Inflammation

INFLAMMATION

Protective response intended to

-eliminate initial cause of cell injury , necrotic cells
- and tissues resulting from original insult

 Damage to tissues can result from various stimuli, including

infections, autoimmune reactions, toxins, radiation and
mechanical injury.
Inflammation

Response of tissue to injury.

Purpose:
 To defend against invading agents

-and to eliminate the injurious agent responsible for

injury

 Get rid the tissue of the consequences of injury -

necrotic cells death
The suffix which indicates inflammation is "-itis"

 Appendix  appendicitis
 Pancreas  pancreatitis
 Meninges  meningitis
 Pericardium  pericarditis
 Gastritis
 Brain - meningitis
Harmful effects of inflammation may be observed in:
 Severe infection
 Chronic infection- Inflamation
 Inadequate response
Harmful effects of chronic and impair repair
-Fibrosis *:typically results from chronic inflammation.
-Formation of scars
e.g Intestinal obstruction
— *a pathological wound healing in which connective tissue replaces normal
parenchymal tissue to the extent that it goes unchecked,

- leading to considerable tissue remodelling and the formation of

permanent scar tissue.
 Stimuli for Acute Inflammation
 Infections : caused by -bacterial, viral, fungal, parasitic etc

 Trauma - blunt and penetrating

 Physical and chemical agents (thermal injury, e.g., burns or frostbite;

irradiation)

 Tissue necrosis -from any cause

 Foreign bodies: splinters, dirt, sutures, wood /iron /metals

 Hypersensitivity reactions- Immune ediated reactions
Defense Mechanisms

Immunity- ability of the body to defend itself against:

-infectious agents, foreign cells, abnormal body cells,
such as cancer cells
Immunity includes:
 Nonspecific Defense Mechanisms

 Specific Defense Mechanisms

IMMUNITY-Phagocytes
Monocytes and macrophages
-Provide a non-specific response to infection

Lymphocytes: Provide a specific immune response to infectious

diseases. There are 2 types: -
a) T-cells: do not produce antibodies,immune responses are
regulated by directly attacking and destroying the specific
antigens
b) B-cells: produce antibodies, responsible for humoral
immunity
-Increase: Viral infections and some leukemias
-Decrease: Prolonged illness, immunosuppression
C: NK cells are cytotoxic
 Cytotoxic T cells, need priming by antigen presenting cellsc while NK-cells directly kills
the tumor cells and bacteria etc
 NK cells are cytotoxic; small granules in their cytoplasm contain proteins such
as perforin and proteases known as granzymes
 perforin forms pores in the cell membrane of the target cell, creating an aqueous channel
through which the granzymes and associated molecules can enter, inducing either apoptosis
or osmotic cell lysis
 Nonspecific Defense Mechanisms
 Phagocytosis- engulf and destroy bacteria and other material

 NK Cells- type of leukocyte that recognizes body cells with

abnormal membranes

 Fever- sign the body is defending itself; phagocytes find and

destroy foreign invaders; releasing substances that raise the
body temp

 Interferon- stimulates the immune system

 Neutrophils
 Most common WBC (50-70%), die as soon as they ingest
another cell
 live for 4-10 hours if not activated

 1st to arrive at infection site through chemotaxis

 Main component of pus- liquefy in tissue

 After phagocytosis they release-free radicals- superoxide which

is hypoclorous acid to kill microbes
Types of inflammation

1. Acute:
 Short duration (minutes – days)
 Fluid and plasma protein (edema)
 Neutrophilic accumulation

2. Chronic:
 Longer duration (days – years)
 Influx of lymphocytes & macrophages.
Acute Inflammation

 Acute inflammation is an immediate and early response to

injury.
 Short duration: Minutes, hours, days.
 Purpose : To get the neutrophils to the site of injury.
-To clear the invading organism/agents and begin the process
of healing.

Chronic Inflammation-Features
Onset- insidious, Longer duration (days to years)
Lymphocytes ,macrophages ,plasma cells
Vascular proliferation & fibrosis (scarring)
 Signs of acute inflammation

1. Rubor (redness)
2. Calor (heat)
3. Tumor (swelling)
4. Dolor (pain)
5. Functio lasea (loss of function)
 Inflammation
The basis of the five cardinal signs

 .
Increased blood flow- due to vascular dilatation/ redness and heat.

Increased vascular permeability- oedema and swelling.

Chemical mediators-release stimulate sensory nerve - pain.

Nerves also stimulated by stretching from oedema.

Chronic pain and swelling result in loss of function

 Response-Inflammation
 Recognition of injurious agent- Neutrophil

 Recruitment of leukocytes- Chemotaxis

 Removal of agent- Killing and Phagocytosis

 Regulation of response

 Resolution –repair and healing

 Chronic inflammation- fibrosis and Scar

 Acute Inflammation- Causes

 Physical & chemical agents

 Tissue necrosis- Hypoxia/ Ischemia (MI)
 Foreign bodies - suture
 Immune reaction- Hypersensitivity/ autoimmune rxn
 Infection- agents: Virus, bacteria
 Trauma
e.g: chronic diseases: asthma, allergy or hay fever, diabetes, etc.

Chronic conditions often worsen as result of aging process,

environment, and impared- inflammation process

Serous Transudates - serum fluid that passes through membrane or

tissue

-Due to increased hydrostatic or decreased osmotic pressure in

vascular system

- pulmonary edema - fluid filling lungs,- CHF

Serous Exudates

Blisters associated with sun burn

Associated with CVD
 Purulent exudate:
-pyogenic; inflammation with pus is called suppurative
-Abscesses, boils, * styes
a red, sore lump near the edge of the eyelid.

Inflammatory-Lesion: Abscess- localized spherical lesion filled

with pus and pyogenic bacteria (usually stphylococci)
 Cellulitis.. – spreading, diffuse infection most commonly
involving strepto infection of subcut- tissues
- hemolytic streptococcus, Streptococcus
pneumoniae
-body is unable to confine infection to localized
area - characterized by congestion and edema

 Inflammatory reactions- result in production of lesion

 Inflammation

Cellular Mediators Vascular

Changes Histamine changes

Leukocyte Vasodilation
migration
Components Involved
1. Vascular changes:
 Vasodilatation: change in vessel
 Structural changes: increased vascular permeability-
flow of plasma proteins

2. Cellular events:
 Recruitment and emigration of leucocytes
 Accumulation at the site of injury

3. Chemical mediators: Redness, swelling, Pain

-Prostaglandins, Histamine, bradykinin
 Vascular changes
1. Initial transient –vasoconstriction

2. Followed by- vasodilatation mediated by histamine,

bradykinin/ PGs

3. Increased -vascular permeability- Neutrophil

4. Stasis- slow of blood flow, due to increased viscosity, allows

neutrophils to marginate.
Increased vascular permeability

 Arteriolar vasodilation and increased blood flow - rise in

intravascular hydrostatic pressure, resulting in movement of
fluid from capillaries into the tissues.

 called a Transudate, is essentially an ultrafiltrate of blood

plasma and contains little protein.
Increased vascular permeability.

1. EC- contraction and retraction

2. Endothelial injury -direct
3. Leukocyte dependent-EC injury
4. Increased transcytosis*
5. Blood vessels-leakage

* a process by which material is internalized in one region of a cell (apical

surface) and delivered via recycling endosomes to another portion
 Cellular events
Cellular Events: Leukocyte Recruitment and Activation

1. Leukocyte recruitment and extravasations

2. Chemotaxis and

3. Phagocytosis-Killing
 Leukocyte Recruitment

There are four steps

1:Margination: rolling, and adhesion

2. Diapedesis /transmigration- across endothelium)

3.Migration toward chemotactic stimulus - Chemotaxis

4. Phagocytosis and Killing

 Margination, Rolling and Adhesion

Margination : accumulation and adhesion of leukocytes to the epithelial cells

of blood vessel walls

They stick to the walls and roll along them until they become firmly attached
to the vessel wall

Rolling-Neutrophils weakly bind to the activated Ecs –as increased expression

of selectins protein (E-selectin and P-selectin.)
and tumble along the surface of EC
Leukocytes tumble on endothelial surface, transiently sticking
along the way

Mediated by SELECTIN family of adhesion molecules

Followed by tight adhesion by-Integrins

 Leukocyte activation followed by
 Neutrophils are stimulated by chemotactic agents-chemokines
and C5a -to express their integrins

 Activated by chemokines and cytokines-TNF and IL-1 activate

EC to ↑ expression of ligands for integrins
Adhesion molecules: 3 families

 Selectins: (P, L and E-Selectin)

 Integrins: VLA-4, LFA-1, Mac-1

ADHESION
Immunoglobulins
 ICAM-1 : intercellular adhesion molecule-1
 VCAM-1: vascular cell adhesion molecule-1.
 PECAM-1: platelet endothelial cell adhesion molecule-1
 Step 4: Adhesion
 Firm attachment of leukocytes to the EC

-mediated by complementary adhesion molecules

 binding of the integrins firmly adheres the neutrophil

to EC.
Transmigrations/ DIAPEDESIS
 Leukocytes migrate thr’u vessel wall by squeezing b/w cells at IC
junctions of EC

 Interaction of platelet endothelial cell adhesion molecule 1 on

leukocytes and EC mediates- transmigration b/w cells.
 Chemotaxis
- the movement of cells toward a chemical mediator-
released at the site of inflammation.

Important chemotactic factors for neutrophils

 Bacterial products
 Leukotrine B4 (LTB4)
 Complement system products- C3a, C5a
 Chemokines/cytokines- IL-8
Phagocytosis
Three steps:
1. Recognition (Opsonin) and attachment

2. Engulfment-subsequent formation of a
phagocytic vacuole.

3. Killing and degradation of the ingested

material
 Recognition and attachment

 Facilitated by OPSONINS.
 Opsonins enhance recognition and phagocytosis of
bacteria
 Important opsonins
1. IgG
2. C3b
3. Plasma protein–Collectins -bind to bacterial cell
 Engulfment
 Binding of opsonised particle triggers engulfment.

 Neutrophil sends out cytoplasmic processes that surround the

bacteria.

 The bacteria are internalized within a phagosome

 The phagosome fuses with lysosome -phagolysosome.

 Release of lysosomal contents-degranulation.

The final step is -Intracellular killing

 Oxygen dependent killing

 Oxygen independent killing

 When a phagocyte ingests bacteria/material, its oxygen consumption

increases.
- respiratory burst/Oxidative Burst, produces –ROS,: i.e superoxide,
hydroxyl radicals, and hydrogen peroxide.

-Myeloperoxidase-enzyme from neutrophil granules.

-Requires hydrogen peroxide and Halide (CL-)
-Produces HOCL (hypochlorous acid)
Oxygen independent killing

 Lysozyme: proteolytic- break down the bacterial cell wall

 Lactoferrin- remove essential iron from bacteria-present in neutrophil

 Hydrolytic enzymes: used to digest the proteins of destroyed

bacteria.

 Defensins: host defense peptides - assists in killing phagocytosed

bacteria.
Summary: Phagocytosis -process
Defects in adhesion

Defects in leukocyte function

 Leukocyte adhesion deficiency

-LAD-1 and LAD-2
-Recurrent bacterial infections
 Diabetes mellitus
 Corticosteroid use
 Acute alcohol intoxication
frustrated phagocytosis

If cells encounter materials that cannot be easily ingested,

such as immune complexes deposited on immovable flat
surfaces (e.g., glomerular basement membrane), the
attempt to phagocytose these substances is not successful.
 Defects in phagocytosis
Chediak-Higashi syndrome: a rare autosomal recessive
lysosomal disorder characterized by frequent infections,
oculocutaneous albinism , bleeding diathesis, and progressive
neurologic deterioration.
 Autosomal recessive condition

 Neutrophils have giant lysosomes, Neutropenia,

 Defects in degranulation.

immune deficiency with an increased susceptibility to infections, and

a tendency to bruise and bleed easily.
Contd….

 rare autosomal recessive disorder that arises from a mutation

of a lysosomal trafficking regulator protein, which leads to a
decrease in phagocytosis.

.
The decrease in phagocytosis results in recurrent pyogenic
infections, peripheral neuropathy etc
 Cell Injury-Mediators

Plasma-
derived
Cell –derived:
Synthesized
Preformed

Fact-XII, C3a/C5a
Histamine PGs,LTs,P
,5-HT AF, IL-
1,ROS
Inflammation/Pain
 Cell Injury-Phospholipids

NSAIDS LOX-: Zileuton,

NSAIDs
Monterlukast
Arachidonic
Diclofenac Acid
Sod
X

COX X COX- LOX

Aspirin,PCM

PGG2: PGI2, LTB4, LTC4

PGD2 TXA2 /LTD4

Vaso-
Bronchocon
sriction

Cyclooxygenase X Inflammation/Pain