1. By
SROTA DAWN
M.PHARM(PHARMACOLOGY)
1ST YEAR ,2ND SEM
VELS SCHOOL OF PHARMACEUTICAL SCIENCES

2. • Inflammation –
Protective response intended to eliminate the initial
cause of cell injury and the necrotic cells and tissues
arising from the injury.
• Inflammation is intimately associated with the repair
process which includes parenchymal cell regeneration
and scarring

4. Acute Inflammation
• Acute - minutes to days
Chronic Inflammation
• Chronic - weeks to years
• Characterized by fluid and
protein exudation
• Lymphocytes and
macrophages
• PMN’s
• ACUTE Inf - PMN’s
(Polymorphonuclear Cells)
• Exudate SG > 1.020
• CHRONIC Inf Mononuclear Cells

5. Acute inflammation
“The immediate and early response to an
injurious agent”
Chronic inflammation
“Inflammation of prolonged duration (weeks
or
months)
in
which
active
inflammation,
tissue
destruction,
and
attempts
at
repair
are
proceeding
simultaneously“

6. Aims
•
•
•
•
•
Eliminate pathologic insult
Remove injured tissue components
Protective response
Hand in hand with repair
Steps:
– Initiation-stimulus
– Amplification: activation of cellular
inflammation
– Termination: Elimination

7. Five classic local signs of acute
inflammation

8. 1.
2.
3.
4.
5.
6.
Transient vasoconstriction
Vasodilation
Exudation of protein rich fluid
Blood stasis
Margination
Emigration/Transmigration

9. • Delivery of leucocytes to the site of
injury
• Ingest & kill bacteria & microbes
• Degrade necrotic tissues & foreign
antigens
• May prolong inflammation
• Rarely induce tissue damage by
releasing
enzymes
&
chemical
mediators, toxic radicals

10. Normal environment a

11. Inflammatory mediators

12. Increased vascular permeability
› Escape of protein rich fluid into
interstitium
› Oedema-excess of fluid in interstitium
or serous cavities
› Imbalance of hydrostatic pressure
 Transudate-low protein, sp gr-< 1.012
› Permeability not altered
 Exudate-high protein, sp gr > 1.020
› Permeability altered
 Pus –rich in polymorphs

14. Protein exits vessels :
 intravascular osmotic pressure
 intravascular hydrostatic pressure
Endothelial gaps at intercellular junctions:
* immediate transient response
*histamine, bradykinin, leukotrienes, subst
anceP

15. Blood pressure and plasma
colloid osmotic forces in
normal and inflamed
microcirculation..
hydrostatic pressure
(red arrows) is about
32 mm Hg
Arteriole pressure is
increased to 50 mm Hg
12 mm Hg
30 mm Hg.
osmotic pressure of
tissues is
approximately 25 mm
Hg (green
arrows), which is
equal to the mean
capillary pressure
osmotic pressure is
reduced (averaging 20
mm Hg) because of
protein leakage across
the venule. The net
result is an excess of
extravasated fluid

16. Increased vascular permeability
 Endothelial cell contraction- Immediate transient
response- only venules-chem mediators
 Cytoskeletal & junctional re-organization
 Direct endothelial injury-Immediate sustained
response-cell necrosis & detachment-All levels
 Leucocyte mediated injury
 Leakage from regenerating capillaries-Angiogenesis

17. Cellular events-Steps
• Extravasation-Journey of the leucocytes from lumen
to interstitial tissue
– Margination, Rolling
– Adhesion
• Transmigration/ Diapedesis
• Chemotaxis - Migration in interstitial tissue towards a
chemical stimulus
• Leucocyte activation
• Phagocytosis
• Release of Leucocyte products

18. Leukocyte Cellular Events
• Margination and Rolling
• Adhesion and Transmigration
• Migration into interstitial tissue

19. Inflammation

20. Chemotaxis
• Movement toward the site of injury along a
chemical gradient
– Chemotactic factors include
•
•
•
•
Complement components (20 serum proteins)
Arachadonic acid (AA) metabolites
Soluble bacterial products
Chemokines, cytokines

21. Leucocyte activation
• Production of Arachidonic acid metabolites by
DAG & increased Ca
• De-granulation & secretion of lyso enzymes &
activation of oxidative burst
• Modulation of leucocyte adhesion molecules
• Priming-Increased rate & extent of leucocyte
activation

22. Phagocytosis & Degranulation
• Phagocytosis (engulf and destroy)
• Degranulation and the oxidative burst
destroy the engulfed particle
• Recognition & attachment
– Opsonins coat target and bind to leukocytes
• Engulfment
• Killing/degradation
– O2 dep: Reactive O2 species in lysosomes & EC
– O2
indep:
Bactericidal
permeability
agents, lysozyme, MBP, lactoferrin

24. Tissue
injury
Vasoactive
mediators
(eg. histamine)
Production of
inflammatory
mediators
Chemotactic
factors (eg. c5a)
Recruitment of inflammatory
cells
Increased
vascular
permeability
Edema
Acute
inflammation
PMNs
Chronic
inflammation
Monos

26. Complement
C5
Kinin
Prekallikrein
XIIa
High Mol. Wt. Kininogen
C3
C5
a
XII
C3a
Kallikrein
Bradykinin
Plasminogen  Plasmin
Fibrin  FSPs
Prothrombin  Thrombin
Fibrinogen
Clotting
Fibrinopeptides
Fibrinolytic

27. • Leads to formation of bradykinin
• Bradykinin causes
– Increased vascular permeability
– Arteriolar dilatation
– Smooth muscle contraction
• Bradykinin is short lived (kininases)
• Vascular actions similar to histamine

28. • Role in immunity (C5-9 complex)
– Membrane Attack Complex (MAC C5-9)
– Punches a hole in the membrane

29. • Role in inflammation (c3a and c5a)
– Vascular effects
• Increase vascular permeability and vasodilation
• Similar to histamine
– Activates lipoxygenase pathway of arachidonic
acid metabolism (c5a)

30. – Leukocyte activation, adhesion and chemotaxis (c5a)
– Phagocytosis
• c3b acts as opsonin and promotes phagocytosis by cells
bearing receptors for c3b

31. Inflammatory
Complement
from
Anaphylatoxins:
C3a, C5a, & C4a trigger mast cells to release
histamine and cause vasodilatation
C5a also activates the lipoxygenase system in PMNs
and monocytes  release of inflammatory
mediators
Leukocyte activation, adhesion, & chemotaxis:
C5a activates leukocytes, promotes leukocyte
binding to endothelium via integrins and is
chemotactic for PMNs, monos, eos, & basos

32. Inflammatory Mediators from
Complement
Phagocytosis:
C3b and C3bi are opsonins
Control:
Convertases are destabilized by "decay accelerating
factor" (DAF)
Inability to express DAF causes paroxysmal
nocturnal hemoglobinuria
C1 inhibitor (C1INH) deficiency causes hereditary
angioneurotic edema

34. Vasoactive amines
• Histamine
– Found in mast cells, basophils and platelets
– Released in response to stimuli
– Promotes arteriolar dilation and venular
endothelial contraction
• results in widening of interendothelial cell junctions
with increased vascular permeability
• Serotonin
– Vasoactive effects similar to histamine
– Found in platelets
– Released when platelets aggregate

35. Bradykinin: Potent biomolecule
1. Vasodilatation
2. Increased vascular permeability
3. Contraction of smooth muscle
4. Pain on injection
5. Short life, kininase degrades
 Vascular Permeability:
- Bradykinin
- Fibrionopeptides
- Fibrin Split Prod.
Factor XII activated by:
1. Plasmin
2. Kallikrein
3. Collagen & basement membrane
4. Activated platelets
5. Co-factor = HMWK
- Factor Xa
- Leukotrienes

36. Arachidonic Acid (AA)
• Where is it located?
– AA is a component of cell membrane phospholipids
• The breakdown of AA into its metabolites
produces a variety of biologic effects

37. Arachidonic acid metabolites
• Metabolites of AA - short-range hormones
• AA metabolites act locally at site of generation
• Rapidly decay or are destroyed

38. Arachidonic Acid
• AA is released from the cell membrane by
phospholipases which have themselves been
activated by various stimuli and/or
inflammatory mediators
• AA metabolism occurs via two major
pathways named for the enzymes that initiate
the reactions; lipoxygenase and
cyclooxygenase

39. AA metabolites (eicosanoids)
Cyclooxygenases synthesize
Prostaglandins
Thromboxanes
Lipoxygenases synthesize
Leukotrienes
Lipoxins

41. PGG2

PGI2
PGH2
TXA2
PGI2
PGD2 ; PGE2
Prostacyclin
PGF2
TXA2
Thromboxane
Vasodilatation
Vasoconstriction
Inhibits Platelet Aggregation
Promotes Platelet Aggregation
Vasodilatation
Edema

42. Arachidonic Acid Pathways
you need to know this
• Lipoxygenase
– 5-HETE
• Chemotaxis
– 5-HPETE
• Leukotriene generation
– Leukotrienes
• Vasoconstriciton
• Bronchospasm
• Increased vascular
permeability
• Cyclooxygenase
– Prostaglandins
• Vasodilatation
• Increased vascular
permeability
– Prostacyclin
• Vasodilatation
• Inhibits platlelet aggregation
– Thromboxane A2
• Vasoconstriction
• Promotes platlelet
aggregation

43. Arachidonic Acid Pathways
you need to know this
• Lipoxygenase
– 5-HETE, 5HPETE, Leukotrienes
• Spasm (Vaso, Broncho)
• Cyclooxygenase
– Prostaglandins - EDEMA
– Prostacyclin vs TXA2
• Vasodilatation vs.
Vasoconstriction
• Platelet aggregation
Inhibits vs. promotes

44. Platelet-Activating Factor (PAF)
• Another phospholipid-derived mediator released
by phospholipases
• Induces aggregation of platelets
• Causes vasoconstriction and bronchoconstriction
• 100 to 1,000 times more potent than histamine
in inducing vasodilation and vascular
permeability
• Enhances leukocyte
adhesion, chemotaxis, degranulation and the
oxidative burst
• It does everything!

45. Cytokines
•
•
•
•
Polypeptides that are secreted by cells
Act to regulate cell behaviors
Autocrine, paracrine or endocrine effects
These “biological response modifiers” are
being actively investigated for therapeutic
use in controlling the inflammatory response.

46. Lymphocyte function
1. Macrophages make IL-1 & TNF-
2. T-cells make TNF- (lymphotoxin)
3. Can be autocrine, paracrine, endocrine
4. IL-1, TNF, IL-6  acute phase
responses, fever, (appetite, slow wave sleep, 
circ. pmn, ACTH,  corticosteroids)
5. TNF notable for role in septic shock and
maintenance of body mass (cachexia in cancer
from   TNF- )

48. Nitric Oxide
•
•
•
NO is a soluble free radical gas
Made by nitric oxide synthetase (NOS) in
endothelium (eNOS), macrophages
(iNOS), and specific neurons in the brain
(nNOS)
Broad range of functions and effects that are
short range
–
–
–
–
Vasodilatation by relaxing smooth muscle.
 platelet aggregation
Inhibits mast cells
Regulates leukocyte recruitment