Pathophysiology

Object
1. Describe etiology/causes and pathogenesis of the selected
disease state.
2. Name the signs and symptoms of the disease.
3. Mention the complication of the disease.
 Inflammation and repair

❖ Introduction
❖ Clinical sign of inflammation
❖ Different types of inflammation
❖ Mechanism of inflammation
❖ Mediators of inflammation
❖ Basic principles of wound healing in the skin
 Inflammation
 Inflammation is the local response of living tissues to injury due
to any agents and that attempt to self protection to remove
harmful stimuli, such as pathogens, toxic compounds, or
irradiation and acts by removing injurious stimuli and being the
healing process.
 Inflammation is a protective response to rid the body of the
cause of cell injury.
 Inflammation is the immune system's response to harmful
stimuli, damaged cells,
 Etiology/Causes
● 1) Infective agent : Bacteria, Virus, Fungi

● 2) Physical agent: Heat, Cold, Radiation. Mechanical injury, UV rays

● 3) Chemical agent: Acid, Organic solvent, Base, Poison.

● 4) Immunological agent: Cell mediated and antigen- antibody reaction.

Sign of inflammation
(Cardinal sign proposed by Cornelius celsus )

1) Rubor (Redness):
Due to increased blood supply of inflamed area.
Vasodilation and increased vascular permeability
2) Tumor (Swelling) :
Due to accumulation of fluid
3) Calor (Heat) :
Due to increase in metabolic activity
4) Dolour (Pain) :
Due to release of pain producing inflammatory molecules (Serotonin,
prostaglandin, cytokinins)
 Types of Inflammation
ACUTE INFLAMMATION CHRONIC INFLAMMATION
 Short duration time (min to  Longer time course
hour/day)  After acute turn into chronic
 Early body reaction response.
 Non specific response  Specific response
 Fluid production is part of  Fibrous tissue production
response  Cells are macrophages
 Cells are neutrophils  Always necrosis
 Occasionally necrosis
TYPES OF INFLAMMATION

On the basis of organ : On the basis of duration :

1) Dermatitis 1) Pre acute : 0-4 hr

2) Nephritis 2) Acute : 3-5 days
3) Meningitis 3) Subacute : 1 week
4) Hepatitis 4) Chronic : Month
5) Arthritis
 Morphological Patterns Of Inflammation

 Serous inflammation
 Fibrinous inflammation
 Purulent inflammation
 Ulcer
 Granulomatous inflammation
 Serous inflammation
 Serous inflammation is marked by the
outpouring of a thin fluid that, depending on the
size of injury, is derived from either the plasma
or the secretions of mesothelial cells lining the
peritoneal, pleural, and pericardial cavities
(called effusion).

For example,
The skin blister resulting from a burn or
viral infection represents a large accumulation of
serous fluid, either within or immediately beneath
the epidermis of the skin.
 Fibrinous inflammation
 Fibrinous inflammation is a form of inflammation which is
characterised by fibrin deposition. It may be acute, but more
often it is a chronic response.
 It results from the exudation/oozing out of a high concentration
of the plasma protein fraction. There is activation of the
coagulation cascade and deposition of fibrin locally.
 Body cavities and potential spaces are sites where fibrinous
inflammation is more common e.g. the:
• pericardial cavity, potentially resulting in restrictive fibrosis
• pleural space
• peritoneal cavity, potentially resulting in adhesions
 Purulent inflammation

● A purulent exudate is an inflammatory

exudate/oozing out with a high concentration
of leukocytes - predominantly neutrophils -
dead cell matter and inflammatory molecules
e.g. cytokines, lysozymes.

● The degree of enzyme proteolysis

determines the thickness of the fluid.
 Ulcer
● Inflammatory ulcers refer specifically to those
ulcerations in which inflammation is the primary
pathologic process resulting in lesion formation;
that is, inflammation is the cause rather than the
consequence of the ulcer.
 Granulomatous inflammation

● The pulmonary system is one of the most commonly affected sites to

encounter granulomatous inflammation. Infectious causes of granuloma are
most prevalent with mycobacteria and dimorphic fungi leading the
differential diagnoses.

● Common reaction patterns include

i) necrotizing granulomas,
ii) non necrotizing granulomas,
iii) suppurative granulomas,
iv) diffuse granulomatous inflammation.
 Acute inflammation

Vascular event Cellular event

 Hemodynamic changes  Extravasation
 Phagocytosis
 Altered Vascular Changes
 Vascular Events

Alteration in the Microvascular tissue.

i) Hemodynamic changes :
Features: Vascular flow change, changes of small blood vessels.
Irrespective of the type of injury: Transient vasoconstriction of
arterioles.
Mild form – Blood flow (3-5 sec)
More severe injury – Blood flow (5 min)
Vascular Events
ii) Vascular changes:
a) Persistent Progressive Vasodilation:
- Mainly arterioles
- Lesser extent – venules and capillaries.
- Increased blood flow

b) Progressive vasodilation :
Elevate the local hydrostatic pressure
Transudation of fluid into the extracellular space-swelling.

c) Stasis of microcirculation :
- Increased concentration of red cells.

d) Leucocytic margination :
- Leucocytes sticks to the vascular endothelium.
- Move and migrate through the gaps between the endothelial cells into the extravascular space.
 Cellular Event

i) Migration, Rolling and adhesion of leukocytes

ii) Transmigration of leukocytes
iii) Chemotaxis
iv) Phagocytosis
i) Migration, Rolling and
adhesion of leukocytes :
- Margination is a peripheral
positioning of white cells along the
endothelial cells.

- Rows of leukocytes tumble slowly

along the endothelium in a process
known as rolling.

- The binding of leukocytes with

endothelial cells is facilitated by cell
adhesion molecules such as selectins,
immunoglobulin, integrins etc.
ii) Transmigrationof leukocytes :
- Leukocytes escape from venules and small veins.
- The most important mechanism of leukocyte emigration is via widening of
inter-endothelial junctions after endothelial cells contractions.

iii) Chemotaxis:
- It is refer to the directional migration of cells in response to chemical.
- It is a unidirectional attraction of leukocytes from vascular channels towards
the site of inflammation.
iv) Phagocytosis:
- It is the process of engulfment by specialized cells of particulate
material, which includes microorganisms, damaged cells, and tissue
debris.
- Phagocytosis involves three district steps :

a) Recognition and attachment :

- It is enhanced if the material to be phagocytosed is coated with certain
plasma proteins called opsonins.
- These opsonins promote the adhesion between the particulate material
and the phagocyte's cell membrane.
b) Engulfment :
- During engulfment, extension of the
Cytoplasm flow around the object to
be engulfed, eventually resulting in
complete enclosure of the particle.

c) Killing/ degradation :
- The ultimate step in phagocytosis of bacteria is
killing/ degradation.
- There are two types of mechanism :
a) Oxygen dependent mechanism
b) Oxygen independent mechanism
Pathogenesis of altered Vascular permeability
● Normal Circumstances – fluid balance – Two opposing sets of forces that causes.

1) Outward movement of fluid from microcirculation :

- Increased hydrostatic pressure
- colloid osmotic pressure of interstitial fluid.

2) Inward movement of interstitial fluid into circulation:

- Intravascular colloid osmotic pressure.
- Hydrostatic pressure of interstitial fluid.
1) Cell injury/ damage

2) Vasodilation (Initial inflammation reaction)

mild 3-5 sec.

3) Release of inflammation mediators like

histamine, PG,NO (30 min.) Redness and
heat. Increase in hydrostatic pressure and
decreased osmatic pressure

4) Transudate: Plasma/fluid leakage

5) Excudate : increase in Vascular permeability

due histamine,PG( endothelial cell gap) leak
out. – cell swelling (tumor,pain)

6) Leukocytic margination : Emigration

Mechanism of inflammation

● Migration : Vasodilation
● Rolling and adhesion : WBCs, Platelets, RBCs, (Endothelial
cell)
● Emigration : Mast cell (responsible for release of histamine)
mast cell enter into cell through pseudopodia
● Chemotaxis : cell rupture
● Degradation : swelling, inflammation , increase in heat
● Inflammation
 Chronic Inflammation
● It is a response of prolonged duration (weeks to month) in which
inflammation, tissue damage and attempts at repair coexist.
● May follow acute inflammation

Etiology of chronic inflammation :

1) Persistent inflammation : (parasite like microorganism)
2) Hypersensitivity Reaction : Excessive inappropriate action of immune
response. (Allergic reaction)
3) Prolonged exposure to toxic agents. (exogenous/ endogenous agent)
Causes of Chronic inflammation:
 Prolonged acute inflammation
 Tissue destruction is extensive
 The bacteria survive and persist in small numbers at the site of acute
inflammation
 Repeated attacks of acute inflammation
 Culminate in chronicity of the process.

Systemic effect of chronic inflammation :

 Fever : mild fever, often with loss of weight and weakness.
 Anemia
 Leukocytosis
 Amyloidosis
Inflammatory response
● Any messenger that acts on blood vessels, inflammatory cells, or other cells
to contribute to an inflammatory response.

● Properties: (Self Study)

1) Mediators are generated from cells or from plasma protein.
2) once activated and released from the cell, most of these are short lived.
Classification of mediators:

Histamine, serotonin, prostaglandin ,Nitric oxide, cytokinin

Morphological Features Chronic Inflammation

1) Chronic Non-specific Inflammation

2) Granulomatous Inflammation

1) Chronic Non-specific Inflammation :

a) Infiltration by monophasic cells like lymphocytes, plasma cells
b) Tissue destruction by microorganism/parasite/inflammatory cell
c) Attempts at repair : Connective tissue deposition at site of tissue damage.
(Granulose tissue formation)
 Mediators of inflammation
 These are the substances that INITIATE & REGULATE Inflammatory reactions.
 These are a large and increasing number of endogenous chemical substance which
mediate the process of inflammation.
 An inflammatory mediator is a messenger that acts on blood vessels and/or cells to
promote an inflammatory response.

Chemical mediators of inflammation are:

 Endogenous compounds
 Released during inflammation
 Increased vascular permeability
 Edema, Destruction of inflammatory agents.
General properties of mediators:
 These mediators can be produced Locally, by the CELLS and are called
CELL- DERIVED. / Derived from inactive precursors present in plasma
which are referred to as PLASMA –DERIVED.
 They can be produced only in response to agents that stimulate
inflammation.
 They can stimulate the release of another mediator.
 They have short lifespan: as they are degraded by enzymatic action very
rapidly.
 They can act on wide variety of cells and may have similar action on
different targets or different actions on similar targets.
 Range of actions of different mediators are: increased vascular
permeability, vasodilatation, chemotaxis, fever, pain and tissue damage.
Chemical mediators of inflammation are derived from cell and plasma.

 Cell derived mediators include histamine, serotonin, leukotriene, platelet

activating factor, cytokinine, prostaglandins
• Cell-derived mediators are released either from their storage in the cell
granules or are synthesized in the cells.

 Plasma derived mediators include kinin system, clotting and fibrinolytic

system
• The most common site of synthesis of plasma-derived mediators is the
liver. After their release from the liver, these mediators require activation.
Cell derived Mediators Source Main Action/ Function
1) Vasoactive amine e.g. i) Histamine Increased vascular permeability
Mast cell, basophils,
Platelets
ii) Serotonin (5-HT) Platelets Increased vascular permeability
2) Arachidonic acid i) Metabolites via COX Vasodilation
metabolism (Cyclooxygenases) pathway

e.g. Prostaglandin
thromboxane A2,
prostacyclin)
Inflammatory cells
ii) Metabolites via (LOX) Increased vascular permeability
lipo-oxygenase pathway
(leuko-
trienes, lipoxins)
Inflammatory cells

Free radicals
( like Nitric oxide and oxygen) Inflammatory cells Tissue damage
metabolite
Cell derived Mediators Source Main Action/ Function

Lysosome Inflammatory cells Phagocytosis (breakdown/digestion of

macromolecule), Cell membrane repair,
response against foreign substance such as
bacteria.
Platelet activating factor Inflammatory cells Increased vascular permeability

Inflammatory cells It helps to control inflammation in your

Cytokine body. Fever.
Plasma derived Source Action/Function
Mediator

Clotting and Fibrinolytic Fibrin split products Increased vascular

system permeability

Kinin system Kinin Increased vascular

permeability

Complement System C3a, C4a,C5a,C5b-9 Increased vascular

permeability
Cellular Mediator:

1) Histamine (β-Imidazolylethylamine) –
Histamine is a vasodilator, a constrictor of smooth muscle, and a potent stimulant
of vascular permeability, respiratory mucus, and gastric acid secretion.
Cell origin : Golgi apparatus of Mast cell, basophiles
Functions : Vascular leakage and platelets, vasodilation, Increased vascular
permeability, Endothelial activation.
H2 receptor mediated anti-inflammatory activity inhibition of human neutrophil
lysosomal enzyme release, inhibition of IgE-mediated histamine release from
peripheral leukocytes, and activation of suppressor T-lymphocytes
2) Serotonin –
- Serotonin (5-hydroxytryptamine, 5-HT) is located mainly in the serotoninergic
neural network of the central nervous system, in the gastrointestinal (GI) tract
and in platelets, where 5-HT is stored.

- 5-HT regulates expression of P- and E-selectins on endothelial cells and

activates the rolling and adhesion of neutrophils. When serotonin is depleted,
this innate immune reaction of neutrophils is reduced.

Cell origin : In chromaffin cells of GIT, Spleen , Nervous tissue.

Functions : Vasoconstriction, incerased vascular permeability.

3) Prostaglandins -

- Prostaglandins are lipid autacoids derived from arachidonic acid.

- They are a subclass of eicosanoids and of the prostanoid class of fatty acid
derivatives.
- Prostaglandin contains 20 carbon atoms, including a 5-carbon ring.
- Cell origin : Mast cell, Leukocyte
- Functions : Vasodilators and inhibit the aggregation of blood platelets, Pain,
Fever
4) Leukotriene

● Leukotrienes are a family of eicosanoid inflammatory mediators produced

in leukocytes by the oxidation of arachidonic acid.
● Leukotrienes use lipid signaling to convey information to either the cell
producing them (autocrine signaling) or neighboring cells (paracrine
signaling) in order to regulate immune responses.
● Cell origin : Mast cell, Leukocyte
● Function : Increased vascular permeability, chemotaxis, leukocyte adhesion
and activation.
5) Lysosome
● It is a membrane bound organelle found in many animal cells.
● The lysosome is involved in various cell processes including plasma membrane repair, cell
signaling.
● Lysosome are termed to be degradative organelles that act as the waste disposal system of
the cell by digesting used material in the cytoplasm, from both inside and outside the cell.
● To being able to break down polymers, lysosomes are capable of digesting large structure
or cellular debris.
● Cell origin : Golgi bodies.
● Function : Phagocytosis (breakdown/digestion of macromolecule), Cell membrane
repair, response against foreign substance such as bacteria.
6) Cytokine
● Cytokine are a broad and loose category of small proteins important in cell
signalling.
● Cytokines include chemokines,interferons,interleukins,tumour necrosis factors.
● The secretion of cytokines from cells is a fundamental response to injury and
infection in the body.
● Some cytokines are potent mediators of inflammation e.g. lymphokines,
monokines, IL-1, IL-8, TNF.
● Cell origin : Golgi bodies.
● Function : It helps to control inflammation in your body.
7) Arachidonic acid

● It is a polyunsaturated fatty
in the cell membrane of body cells.
● Cell origin : phospholipids
● Function : Vasodilation,
Inceased vascular permeability
Clotting and Fibrinolysis system

● To control of inflammation.

● The two final phase in the hemostatic process are

i) Plasma coagulation with the formation of a fibrin clot
ii) Fibrinolysis leading to dissolution of fibrin clots.

plasma origin : Fibrin split products/fibrin degradation product

Function : Regulatory mechanism limit clot formation to the site of injury and
control its size and stability.
Kinin system
● It is a hormonal system that plays a major role in inflammation.
● It consists of blood proteins that play a role in inflammation.
● They act on phospholipase and increased arachidonic acid release and thus
prostaglandin production.
● It activated by factor XII by coagulation system.
● It may directly stimulate pain.
● origin : kinin
● Function : Increased vascular permeability
 Basic principles of wound healing in the skin
● Wound healing refers to a living organism's replacement of destroyed or
damaged tissue by newly produced tissue.

● Repair and regeneration are the body response against the injury to restore
normal function and structure.

● The epidermis (Surface, epithelial cell) and dermis (deeper, connective

layer) form a protective barrier against the external environment.
 Cell cycle/ Cell division cycle :

1) G0 PHASE / Resting phase

2) G1 PHASE
3) S PHASE Interphase
4) G2 PHASE

5) M PHASE / Mitosis (Cell division)

Regenerating or dividing cells under goes in three group :
1) Labile cell
2) Stable cell
3) Permanent cell

4) Labile cell –
• These cells continue divide and multiply throughout life.

• Labile cells exhibit a very short G1 phase and never enter G0 phase, as they are
continually proliferating throughout their life.

• E.g. Epithelial cells of the epidermis, alimentary tract, respiratory tract, urinary tract,
cervix, vagina, uterine endometrium, bone marrow and cells of lymph nodes and spleen.
2) Stable cells-
• Decrease or loss their proliferation capacity after adolescent but retain the capacity
during the injury or in response to certain stimuli.

• Stable cells are cells that multiply only when needed.

• They spend most of the time in G0 phase but can be stimulated to enter the cell cycle
when needed.

• E.g. Parenchymal cells of organ like liver, pancreas, kidney, adrenal gland.
• Mesenchymal cells like Bone, cartilage cells, Smooth Muscle cells.

3) Permanent cells –
• After the birth these cells lose their ability to proliferate, Non-dividing cells and die after
injury. These are cells that are incapable of regeneration.

• E.g. Neurons of Nervous system, Skeletal muscles and Cardiac muscle cells.
 REPAIRS OF WOUND IN SKIN
● In normal skin, the epidermis and dermis exists in steady state equilibrium,
forming a protective barrier against the external environment.
● It is a example of combination of regeneration and repair.

WOUND HEALING PHASES :

1) INFLAMMATORY PHASE
2) PROLIFERATION
3) MATURATION OR REMODELING
WOUND HEALING PHASES :

There are four stages of wound healing :

1) Homeostasis (blood clotting)

2) Inflammation

3) Proliferation (growth of new tissue)

4) Maturation (remodeling)
1) Homeostasis (blood clotting)

● Within the first few minutes of injury, platelets in the blood begin to stick to
the injured site.

● They change into an amorphous shape, more suitable for clotting, and they
release chemical signals to promote clotting.

● This results in the activation of fibrin, which forms a mesh and acts as "glue"
to bind platelets to each other. This makes a clot that serves to plug the break
in the blood vessel, slowing/preventing further bleeding.
Inflammation

● During this phase, damaged and dead cells are cleared out, along with
bacteria and other pathogens or debris.

● This happens through the process of phagocytosis, where white blood cells
engulf debris and destroy it.

● Platelet –derived growth factors are released into the wound that cause the
migration and division of cells during the proliferative phase.
Proliferation (growth of new tissue)
 In this phase, angiogenesis, collagen deposition, granulation tissue
formation and epithelialisation occurs.

 Wound Rebuilt with granulation tissue (depend on the fibroblast receiving

sufficient level of oxygen and nutrients supplied by the blood vessels )
(composed of collagen and extracellular matrix).

 A new network of blood vessels develop process known as (angiogenesis).

 Epithelial cells finally resurface the wound called epithelialisation.

Maturation (remodeling)
● Final phase, remodelling of collagen from type III or type I scar tissue is
only 80% as strong as original tissue.

● Cellular activity reduces and the number of blood vessels in the wounded
area decrease. (3 weeks to 2 years).

● Collagen is realigned along tension lines, and cells that are no longer needed
are removed by cell death.
Complication during wound healing
● Infection of wound due to entry of bacteria delays the healing.

● After healing if epithelial cells persist for long time in wound it cause implantation or
epidermal cyst.

● Due to the effect of hemosiderin (Derived from RBC’S) it produces pigmentation on skin

● In adequate formation of granulation tissue produce deficient scar.

● Rarely scar may leads to carcinoma which is known as neoplasia.

 Factor influencing Healing

I) Local Factor : II) Systemic Factor :

i) Infection – Delay the healing i) Age

ii) Poor blood supply – Delay the healing ii) Nutrition
iii) Ionizing radiation – Delay healing iii) Uncontrolled Diabetes
iv) Ultraviolet light – Facilitates healing iv) Hematologic abnormalities
PATHOLOGICAL ASPECTS OF REPAIR
Repair is the replacement of injured tissue by fibrous tissue. It is a complex system and
consist series of events :
- Due to the injury.
- for the removal of damage and dead tissue
- Inflammation is occur
- Then Proliferation and migration of parenchymal and connective tissue is held
- Formation of new blood vessels (Angiogenesis) and granulation.
- Synthesis of proteins and collagen deposition
- Tissue remodeling
- Wound Contraction
- Acquisition of wound strength.