dividing capacity, but undergo rapid division in
response to injury:
 Liver, Pancreas
 Kidney, Endothelial cells
 Smooth muscle cells, Fibroblast cells
3. Permanent cells: lack the capacity of dividing in postnatal life:
 Neurons
 Cardiac muscle cells
 B. State of the supporting framework or stroma

Intact basement membranes: cells proliferate in organised fashion.

Destroyed basement membranes: cells proliferate in a random fashion.

An example:

In mild viral hepatitis:

The supporting stroma is intact and hepatocytes regenerate and retain

the normal lobular structure.

In liver abscess:

There is severe damage to the hepatocytes and the supporting stroma,

the scarring results leading to loss of the normal liver architecture.
 Repair by connective tissue (fibrosis)

This process has 4 general components:

a. Formation of new blood vessels (angiogenesis).

b. Migration and proliferation of fibroblasts.

c. Deposition of extracellular matrix (ECM).

d. Maturation and reorganization of the fibrous tissue

(remodeling).
 Repair by connective tissue (fibrosis)

 Repair begins within 24hrs of injury:

 Emigration of fibroblasts

 Fibroblast and endothelial cell proliferation

 By 3 to 5 days, a granulation tissue is formed:

The term “Granulation tissue” is derived from its pink soft granular gross
appearance.

 Granulation tissue is the hallmark of healing process and it composes of:

 Newly formed blood vessels

 Fibroblasts

 Few inflammatory cells

 Loose ECM
 Collagen
fibers

New blood
vessels

Granulation tissue: Trichrome stain that stains collagen blue

Collagen
fibers

New blood
vessels

Mature scar (Trichrome stain): Dense collagen and few blood vessels
 Cutaneous Wound Healing
Phases of cutaneous wound healing:

1. Inflammation

2. Formation of granulation tissue

3. ECM deposition and remodeling

Cutaneous wound healing occurs by:

A. Healing by primary union (first intention):

 Healing of clean uninfected surgical incision approximated by surgical

sutures.
B. Healing by secondary union (second intention): Occurs when:
 An extensive tissue loss: infarction, ulceration, abscess or large wounds.
 The cellular regeneration alone cannot restore the original architecture.
 Large skin defects may be reduced by contraction of Myofibroblasts
Cutaneous Wound Healing
 Pathologic aspects of repair
Factors that affect the healing process:

1. Infection: It is the single most important cause of delay in healing by

prolonging the inflammation phase and increasing local tissue injury

2. Nutrition: Vitamin C deficiency inhibits collagen synthesis.

3. Drugs: Glucocorticoids (steroids) have anti-inflammatory effects but they

may result in poor wound strength caused by diminished fibrosis.

4. Mechanical factors: such as increased local pressure or torsion may

cause wounds to pull apart.

5. Poor blood perfusion: impairs healing process.

6. Existence of foreign bodies: Fragments of glass may impair healing.

7. Type and volume of the injured tissue

8. Abnormality of cell growth and ECM production: More collagen

accumulation leads to prominent, raised scars known as keloids.
Keloid: Scar hypertrophy