Basic pathology of inflammation

1. Dr. NINU RAJU THOTTAN
1 MD
MATERIA MEDICA

2.  Inflammation is defined as the local response of
living mammalian tissues to injury due to any agent.
 It is a body defense reaction in order to eliminate or
limit the spread of injurious agent, followed by
removal of the necrosed cells and tissues.
DEFINITION

3. Agents causing inflammation
 1. Infective agents like bacteria, viruses and their
toxins, fungi, parasites.
 2. Immunological agents like cell-mediated and
antigen antibody reactions.
 3. Physical agents like heat, cold, radiation,
mechanical trauma.
 4. Chemical agents like organic and inorganic
poisons.
 5. Inert materials such as foreign bodies.

4. SIGNS OF INFLAMMATION
The Roman writer Celsus in 1st century A.D. named
the famous 4 cardinal signs of inflammation as:
 rubor (redness);
 tumor (swelling);
 calor (heat);
 dolor (pain).
 fifth sign functio laesa (loss of function) was later
added by Virchow.

5. TYPES OF INFLAMMATION
 Depending upon the defense capacity of the host
and duration of response, inflammation can be
classified as
 acute
 chronic

6. Acute inflammation
 divided into
 I. Vascular events.
 II. Cellular events.

7. Vascular events
 transient vasoconstriction
 persistent progressive vasodilatation  redness and
warmth
 elevate the local hydrostatic pressure 
transudation of fluid into the extracellular space 
swelling
 Slowing or stasis of microcirculation  increased
concentration of red cells  raised blood viscosity
 leucocytic margination .

9. Vasodilation
 Brief arteriolar vasoconstriction followed by
vasodilation
 Accounts for warmth and redness
 Opens microvascular beds
 Increased intravascular pressure causes an early
transudate (protein-poor filtrate of plasma) into
interstitium

10. Vascular leakage
 Vascular permeability (leakiness) commences
 Transudate gives way to exudate (protein-rich)
 Increases interstitial osmotic pressure contributing to
edema

11. Vascular leakage
 Five mechanisms known to cause vascular leakiness
 Histamines, bradykinins, leukotrienes cause an early, brief (15 – 30
min.) immediate transient response in the form of endothelial cell
contraction that widens intercellular gaps of venules.
 Cytokine mediators (TNF, IL-1) induce endothelial cell junction
retraction through cytoskeleton reorganization (4 – 6 hrs post
injury, lasting 24 hrs or more)
 Severe injuries may cause immediate direct endothelial cell damage
(necrosis, detachment) making them leaky until they are repaired
(immediate sustained response), or may cause delayed damage as in
thermal or UV injury, or some bacterial toxins (delayed prolonged
leakage)
 Marginating and endothelial cell-adherent leukocytes may pile-up
and damage the endothelium through activation and release of
toxic oxygen radicals and proteolytic enzymes (leukocyte-dependent
endothelial cell injury) making the vessel leaky
 Certain mediators (VEGF) may cause increased transcytosis – in
neovascularisation

12. 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

14. 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.

15. Margination and Rolling
 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 upregulated on endothelium
by cytokines (TNF, IL-1) at injury sites

16. 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
(Intercellular Adhesion Molecule-ICAM, vascular cell adhesion molecule -VCAM, Lymphocyte function-
associated antigen -LFA, very late activation antigen 1-VLA)

17. Transmigration (diapedesis)
 Occurs after firm adhesion within the systemic
venules and pulmonary capillaries via PECAM –1
(CD31)
 Must then cross basement membrane
 Collagenases
 Integrins
 Platelet endothelial cell adhesion molecule (PECAM-1)

18. Chemotaxis
 Leukocytes follow chemical gradient to site of
injury (chemotaxis)
 Soluble bacterial products
 Complement components (C5a)
 Cytokines (chemokine family e.g., IL-8)
 Leukocytes:
 extend pseudopods with overlying surface adhesion
molecules (integrins) that bind ECM during
chemotaxis

20. Phagocytosis and Degranulation
 Once at site of injury, leukocytes:
 Recognize and attach
 Engulf (form phagocytic vacuole)
 Kill (degrade)

21. Recognition and Binding
 Opsonized by serum complement, immunoglobulin (C3b,
Fc portion of IgG)
 Corresponding receptors on leukocytes (FcR, CR1, 2, 3)
leads to binding

22. Phagocytosis and Degranulation
 Triggers an oxidative burst ; engulfment and formation of
vacuole which fuses with lysosomal granule membrane
(phagolysosome)
 Granules discharge within phagolysosome and
extracellularly (degranulation)

23.  Disposal of microorganisms can proceed by following
mechanisms:
A. Intracellular mechanisms:
 i) Oxidative bactericidal mechanism by oxygen free
radicals
a) MPO-dependent
b) MPO-independent
 ii) Oxidative bactericidal mechanism by lysosomal
granules
 iii) Non-oxidative bactericidal mechanism
B. Extracellular mechanisms:

24.  Oxidative bactericidal mechanism by oxygen free radicals
 MPO-dependent killing : In this mechanism, the enzyme
MPO acts on H2O2 in the presence of halides (chloride,
iodide or bromide) to form hypohalous acid (HOCl, HOI,
HOBr). This is called H2O2-MPO-halide system and is
more potent antibacterial system in polymorphs than
H2O2 alone.

25.  MPO-independent killing : Mature macrophages lack the
enzyme MPO and they carry out bactericidal activity by
producing OH– ions and superoxide singlet oxygen (O’)
from H2O2 in the presence of O’2 (Haber-Weiss reaction)
or in the presence of Fe++ (Fenton reaction):

26. Leukocyte granules
 Other antimicrobials in leukocyte granules:
 Bactericidal permeability increasing protein (BPI)
 Lysozyme
 Lactoferrin
 Defensins (punch holes in membranes)

29. Chemical mediators
I. CELL-DERIVED MEDIATORS
 1. Vasoactive amines (Histamine, 5-hydroxytryptamine, neuropeptides)
 2. Arachidonic acid metabolites (Eicosanoids)
i. Metabolites via cyclo-oxygenase pathway (prostaglandins, thromboxane
A2, prostacyclin, resolvins)
ii. Metabolites via lipo-oxygenase pathway (5-HETE, leukotrienes, lipoxins)
 3. Lysosomal components (from PMNs, macrophages)
 4. Platelet activating factor
 5. Cytokines (IL-1, TNF-α, TNF-β, IFN-γ, chemokines)
 6. Free radicals (Oxygen metabolites, nitric oxide)
II. PLASMA-DERIVED MEDIATORS (PLASMA PROTEASES) Products of:
 1. The kinin system
 2. The clotting system
 3. The fibrinolytic system
 4. The complement system

30. CHEMICAL MEDIATORS

34. Vasodilatation:
•Histamine
•Prostaglandins
•Nitric oxide
Increased vascular permeability:
•Histamine
•Anaphylatoxins C3a and C5a
•Kinins
•Leukotrienes C, D, and E
•PAF
•Substance P
Chemotaxis:
•Complement fragment C5a
•Lipoxygenase products,
lipoxins & leukotrines (LTB4)
•Chemokines
Tissue Damage
•Lysosomal products
•Oxygen-derived radicals
•Nitric Oxide
Events in Acute Inflammation

35. Prostaglandins :
• Vasodilation
• Pain
• Fever
• Potentiating edema
IL-1 and TNF:
• Endothelial-leukocyte interactions
• Leukocyte recruitment
• Production of acute-phase reactants
Diversity of Effects of Chemical Mediators

36. Summary of Mediators of Acute Inflammation
ACTION
Mediator Source Vascular Leakage Chemotaxis Other
Histamine and
serotonin
Mast cells, platelets + -
Bradykinin Plasma substrate + - Pain
C3a Plasma protein via liver + - Opsonic fragment (C3b)
C5a Macrophages + +
Leukocyte adhesion,
activation
Prostaglandins
Mast cells, from
membrane
phospholipids
Potentiate other
mediators
- Vasodilatation, pain, fever
Leukotriene B4 Leukocytes - +
Leukocyte adhesion,
activation
Leukotrienes
C4 D4 E4
Leukocytes, mast cells + -
Bronchoconstriction,
vasoconstriction
Platelet
Activating Factor
(PAF)
Leukocytes, mast cells + +
Bronchoconstriction,
leukocyte priming
IL-1 and TNF Macrophages, other - +
Acute-phase reactions,
endothelial activation
Chemokines Leukocytes, others - + Leukocyte activation
Macrophages,
endothelium
+ + Vasodilatation, cytotoxicity

37. Possible outcomes of acute inflammation
 Complete resolution
 Little tissue damage
 Capable of regeneration & restoration of injury cell to normal
 Resolution involves – neutralization, spontaneous decay of
chemical mediators ,subsequent return of normal vascular
permeability ,cessation of leukocyte infiltration ,death by apoptosis
removes edema ,protein, foreign substance & necrotic debris .
 Scarring (fibrosis)
 In tissues unable to regenerate
 Excessive fibrin deposition organized into fibrous tissue
 in many pyogenic infection – intense neutrophil infiltration
&liquefaction of tissue – pus formation- fibrosis.
 Abscess formation occurs with some bacterial or fungal
infections
 Pneumonia, chronic lung abscess, peptic ulcer of duodenum or
stomach –persist months or yrs
 Progression to chronic inflammation

38. CHRONIC INFLAMMATION

39.  Chronic inflammation is defined as prolonged
process in which tissue destruction and
inflammation occur at the same time.
1. Chronic inflammation following acute inflammation
2. Recurrent attacks of acute inflammation
3. Chronic inflammation starting de novo

40. GENERAL FEATURES OF
CHRONIC INFLAMMATION
 1. MONONUCLEAR CELL INFILTRATION.
 phagocytes
 lymphoid cells.
 Phagocytes -- circulating monocytes, tissue macrophages,
epithelioid cells and sometimes, multinucleated giant cells.
 The macrophages comprise the most important cells in chronic
inflammation.
 On activation, macrophages release several biologically active
substances e.g. acid and neutral proteases, oxygen-derived
reactive metabolites and cytokines. These products bring about
tissue destruction, neovascularisation and fibrosis.
 Other chronic inflammatory cells -- lymphocytes, plasma cells,
eosinophils and mast cells.

41.  2. TISSUE DESTRUCTION OR NECROSIS.
 brought about by activated macrophages which release a
variety of biologically active substances e.g. protease,
elastase, collagenase, lipase, reactive oxygen radicals,
cytokines (IL-1, IL-8, TNF-α), nitric oxide, angiogenesis
growth factor etc.
 3. PROLIFERATIVE CHANGES.
 As a result of necrosis, proliferation of small blood
vessels and fibroblasts is stimulated resulting in
formation of inflammatory granulation tissue.
Eventually, healing by fibrosis and collagen laying takes
place.

42. TYPES OF CHRONIC
INFLAMMATION
1. Non-specific, when the irritant substance produces
a nonspecific chronic inflammatory reaction with
formation of granulation tissue and healing by
fibrosis e.g. chronic osteomyelitis, chronic ulcer.
2. Specific, when the injurious agent causes a
characteristic histologic tissue response e.g.
tuberculosis, leprosy, syphilis.

43.  1. Chronic non-specific inflammation. It is
characterised by non-specific inflammatory cell
infiltration e.g. chronic osteomyelitis, lung abscess.
 2. Chronic granulomatous inflammation. It is
characterised by formation of granulomas e.g.
tuberculosis, leprosy, syphilis, actinomycosis,
sarcoidosis etc.

44. GRANULOMATOUS INFLAMMATION
 Granuloma is defined as 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.
The word ‘granuloma’ is derived
from granule meaning
circumscribed granule-like lesion,
and -oma which is a suffix
commonly used for true tumours
but here it indicates a localised
inflammatory mass or collection
of macrophages

46. COMPOSITION OF
GRANULOMA
 1. Epithelioid cells
 2. Multinucleate giant cells
 3. Lymphoid cells
 4. Necrosis
 5. Fibrosis