Inflammation Acute vs Chronic Mediators

1. Inflammation
Ashish Patil, M.D., Ph.D.

2. Inflammation
 Inflammation is a 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(Robins and Cotran; 7th ed.)

3. History
 Egyptian papyrus (3000 BC)
 Celsus (1st century AD) – 4 cardinal
signs of
 inflammation
 Virchow – fifth clinical sign i.e. functio
laesa
 John Hunter (1973)– inflammation is not
a disease but a non-specific response that
has a salutary effect on its host.

4. Inflammation
 Inflammation is the body's normal response
to injuries or infections. Cells of the
immune system travel to the site of injury or
infection and cause inflammation.

5. Players of Inflammation
 Circulating cells
 Circulating proteins
 Connective tissue cells
 Extracellular matrix

6. Players of Inflammation
Circulating cells
 Neutrophils
 Eosinophils and
Basophils
 Lymphocytes and
Monocytes
 Platelets
Circulating Proteins :
 Clotting Factors
 Kininogens
 Complement
components

7. Players of Inflammation
Connective tissue cells
 Mast cells
 Macrophages
 Lymphocytes
 Fibroblast
Extra cellular Matrix :
 Fibrous
StructuralProteins
(e.g. Collagen &
Elastin)
 Gel forming
proteoglycans
 Adhesive
glycoprotein
 (e.g. Fibronectin)

8. Inflammation is divided into
two basic patterns:
 Acute Inflammation
 Chronic Inflammation

9. Inflammation is divided into
two basic patterns:
 Acute Inflammation : It is the immediate
and early response to injury, designed to
deliver leukocytes to the site of injury.
 Chronic Inflammation : It is considered to
be inflammation of prolonged duration
(weeks to months to years) in which active
inflammation, tissue injury and healing
proceed simultaneously.

10. Acute inflammation
 Acute Inflammation : It is the immediate
and early response to injury, designed to
deliver leukocytes to the site of injury.
 Characterized by 5 cardinal signs

11. Classical Signs of
Inflammation
 Heat (Calor)
 2. Redness (Rubor)
 3. Swelling (Tumor)
 4. Pain (Dolor)
 5. Loss of function (Functio laesa)
(Virchow)

12. Acute Inflammation
 STIMULI FOR ACUTE INFLAMMATION
 Infections (bacterial, viral, parasitic) and microbial
toxins
 Trauma (blunt and penetrating)
 Physical and chemical agents (thermal injury, e.g., burns
or
 frostbite; irradiation; some environmental chemicals)
 Tissue necrosis (from any cause)
 Foreign bodies (splinters, dirt, sutures)
 Immune reactions (also called hypersensitivity reactions)

13. Acute inflammation has
three main components:
 Vascular Component
 Cellular Cellular Component
 Mediator Component

14. Acute inflammation
(Vascular Componet)
 Vascular Changes :
Alteration in the vessel
caliber resulting in
increased blood flow
(vasodilation) and
structural changes that
permits plasma
proteins to leave
circulation (increased
vascular permeability).

15. Vascular changes & fluid leakage during
acute inflammation lead to edema in a
process called as exudation

16. Increased Vascular
Permeability

17. Increased Vascular
Permeability

18. Increased Vascular
Permeability

19. Increased Vascular
Permeability

20. Exudate vs Transudate

21. The vascular changes during early phase of
acute inflammation (Triple Response)

24. Acute inflammation has
three main components:
 Vascular
 Cellular
 Mediator

25. Acute inflammation Cellular
Event:
 Cellular Events : Emigration of leukocytes from
the microcirculation and accumulation in the focus
of injury (cell recruitment and activation).

26. Cellular Events of Acute
Inflammation

27. Cellular events
 Margination
 Rolling
 Adhesion
 Transmigration

28. Cellular events

29. Chemotaxis and Activation
 After extravasating from the blood,
leukocytes migrate toward sites of injury
along a chemical gradient in a process
called chemotaxis.

30. Chemotaxis and Activation
 Both exogenous and endogenous substances can be
chemotactic for leukocytes.
 Soluble bacterial products : N-formylmethionine
termini.
 Components of complement system : C5a
 Products of lipoxygenase pathway : leukotriene B4
 Cytokines : IL-1, IL-8

31. Antimicrobial mechanisms of
neutrophils.
 Phagocytosis involves the ingestion of
the microorganism into a phagocytic
vacuole that upon maturation becomes a
phagolysosome. In this new organelle,
the microorganism is destroyed by the
action of low pH, and degrading
enzymes. Neutrophils also degranulate
and release to their environment the
contents of their granules. When the
microorganism is too large to be
ingested, neutrophil can also produce
extracellular traps (NETs) formed by
DNA fibers and proteins from the
granules

32. Phagocytosis and Degranulation
 Phagocytosis and the elaboration of degradative enzyme
are two major benefits of having recruited leukocytes at the
site of inflammation.
 Phagocytosis consists of three distinct but interrelated
steps:
1. Recognition and attachment of the particle to the ingesting
leukocyte.
2. Engulfment with subsequent formation of a phagocytic
vacuole
3. Killing and degradation of the ingested material.

33. Phagocytosis and Degranulation

34. Mediators of Acute inflammation

35. Coagulation Cascade

36. Coagulation Cascade

37. Plasma proteins– Kinin
system
Hypotension
Bronchoconstriction
Vascul;ar permeability
Edema

38. Plasma proteins– Kinin
system

39. Plasma Proteins Complement
System

40. Plasma Proteins Complement
System

46. Plasma Proteins Complement
System

50. The coagulation cascade is a starting point for both the
kallikrein-kinin system (KKS) and the complement
system. Activation is indicated by solid arrows and
inhibition by dotted arrows
Cardiovasc Hematol Agents Med Chem. 2009 Jul; 7(3): 234–250.

51. Outcomes of acute inflammation

52. Outcomes of acute inflammation
 1. resolution - restoration to normal, limited injury
– chemical substances neutralization
– normalization of vasc. permeability
– apoptosis of inflammatory cells
– lymphatic drainage
 2. healing by scar
– tissue destruction
– fibrinous inflammtion
– purulent infl.  abscess formation (pus, pyogenic
membrane, resorption - pseudoxanthoma cells - weeks
to months)
 3. progression into chronic inflammation

53. Abscess
 A localized collection of pus (suppurative
inflammation) appearing in an acute or
chronic infection, and associated with tissue
destruction, and swelling.
 Pathogenesis: the necrotic tissue is
surrounded by pyogenic membrane, which
is formed by fibrin and help in localize the
infection.

54. Abscess
Apoptosis of neutrophils
Release of Lysosomal Enzymes
Liquefactive Necrosis
Pus

55. Chronic inflammation
 Inflammation of prolonged duration (weeks
or months) in which active inflammation,
tissue destruction, and attempts at repair are
proceeding simultaneously

56. Chronic inflammation
 Reasons:
– persisting infection or prolonged exposure to
irritants (intracell. surviving of agents - TBC)
– repeated acute inflamations (otitis, rhinitis)
– primary chronic inflammation - low virulence,
sterile inflammations (silicosis)
– autoimmune reactions (rheumatoid arthritis,
glomerulonephritis, multiple sclerosis)

63. Chronic inflammation
 Chronic inflammatory cells ("round cell"
infiltrate)
– lymphocytes
– plasma cells
– monocytes/macrophages
 lymphocytes  plasma cells, cytotoxic (NK)
cells, coordination with other parts of immune
system
 plasma cells - production of Ig
 monocytes-macrophages-specialized cells
(siderophages, gitter cells, mucophages)

69. Granulomatous inflammation
 Distinctive chronic inflammation type
 Cell mediated immune reaction (delayed)
 aggregates of activated macrophages 
epithelioid cell  multinucleated giant cells
(of Langhans type x of foreign body type)
 NO agent elimination but walling off
 Intracellular agents (TBC)

71. Granulomatous inflammation
 1. Bacteria
– TBC
– leprosy
– syphilis (3rd stage)
 2. Parasites + Fungi
 3. Inorganic metals or dust
– silicosis
– berylliosis
 4. Foreign body
– suture (Schloffer „tumor“), breast prosthesis
 5. Unknown - sarcoidosis

75. Local Vs Systemic Effects of
Inflammation

78. Morphologic patterns of
inflammation
1. Serous
2. Fibrinous
3. Suppurative
4. Pseudomembranous
5. Ulceration


79. Morphologic patterns of
inflammation
 Serous - excessive
accumulation of fluid,
few proteins - skin
blister, serous
membranes - initial
phases of inflamm.

80. Morphologic patterns of
inflammation
 Fibrinous - higher
vascular permeability -
exudation of
fibrinogen -> fibrin -
e.g. pericarditis (cor
villosum, cor hirsutum
- "hairy" heart
 fibrinolysis 
resolution;
organization 
fibrosis  scar

81.  Suppurative (purulent) - accumulation of
neutrophillic leucocytes - formation of pus
(pyogenic bacteria)
 Interstitial
– Phlegmone (cellulitis) – diffuse soft tissue
– Abscess - localized collection
 acute – border – surrounding tissue
 chronic – border - pyogenic membrane
 Formation of suppurative fistule
 Accumulation of pus in preformed cavities -
empyema (thoracic)
Morphologic patterns of
inflammation

82.  Pseudomembraneous Inflammation
 Very severe ulcerative inflammation of mucous
membranes
 Extensive Necrosis of surface epithelium
 Severe acute Inflammation of underlying tissue
 Pseudo membrane, consisting of exudate, fibrin,
neutrophils RBC, Bacteria and tissue debris
 e.g. Diphtheria – Larynx .
 pseudomembraneous Colitis –clostridium difficile
Morphologic patterns of
inflammation

83. Pseudomembranous Collitis

84.  Ulceration - inflammatory necrosis of the surface -
ulcer (skin, gastric)
Morphologic patterns of
inflammation

85. Complication of suppurative
infection
 Bacteremia (no clinical symptoms!; danger of
formation of secondary foci of inflammation
(endocarditis, meningitis)
 Thrombophlebitis - secondary inflammation of
wall of the vein with subsequent thrombosis -
embolization - pyemia - hematogenous abscesses
(infected infarctions)
 Lymphangiitis, lymphadenitis
 SEPSIS: life-threatening organ dysfunction
caused by dysregulated host response to
infection

86. SIRS & Sepsis
 Systemic inflammatory response syndrome
 (SIRS) is the clinical expression of the
action of complex intrinsic mediators of the
acute phase reaction.
 SIRS can be precipitated by events such
as infection, trauma, pancreatitis, and
surgery.

87. SIRS & Sepsis

88. SIRS & Sepsis

89. Wound Healing

91. Types of wound healing

96. Why Aspirin causes bleeding and selective
COX-2 inhibitor causes blood clot

98. Thank You