Acute Inflammation (2).ppt pathology subject

Inflammation-A reaction of a living tissue and its microcirculation to a pathological insult.
ACUTE INFLAMMATION

1. ACUTE INFLAMMATION
MODERATOR – DR. KALPANA SHARMA
PRESENTED BY – DR. POOJA GURJAR

2. WHAT IS INFLAMMATION?
A reaction of a living tissue & its micro-circulation to a
pathogenic insult.
A defense mechanism for survival .

3. TYPES OF INFLAMMATION
Time course
Acute inflammation: occurs in less than 48 hours
Chronic inflammation: can take weeks, months,
years
Cell type
Acute inflammation: involves neutrophils
Chronic inflammation: Mononuclear cells
(Macrophages, Lymphocytes, Plasma cells).

4. ETIOLOGIES
Microbial infections: bacterial, viral, fungal, etc.
Physical agents: burns, trauma--like cuts, radiation
Chemicals: drugs, toxins, or caustic substances like
battery acid.
Immunologic reactions: e.g. rheumatoid arthritis.

5. ACUTE INFLAMMATION
Three main processes occur at the site of
inflammation, due to the release of chemical
mediators :
Increased blood flow (redness and warmth).
Increased vascular permeability (swelling, pain &
loss of function).
Leukocytic Infiltration.

6. The major local manifestations of
acute inflammation, compared
to normal.
(1)Vascular dilation and increased
blood flow (causing erythema
and warmth).
(2)Extravasation and deposition of
plasma fluid and proteins
(edema).
(3)leukocyte emigration and
accumulation in the site of
injury.

7. VASCULAR LEAKAGE
Vascular permeability (leakiness) commences
following
 in which transudate gives way to exudate (protein-rich)
 and Increases interstitial osmotic pressure contributing to
edema (water and ions)

8. Mechanism of vascular leakage

9. Mechanism of vascular
leakage contd.

10. LEUKOCYTE CELLULAR EVENTS
Leukocytes leave the vasculature
routinely through the following
sequence of events:
Margination and rolling
Adhesion and transmigration
Chemotaxis and activation
They are then free to participate in:
Phagocytosis and degranulation
Leukocyte-induced tissue injury

11. `

12. Endothelial Molecule Leukocyte Receptor Major Role
P-selectin Sialyl-Lewis X
PSGL-1
Rolling (neutrophils, monocytes,
lymphocytes)
E-selectin Sialyl-Lewis X Rolling, adhesion to activated
endothelium (neutrophils, monocytes, T
cells)
ICAM-1 CD11/CD18 (integrins)
(LFA-1, Mac-1)
Adhesion, arrest, transmigration (all
leukocytes)
VCAM-1 α4β1 (VLA4) (integrins)
α4β7 (LPAM-1)
Adhesion (eosinophils, monocytes,
lymphocytes)
GlyCam-1 L-selectin Lymphocyte homing to high endothelial
venules
CD31 (PECAM) CD31 Leukocyte migration through
endothelium

ALL THESE STEPS OCCUR DUE TO FOLLOWING RECEPTOR MOLECULE
BINDING

13. MARGINATION AND ROLLING
With increased vascular permeability, fluid leaves the vessel
causing leukocytes to settle-out of the central flow column and
“marginate” along the endothelial surface
Endothelial cells and leukocytes have complementary surface
adhesion molecules which briefly stick and release causing the
leukocyte to roll along the endothelium like a tumbleweed until it
eventually comes to a stop as mutual adhesion reaches a peak
- Early rolling adhesion mediated by Selectin family:
E-Selectin (endothelium), P-Selectin (platelets, endothelium), L-Selectin
(leukocytes) bind other surface molecules (i.e.,CD34, Sialyl-Lewis
X-modified GP) that are up regulated on endothelium by cytokines
(TNF, IL-1) at injury sites

14. ADHESION
Rolling comes to a stop and adhesion
results
Other sets of adhesion molecules
participate:
Endothelial: ICAM-1, VCAM-1
Leukocyte: LFA-1, Mac-1, VLA-4
(ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-
4)
Ordinarily down-regulated or in an
inactive conformation, but inflammation
alters this

15. Regulation of endothelial and leukocyte adhesion molecules. A,
Redistribution of P-selectin. B, Cytokine activation of endothelium. C,
Increased binding avidity of integrins .
SOME OTHER PROCESS AIDING IN OCCURRENCE OF INFLAMMATION PROCESS

16. Regulation of endothelial and leukocyte adhesion molecules. A, Redistribution of P-
selectin. B, Cytokine activation of endothelium. C, Increased binding avidity of
integrins
)

17. Regulation of endothelial and leukocyte adhesion molecules. A,
Redistribution of P-selectin. B, Cytokine activation of endothelium. C,
Increased binding avidity of integrins .
)

18. TRANSMIGRATION
(DIAPEDESIS)
Occurs after firm adhesion within the systemic venules
and pulmonary capillaries via PECAM –1 (CD31)
 then the cross basement membrane by secreting
Collagenases.
- Early in inflammatory response mostly PMNs takes part, but
as cytokine and chemotactic signals change with progression
of inflammatory response, alteration of endothelial cell
adhesion molecule expression activates other populations of
leukocytes to adhere (monocytes, lymphocytes, etc)

19. CHEMOTAXIS
Leukocytes follow chemical gradient to
site of injury (chemotaxis)by following
chemoattractant/chemotactic agent-
Soluble bacterial products
Complement components (C5a)
Cytokines (chemokine family e.g., IL-8)
LTB
4 (AA metabolite)
Chemotactic agents bind surface
receptors inducing calcium mobilization
and assembly of cytoskeletal contractile
elements

20. CHEMOTAXIS AND
ACTIVATION
Leukocytes:
 extend pseudopods with overlying surface
adhesion molecules (integrins) that bind ECM
during chemotaxis
undergo activation:
Prepare AA metabolites from phospholipids
Prepare for degranulation and release of
lysosomal enzymes (oxidative burst)
Regulate leukocyte adhesion molecule
affinity as needed

21. CHEMICAL MEDIATORS
Substance that initiate and regulate
inflammatory reaction.
May or may not utilize a specific cell surface
receptor for activity
May also signal target cells to release other
effector molecules that either amplify or
inhibit initial response (regulation)
Are tightly regulated:
Quickly decay (AA metabolites), are
inactivated enzymatically (kininase), or are
scavenged (antioxidants)

22. TYPES OF CHEMICAL
MEDIATORS
Plasma-derived:
Complement, kinins, coagulation factors
Many in “pro-form” requiring activation (enzymatic
cleavage)
Cell-derived:
Preformed, sequestered and released (mast cell
histamine)
Synthesized as needed (prostaglandin)

23. Chemical mediators of inflammationChemical mediators of inflammation

24. Leukotrienes and Prostaglandins: Potent mediators of inflammationLeukotrienes and Prostaglandins: Potent mediators of inflammation
Derived from Arachidonic acid (AA): 20-carbon, unsaturated fatty acid Derived from Arachidonic acid (AA): 20-carbon, unsaturated fatty acid
produced from membrane phospholipids. produced from membrane phospholipids.
Principal pathways:Principal pathways:
5-lipoxygenase: Produces a collection of leukotrienes (LT)5-lipoxygenase: Produces a collection of leukotrienes (LT)
Cyclooxygenase (COX): Produces prostaglandin H2 (PGH2)Cyclooxygenase (COX): Produces prostaglandin H2 (PGH2)
PGH2 serves as substratePGH2 serves as substrate
 for two enzymatic pathways:for two enzymatic pathways:
Prostaglandins (PG)Prostaglandins (PG)
Thromboxanes (Tx). Thromboxanes (Tx).

25. Generation of arachidonic acid metabolites and their roles in inflammation.Generation of arachidonic acid metabolites and their roles in inflammation.
The molecular targets of some anti-inflammatory drugs are indicated by a red X.The molecular targets of some anti-inflammatory drugs are indicated by a red X.
COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid;COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid;
HPETE, hydroperoxyeicosatetraenoic acid.HPETE, hydroperoxyeicosatetraenoic acid.

26. PHAGOCYTOSIS AND
DEGRANULATION
Once at site of injury, leukocytes:
Recognize and attach
Engulf (form phagocytic vacuole)
Kill (degrade)

27. RECOGNITION AND BINDING
Opsonized by serum complement, immunoglobulin
(C3b, Fc portion of IgG)
Corresponding receptors on leukocytes (FcR, CR1, 2,
3) leads to binding

28. PHAGOCYTOSIS AND
DEGRANULATION
Triggers an oxidative burst (next slide) engulfment and
formation of vacuole which fuses with lysosomal
granule membrane (phagolysosome)
Granules discharge within phagolysosome and
extracellularly (degranulation)

29. OXIDATIVE BURST
Reactive oxygen species formed through oxidative
burst that includes:
Increased oxygen consumption
Glycogenolysis
Increased glucose oxidation
Formation of superoxide ion
2O
2 + NADPH  2O
2
-rad
+ NADP
+
+ H
+
(NADPH
oxidase)
O
2 + 2H
+
 H
2O
2 (dismutase)

30. Production of microbicidal reactive oxygen intermediates Production of microbicidal reactive oxygen intermediates
within phagocytic vesicleswithin phagocytic vesicles

31. REACTIVE OXYGEN SPECIES
Hydrogen peroxide alone insufficient
MPO (azurophilic granules) converts hydrogen
peroxide to HOCl
-
(in presence of Cl
-
), an
oxidant/antimicrobial agent
Therefore, PMNs can kill by halogenation, or
lipid/protein peroxidation

32. DEGRADATION AND CLEAN-
UP
Reactive end-products only active within
phagolysosome
Hydrogen peroxide broken down to water and
oxygen by catalase
Dead microorganisms degraded by lysosomal acid
hydrolases

34. Summary of leukocyte
cellular event

35. DEFECTS OF LEUKOCYTE
FUNCTION
Defects of adhesion:
LFA-1 and Mac-1 subunit defects lead to impaired
adhesion (LAD-1)
Absence of sialyl-Lewis X, and defect in E- and P-selectin
sugar epitopes (LAD-2)
Defects of chemotaxis/phagocytosis:
Microtubule assembly defect leads to impaired
locomotion and lysosomal degranulation (Chediak-
Higashi Syndrome)

36. DEFECTS OF LEUKOCYTE
FUNCTION
Defects of microbicidal activity:
Deficiency of NADPH oxidase that generates superoxide,
therefore no oxygen-dependent killing mechanism
(chronic granulomatous disease)

37. Disease Defect
Genetic
Leukocyte adhesion deficiency 1 β chain of CD11/CD18 integrins
Leukocyte adhesion deficiency 2 Fucosyl transferase required for synthesis of
sialylated oligosaccharide (receptor for selectin)
Chronic granulomatous disease Decreased oxidative burst
X-linked NADPH oxidase (membrane component）
Autosomal recessive NADPH oxidase (cytoplasmic components)
Myeloperoxidase deficiency Absent MPO-H2O2 system
Chédiak-Higashi syndrome Protein involved in organelle membrane docking
and fusion
Acquired
Thermal injury, diabetes, malignancy,
sepsis, immunodeficiencies
Chemotaxis
Hemodialysis, diabetes mellitus Adhesion
Leukemia, anemia, sepsis, diabetes,
neonates, malnutrition
Phagocytosis and microbicidal activity

38. Morphologic patterns of Acute
Inflammation
Serous
Watery, protein-poor effusion (e.g., blister)
Fibrinous
Fibrin accumulation
Either entirely removed or becomes fibrotic
Suppurative
Presence of pus (pyogenic staph spp.)
Often walled-off if persistent
Ulceration
Necrotic and eroded epithelial surface
Underlying acute and chronic inflammation
Trauma, toxins, vascular insufficiency

39. Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic
inflammation

40. Figure 2-26 The morphology of an ulcer. A, A chronic duodenal ulcer. B,
Low-power cross-section of a duodenal ulcer crater with an acute
inflammatory exudate in the base.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 25 August 2008 10:13 AM)
© 2007 Elsevier

42. Tubercular necrosis showing granulomatous inflammation
and fibrosis

43. Acute appendicitis with purulent inflammation

44. Thank you!