INFLAMMATION

Contents:

History

Signs

Acute and Chronic Inflammation

Mechanisms of Inflammation

Chemical mediators

References

Complex reaction to injurious agents such as microbes and damaged usually necrotic cells that consists
of vascular responses, migration and activation of leukocytes and systemic reactions.

Reaction of vascularised living tissues to local injury.

Sequence of specific physiological behaviors that occur in response to a nonspecific agent

It is fundamentally a protective response, the ultimate goal of which is to rid the organism of both the
initial cause of cell injury and its consequences

3 Lines Of Defence

History

Inflammation has a rich & ancient history, intimately linked to the history of wars, wounds, & infections.

CORNELIUS CELSUS, a roman writer of 1st century A.D, described the 4 cardinal signs of inflammation :
RUBOR, TUMOR, CALOR & DOLOR (redness, swelling, heat & pain).

To these a fifth sign functio laesa (loss of function) was added by Virchow.

SIR THOMAS LEWIS : on the basis of simple experiments involving the inflammatory response in skin,
established the concept that chemical substances, locally induced by injury, mediate the vascular
changes of inflammation. Lewis experiment induced the changes in the skin of inner aspect of forearm
by firm stroking with a blunt point.

The reaction so elicited is known as TRIPLE RESPONSE or REDLINE RESPONSE consisting of following:

 Redline appears within a few seconds following stroking & results from local vasodilation of
capillaries & venules.
  Flare is the bright reddish appearance or flush surrounding the redline & results from
vasodilation of adjacent arterioles.

 Wheal is the swelling or edema of the surrounding skin occurring due to transudation of fluid
into the extravascular spaces.

Levis Experiment

Types Of Inflammation

Acute : Short term response

Involves:

- Hemodynamic changes

- Exudate formation

- Presence of granular leukocytes

Chronic : Persistant

Involves:

- Presence of nongranular leukocytes

- Results in more extensive scar formation.

VASCULAR EVENTS DURING INFLAMMATION

Transient vasoconstriction of arterioles(3 – 5 secs)

Persistent progressive vasodilation: involves mainly the arterioles.

Results in increased blood volume in microvascular bed resulting in edema.

Slowing or Stasis: due to increase permeability of microvasculature resulting in increased concentration

of RBCs leading to increased blood viscosity.

Peripheral orientation of leucocytes (esp. neutrophils) along vascular endothelium – margination

CHANGES IN VASCULAR PERMEABILITY:

 3 patterns:

1. Immediate transient response:(15-30mins) elicited by histamine & other chemical mediators &
by mild injury
 2. Immediate sustained response: in severe injuries associated with necrosis of endothelial cells.
Remains for several hours to days, all micro circulation is affected.

3. Delayed prolonged leakage:

It occurs after delay lasts for several hours/days. Mainly Venules & capillaries are involved.

CELLULAR EVENTS

MARGINATION

ADHESION

EMMIGRATION

PHAGOCYTOSIS

EXTRACELLULAR RELEASE OF LEUCOCYTE PRODUCTS

MARGINATION:

Slowing & stagnation of normal blood flow, white

cells come in contact with endothelium.

The cells first tumble slowly along the walls of capillaries & venules.

In time endothelium appears to be virtually

lined by such cells - PAVEMENTING

ADHESION:

White cells following margination adhere in great number to the endothelial surface.

Although a number of factors may influence adhesion. Recent advances show that increased leukocytes
adhesion in inflammation involves specific interaction between complementary `adhesion molecules`
present on leukocyte & endothelial surfaces.

Emigration

Emigration refers to process by which motile white cells escape from the blood vessels to the vascular
tissues. All leukocytes use the same pathway- called as Diapedesis

The leukocytes crawl along the endothelial surface ,insert large pseudo pods into the junction and
assume position b/w endothelial cells and basement membrane.
Red cells may also leave in severe injuries.

CHEMOTAXIS:

Is defined as the unidirectional migration of cells toward the attractant.

Both exogenous & endogenous substances can act as attractants.

Chemotactic factors of neutrophils are

Bacterial products.

PHAGOCYTOSIS:

IT INVOLVES 3 DISTINCT BUT INTER RELATED STEPS.

Recognition & attachment:

Most organisms are recognized when they are coated with opsonins.

ENGULFMENT:

Once the phagocyte recognizes the foreign particle engulfment occurs.

During engulfment there is extension of pseudopods around the opsonized particle to form the
phagocytic vacuole.

Lysosome of the cell fuses with this vacuole to form phagolysosome or phagosome.

Degranulation

Neutrophils & monocytes get progressively degranulated, during which there is some leakage of
hydrolytic enzymes and metabolic products into the external medium.

KILLING / DEGRADATION:

Undergoes by 2 processes.

1. O2 dependent bactericidal mechanism

The generation of O2 metabolite is attributable to the rapid activation of an NADPH OXIDASE

Which oxidizes NADPH & reduces O2 to superoxide ion.

These superoxide converts into H2O2 which has bactericidal properties through-

Myeloperoxidase dependent killing

Myeloperoxidase independent killing

2. O2 independent mechanism

Agents released from granules of phagocytic cells do not require oxygen for bactericidal activity.

Includes:

Lysosomal hydrolases

Permeability increasing factors

Defensins

Cationic proteins

Chemical Mediators Of Inflammation

Vasoactive amines

Histamine:

stored in granules of mast cells,basophils and platelets

Action is vasodilation,increased vascular permeability,itching and pain.

5-Hydroxytryptamine:

Present in chromaffin cells of GIT,spleen,nervous tissue,mast cells and platelets

Action -Incresed vascular permeability and vasodilation.

Arachidonic acid metabolites

Fatty acid

Sources –directly from diet

Conversion of essential fatty acid ,linoleic acid into arachidonic acid

Via COX pathway

COX is a fatty acid enzyme which acts on activated arachidonic acid to form prostaglandin
endoperoxide(PGG2).

It results in formation of 3 metabolites-

Prostaglandins

Thromboxane A2

Prostacyclins(PGI2)
Prostaglandins(PGD2, PGE2, PGF2)

Increased venular permeability

Vasodilation

Bronchodilation

PGF2 causes bronchoconstriction.

Thromboxane A2

Vasoconstrictor

Bronchoconstriction

Platelet aggregation

Prostacyclins

Vasodilation

Bronchodilation

Anti aggregating agent for platelets

Via LOX pathway

Enzyme LOX acts on activated arachidonic acid to form 5-HPETE (hydroperoxy eico-satetraenoic acid).

Further peroxidation of 5-HPETE,forms

5-HETE- chemotaxis

Leucotrienes –vasoconstriction, bronchoconstriction

Incresed vascular permeability.

Lysosomal components

Inflammatory cells such as neutrophils and monocytes have lysosomal granules which on release
elaborate a variety of mediators of inflammation.

Granules of neutrophils

Granules of monocytes and tissue macrophages

Also release acid proteases, collagenases, elastase and plasminogen activator

More active in chronic inflammation

Released from IgE sensitised basophils or mast cells, leucocytes , endothelium and platelets

Actions

increased vascular permeability,

vasodilation in low conc.

Vasoconstriction in high conc.

Bronchoconstriction

Adhesion of leucocytes to endothelium

chemotaxis

Cytokines

Polypeptides

Produced by lymphocytes (lymphokines)

and activated monocytes (monokines)

May act on self cells producing them or other cells

Actions of cytokines

IL-1 and TNF-a, TNF-B

Increased leucocyte adherence, thrombogenicity, elaboration of other cytokines, fibroblastic

proliferation.

IF-gamma-

activation of macrophages & neutrophils,synthesisof nitric acid synthase.

Chemokines

chemotaxis

NO & O2 metabolites

Nitric oxide

Vascular realxation factor produced by endothelial cells.

Actions –vasodilation, anti-platelet activating factor, microbicidal

Oxygen derived metabolites

Superoxide oxygen,H2O2,OH’,and toxic NO products

Endothelial damage resulting in increased vascular permeability

Tissue matrix damage

Damage to other cells.

Plasma derived mediators

4 interlinked sysytems-

Kinin

Clotting

Fibrinolytic

Complement

Hageman factor (factorXII) of clotting system plays a key role in interaction of these 4 systems.

Activation of this factor is brought about by contact of this factor leaking through the endothelial gaps.

Kinin system

Plasma prekallikrein kallikrein

Prekallikrein activator

High molecular wt kininogen

kallikrein

Bradykinin(smooth muscle contraction, vasodialtion, increased vascular permeability,pain)

Clotting system

Factor XII thrombin

Fibrinogen

thrombin

fibrin, fibrinopeptide (vascular permeability, chemotaxis, anticoagulant activity)

Fibrinolytic system
Plasminogen (from kallikrein, endothelial cells and leucocytes)

Plasmin

 Activates XII to form prekallikrein activator

 Forms C3a from C3 which is a permeability factor

 Degardes fibrin to form fibrin split products which increas vascular permeability and are
chemotactic

Complement system

Activation occurs by classic pathway through antigen antibody complexes

Alternate pathway via non immunogenic agents such as bacterial toxins, cobra venoms and IgA.

Yields-C3a,C4a,C5a

Actions-release of histamine, vascular permeability, phagocytosis, chemotaxis

Chronic inflammation

Prolonged process in which tissue destruction and inflammation occurs at the same time.

General features of chronic inflammation

Types of chronic inflammation

Granulomatous inflammation

Definition :

A circumscribed ,tiny lesion about 1 mm in diameter, composed predominantly of collection of modified

macrophages called epithelioid cells and rimmed at the periphery by lymphoid cells.

Altered Inflammatory Response

References :

1. ROBBINS PATHOLOGIC BASIS OF DISEASE- 7TH ED.

2. TEXTBOOK OF MEDICAL PHYSIOLOGY- GUYTON

3. PATHOLOGY FOR DENTAL STUDENTS – HARSH MOHAN,4 TH EDITION