INFLAMMATION

Overview
 For successful survival, it is imperative that organisms are
able to deal with injurious stimuli.
 In higher animals, response to injury is complex and
involves both local and systemic reactions.
 Systemic response is both neural and humoral in nature. It
produces a variety of metabolic alteration that are seen
after any injury.
 Local responses consist of changes that allow different
fighters of the body to reach the site of injury.
 Both local and systemic responses continue as long as
tissue damage is taking place. This helps in overcoming the
harmful stimulus. It also facilitates removal of the detritus
that is the product of this conflict.
 Definition of Inflammation
 Definition 1: It is the reaction of the vascular
and supporting elements of a tissue to injury.
It results in formation of protein rich exudate,
provided the injury is not severe enough to
destroy the area.
 Definition 2: It is the response of vascularized
connective tissue to injurious stimulus
Significance of Inflammatory Response
Advantages:
 It destroys or limits the growth of offending
microbes.

 It isolates the injured area.

 It inactivates toxic substances that are

produced during the inflammatory response.

 It prepares the damaged area for

subsequent healing and repair.
Significance of Inflammatory Response
Disadvantages:
 It produces pain and swelling and thus disability.
 It may result in rupture of a viscus or a large vessel.
 Excessive scar tissue can form. This produces
contractures, adhesions and keloids.
 Fistula formation can occur.
 Inflammatory detritus can itself propagate the
inflammatory response.
 An inappropriate immune response can produce several
acute and chronic diseases.
 Abscess formation can act as a space occupying lesion.
 Inflammation is responsible for diseases like
atherosclerosis, MI and neuro-degenerative disorders.
 Different types of Inflammatory Responses
 Acute Inflammation: It is of shorter duration-
measured in hours or few days. It is
characterized by presence of exudation that
produces edema. Emigrating cells are mainly
neutrophil leukocytes.
 Chronic Inflammation: It is of longer duration-
measured in days or even years. Emigrating
cells are mainly mononuclear leukocytes. In
addition features of repair are an important
constituent of chronic inflammation.
Cardinal Signs of Inflammation

 Redness (rubor): occurs due to vascular

dilatation.
 Heat (calor): occurs due to hyperemia in the
affected part.
 Swelling (tumor): Due to edema and
collection of cells.
 Pain (dolor): due to release of factors like
bradykinin and PGs
 Loss of function (functio leasa)
Clinical appearance of Inflamed tissue
Acute Inflammation
Apthous Ulcer showing features of Acute Inflammation
Apthous Ulcer showing features of Acute Inflammation
Inflamed Pharynx
Naked eye appearance of early acute inflammation
Pyogenic Granuloma
Acute Peritonitis
Acute Appendicitis
Acute Peritonitis
Acute Pyelonephritis
 Certain Definitions
 Exudate: It is escape of fluid, proteins and blood cells from
vascular system into interstitial tissue or body cavities. It has high
protein concentration (SG > 1.018). Exudation occurs because of
change in vascular permeability.
 Transudate: It is escape of fluid from vascular system into
interstitial tissue or body cavities due to increased hydrostatic
pressure. Its protein content is lower (SG < than 1.012).
 Edema: It is presence of excessive fluid in interstitial tissues or
body cavities. Nature of fluid can be either exudate or transudate.
 Pus: It is the form of inflammatory exudate that is rich in
leukocytes and cell debris.
 Opsonins: Factors in plasma that enhance phagocytosis.

(Sir Almorth Wright following up one of Metchenikoff’s most suggestive biological

romances, discovered that the white blood corpuscles or phagocytes which attack and
devour disease germs for us, do their work only when we butter the disease germs
appetizingly for them with a natural sauce which is named opsonin - Sir Bernard Shaw)
Characteristics of Acute Inflammation
Vascular Events:
 Changes in vascular caliber and flow.
 Increased vascular permeability and formation of
fluid exudate.
Cellular Events
 Leukocyte adhesion and transmigration
 Chemotaxis
 Leukocyte activation
 Phagocytosis
 Release of leukocyte products with resultant
tissue injury
Vascular Events in Acute Inflammation

Initial Vasoconstriction Arteriolar dilatation

Due to action of histamine
Due to the action of
histamine and leukotrienes

Fluid Exudation Increased Vascular Permeability

Due to endothelial cell

retraction/damage
Vascular Dilatation
Ultrafiltration of fluid
 Cellular Events in Acute Inflammation
 Margination and rolling of Neutrophils
 Adhesion and pavementing of neutrophils
 Neutrophil emigration/diapedesis
 Chemotaxis
 Leukocyte activation
 Phagocytosis
 Release of leukocyte products and leukocyte
induced tissue injury.
Neutrophil Emigration
Diagrammatic representation of Leukocyte
Adhesion and Transmigration
Diagrammatic representation of Chemotaxis
Inflammatory Exudate on the surface
of Colon
Purulent exudate over surface of the brain
Appendix showing vascular congestion and emigration of neutrophils
Emigrated neutrophils in alveoli of Lung
Emigrated neutrophils in alveoli of Lung
Neutrophils collecting in between
cardiac muscle fibers
Colon showing mucosal erosion and collection of
fibrinoid exudate on the surface
 Events of Acute Inflammation – Some Salient
Features
 Pavementing is induced due to increased expression of adhesion
molecules, a process enhanced by C5a, LKB4 and TNF.

 Adhesion molecules belong to the family of selectins, integrins,

immunoglobulin superfamily and mucin like glycoproteins.

 Diapedesis is coordinated by chemokines. Chemotaxis is regulated

by chemokines and other factors like bacterial products,
complement components and leukotrienes.

 Genetic disorders of adhesion molecules can increase

susceptibility to bacterial infections.

 On reaching the site of injury, leukocytes are activated, a process

induced by chemotactic factors, Ag:Ab complexes and product of
bacteria. Activated leukocytes produce AA metabolites, release
lysosomal enzymes and secrete various cytokines.
 Phagocytosis
 Process of phagocytosis involves: recognition, engulfment, killing
and degradation of the offending agent.

 Recognition is carried out with the help of mannose and

scavenger receptors present on the surface of phagocytes.

 Phagocytosis is enhanced when microbes are opsonized.

 Microbe is taken up in the phagosome that fuses with lysosome to

form phagolysosome.

 Killing of microbes involves generation of ROS. In addition

H20:MPO system generates HOCL. These are very potent
microbicidal substances.
Gram stain to show phagocytosis of bacteria by
neutrophils
 Macroscopic appearance of Acute Inflammation
 Serous inflammation: when there is elaboration of plenty of thin
watery fluid. E.g. blister formation.
 Catarrhal inflammation: When there is excessive mucus production.
Also called phlegmonous inflammation.
 Fibrinous inflammation: If injury produces large vascular gaps, bigger
molecules like fibrinogen leak our. They polymerize to form fibrin .
 Suppurative inflammation: Presence of large number of dead
neutrophils and necrotic debris produces purulent inflammation.
 Cellulitis: When thin watery exudate produced during inflammation
spreads widely into subcutaneous tissue.
 Pseudo-membranous inflammation: A membrane of necrotic material
admixed with fibrin is formed over the surface of the diseased organ.
 Gangrenous inflammation: when edematous tissue is under high
tension, it may produce vascular occlusion and infarct.
 Outcome of Acute Inflammation
 Complete resolution: If injury is of short duration and of limited
intensity, tissue destruction may be minimal. In this situation,
tissue regeneration with complete restoration to normalcy is
possible.

 Organization: When there is substantial tissue destruction, it cannot

regenerate fully. As plenty of granulation tissue is formed, fibrosis
is substantial. Similarly, fibrinous exudate also heals by the process
of organization.

 Suppuration: Pyogenic organisms, certain chemicals and certain

other factors invite massive collection of exudate and neutrophils.
Product of neutrophil liquefy contents of the exudate and produce
pus.

 Chronic inflammation: If the injurious stimulus is persistent or there

is interference with the normal process of healing, chronic
inflammation may be produced.
Organizing Pneumonia
Liver Abscess
Abscess formation in liver
Lung Abscess
Brain Abscess
Chronic Inflammation in Kidney showing fibrosis
Keloid
Keloid Formation
Contracture
 Chemical Mediators of Inflammation
Different events during inflammation are
regulated by certain chemicals called CMOI.
Properties of CMOI are as follows:
• They are present either in plasma or in different cells. Those present
in plasma are synthesized in liver and secreted.
• Majority of cell derived CMOIs are synthesized in response to injury,
except for some pre-formed mediators like histamine, serotonin and
lysosomal enzymes.
• CMOIs act by binding to specific receptors. Some have enzymatic
properties.
• Many CMOIs act as opsonins.
• Majority of CMOIs have a short half-life. If not inactivated timely, they
can be potentially harmful.
 Chemical Mediators of Inflammation
 Vasoactive amines: Histamine and serotonin
 Plasma proteases: Complement system, kinin
system, clotting system
 Arachidonic acid metabolites: PGs, leukotrienes
and lipoxins
 Platelet activating factor
 Cytokines and Chemokines
 Nitric Oxide
 Lysosomal enzymes of leukocytes.
 Oxygen derived free radicals.
 Neuropeptides
 Action of Various CMOIs
Histamine
 It is derived chiefly from granules of mast cells and
basophils

 Action: vasodilatation and increased vascular permeability.

Serotonin
 It is derived from platelets. Its role in humans is not well
defined
 Actions: Similar to histamine
Kinin System
 Bradykinin is produced by the action of kallikrein on high
molecular weight kininogen
 Action: Pain, smooth muscle contraction, vasodilatation and
increased vascular permeability
 Action of Various CMOIs (cont.)
Complement System
 They are a group of plasma proteins derived from liver and labeled
as C1 to C9.
 They circulate in plasma as inactive precursors. Their activation
occurs in a cascading manner, similar to what is seen in activation of
coagulation cascade.
 Critical event in activation of this system is formation of C3 cleavage
products.
 C3 cleavage can occur by three pathways
– Classical pathway
– Alternate pathway
– Lectin pathway
 Action: Microbial lysis, promotion of phagocytosis, vascular
dilatation, increased vascular permeability.
 Excess complement activity is prevented by natural inhibitors like
DAF and C1INH. Absence of these inhibitors is responsible for
diseases like PNH and hereditary angioneurotic edema.
Complement System
 Action of Various CMOIs (cont.)
Arachidonic Acid Metabolites
 AA is a constituent of cell membranes. It is derived either
from dietary sources or synthesized within body from
linoleic acid.
 Perturbation of cell membranes by injury releases AA,
which is metabolized further by either of the following
pathways:
• Cyclooxygeneae pathway: PGs and thromboxanes are formed.
• Lipooxygenase pathway: Leukotrienes and lipoxins are
produced.
 PGs have following pro-inflammatory properties:
• PGD2, PGE2, and PG2α produces vasodilatation.
• PGI2 increases vascular permeability.
• PGE2 produces pain
 Leukotrienes produce following effects:
• LTB4 is a potent chemotactic agent. It also enhances leukocyte
adhesion.
• LTC4, LTD4 and LTE4 cause bronchospasm and increse vascular
permeability.
 Action of Various CMOIs (cont.)
Platelet Activating Factor
• Variety of cells elaborate PAF, important amongst these are
mast cells, neutrophils, macrophages and endothelial cells.
• Action: Affects multiple steps of inflammation. It also
enhances synthesis of other CMOIs esp. eicosanoids.
Cytokines and Chemokines
• Activated macrophages produce IL-1 and TNFα. T cells
produce TNFß.they have following effects:
– Endothelial activation.
– Neutrophil priming
– Acute phase responses.
• Chemokines recruit leukocytes to the site of injury.
Nitric Oxide
• It is produced by endothelial cells, neurons and
macrophages.
• Action: It depresses mast cell activity and leukocyte
recruitment. It reacts with oxygen radicals to form
peroxynitrites that have potent anti-microbial effect.
 Action of Various CMOIs (cont.)
Clotting System
• Platelets, SMCs, ECS, and many other cell types express
receptors called protease activated receptors.
• When thrombin binds to PAR, these cells get activated.
Activated cells show increased expression of adhesion
molecules. Increased production of chemokines and AA
metabolites also takes place.
Lysosomal Enzymes of Leukocytes
• Lysosomes of neutrophils and monocytes contain acid and
neutral proteases, in addition to several other potent enzymes.
• Neutral proteases cleave C3 and activate the kinin system.
• Leakage of these enzymes outside of cell is responsible for
damaging normal tissues during inflammatory response.
Oxygen derived Free radicals
• Effect of free radicals apart from helping in destruction of
microorganisms is:
– Endothelial cell damage – this increases vascular permeability
– Inactivation of anti-proteases.
– Injury to normal cells
 Acute Phase Response
Acute phase response represents systemic
manifestations of acute inflammation. They are also
known as systemic inflammatory response syndrome
(SIRS). Its manifestations are as follows:
 Fever, rigor, chills
 Leukocytosis
 Raised level of acute phase proteins: CRP, Serum
amyloid A (SAA), fibrinogen and many others.
 Increased pulse and BP, anorexia, nausea, somnolence
and malaise.
 In some instances, septic shock and acute respiratory
distress syndrome.
 Events of Inflammation and Corresponding Mediators

Event Chemical Mediator

Vascular dilatation Histamine, PGE2 and PGI2, NO, PAF

Increased Vascular Transient Phase – histamine

Permeability Prolonged phase – bradykinin, NO, C5a, LTB4,
PAF

Fever IL-1 and PG

Pain PGs and bradykinin

Tissue damage ROS and lysosomal enzymes

Leukocyte adhesion IL-8, C5a, LTB4, PAF, IL-1 and TNFα

Chemotaxis and leukocyte C5a, chemokines, bacterial products and LTB4

adhesion