1. بسم الله الرحمن الرحيم Inflammation Dr. Samar Saleh
Pathology Department
Faculty of Medicine
University of Mosul

2. Definition of INFLAMMATION
Inflammation is the response of living tissues to cell injury.
Its purpose is to localize & eliminate the causative agent, to limit tissue injury & then to restore the tissue to normality or as close to normality as possible.
It is often beneficial, but sometime harmful.
The nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix “-itis” e.g.,
Appendicitis ,Dermatitis ,Cholecystitis , hepatitis ,lung , brain …..ect.

3. Cardinal signs of (acute) inflammation
Rubor = redness due to V.D.
Tumor = swelling due to exudate.
Calor = heat due to V.D.
Dolor = pain due to secretion of PG,BK & nerve compression & irritation.
(described by Celsus 1st. Century AD)
Functio laesa = loss of function due to pain & swelling i.e. reflux immobilization due to pain.
(added by R. Virchow)
Cellulits = acute skin infection commonly caused by Streptococcus pyogenes or Staphylococcus aureus

5. Causes of Inflammation:
1.Infections:e.g., bacterial, viral, parasitic fungal …..
2.Physical agents: e.g., heat, cold, radiation…….
3.Chemical agents: e.g., acid, alkaline, drugs……..
4.Hypersensitivity: e.g., rheumatic fever………..
5.Tissue necrosis: e.g., Ischemic necrosis.

6. Components involved in inflammation
Blood vessels.
Plasma & plasma proteins.
Cells
Circulating cells include :Neutrophiles, Monocytes, L, E, B, & plasma cells.
Connective tissue cell include : mast cells, fibroblasts, Macrophage & Lymphocytes.
Extra-celluar matrix
Collagen, elastic tissue, adhesive glycoproteins, protoglycans & basement membrane.

7. Types of inflammation 1.Acute inflammation. 2.Chronic inflammation.
3. Acute on chronic inflammation.

8. Acute inflammation Chronic inflammation
Short duration: hours -days –weeks.
Exudative fluid (protein rich fluid + inflammatory cells + debris).
Main inflammatory cells
Neutrophile & Macrophage.
Chronic inflammation
Long duration: months – years.
Fibrosis ( productive ).
Main inflammatory cells
L, M, plasma cells + fibroblasts & endothelial cells.

9. Definitions:
Edema: excess fluid in interstitial tissue or body cavities. May be either an exudate or transudate
Exudate: an inflammatory extravascular fluid that has a high protein concentration( gm/l), cellular debris, and a specific gravity above
Transudate: an extravascular fluid with low protein content and a specific gravity of less than essentially an ultrafiltrate of blood plasma resulting from eleveted hydrostatic pressure or diminished osmotic forces in the plasma.
Pus (purulent exudate): an inflammatory exudate rich in leukocytes (mostly neutrophils), cellular debris, and in many cases microbes.

10. Vascular changes and fluid leakage during acute inflammation lead to Edema in a process called Exudation
Transudate
result of hydrostatic
or osmotic imbalance
ultrafiltrate of plasma
Low protein content
specific gravity < 1.015
Exudate
result of inflammation
vascular permeability
high protein content
specific gravity >1.020

11. Exudate
Due to increase vascular permeability induced by chemical mediators and due to the direct damage of the vessels, excessive fluid passes to the extra-cellular spaces result in edema.
It is consist of:
1.Fluid rich in plasma proteins.
2.Fibrin.
3.Cells: Neutrophils, Macrophages, eosinophils, few lymphocytes & red blood cells.
4.Debris.

13. What are the function of EXUDATE?
1.It dilutes toxins.
2.It contains fibrin which localize infection.
3.It carries oxygen, nutrients to the inflammatory cells.
4.It carries Drugs, antibodies against bacteria.
It may have harmful effects e.g. causing life- threatening hypersensitivity reactions, or relentless and progressive organ damage from chronic inflammation and subsequent fibrosis ( e.g. rheumatoid arthritis, atherosclerosis).

15. Acute inflammation
It is the response of living vascularised tissue to injury .
This response is:
1.Uniform,
2.Last for short time.
3.Characterised by exudation of fluid (Edema) and cells (Neutrophile).
Neutrophiles are predominant inflammatory cells in early stages ( hours).
Monocytes ( macrophages) predominate inflammatory cells in later stages ( hours).

16. Processes of acute inflammatory response
I- Vascular changes
Alteration in vascular caliber resulting in local increase in blood flow.
Structural changes resulting in increase vascular permeability.
II- Leukocyte cellular events
Margination or pavementation & rolling
Adhesion & transmigration.
Chemotaxis & activation.
Phagocytosis & degranulation.
Release of leukocyte products.

17. 17

21. Exogenous: bacterial products Endogenous:
Chemotaxis & activation
Chemotaxis:controled movement of WBCs toward a chemical gradient known as chemotaxins.
Chemotaxins:The substance which induce (stimulate) chemotaxis e.g. bacteria, chemical mediators……….
Types of chemotaxins:
Exogenous: bacterial products
Endogenous:
C5a (complement factor)
LTB4 (lipo-oxygenase pathway)
IL-8 (Cytokines)
PAF (platelate activating factor)

23. Phagocytosis & degranulation
By neutrophiles & macrophages.
Three steps
1-Recognition & attachment
facilitated by coating of microorganisms by serum proteins called OPSONINS. Mainly IgG & C3b that bind to Fc & C receptors on the WBC.
2-Engulfment
through formation of pseudopodia, phagosome, phagolysosome.
3-Killing or degradation
through formation of free radicals (Superoxides, hydrogen peroxide (H2O2) & hydrochloride (HOCL) ).

24. Release of leukocyte products These include:
Lysosomal enzymes (protease).
Oxygen-derived active metabolites (free radicals).
Products of Arachidonic acid metabolism (lipo- oxygenase & cyclo-oxygenase products) .

25. Functions of leukocytes
Leukocytes extra-vasation have critical function in inflammation it:
1.Ingest offending agents.
2. Kill bacteria.
3.Digest necrotic materials.
4.Release lysosomal enzymes.
5.Release free radicles.
6. Release chemical mediators.

27. Diapedesis
Passage of RBCs through the defect created by the WBCs. It is a passive process.

28. Summary Changes of Acute Inflammation
Transient vasoconstrictionProlonged vasodilatationIncreased blood flow (Active hyperemia  increased vascular permeability-Stasis of blood Swelling of endothelial cells  margination or pavementation of WBC Exudation of WBC (emigration) and passage of RBC(Diapedesis) & exudation of fluid.

29. Chemical Mediators 2.Increased permeability of the blood vessels.
A substances which play a role in genesis and modulation of inflammatory reaction.
They are responsible for:
1.Vasodilatation.
2.Increased permeability of the blood vessels.
3.Emigration of WBC (Chemotactic agent).

30. Types of chemical mediators
1.Those formed in plasma 2.Those formed in tissue cells.

31. Mediators of acute inflammation
Plasma factors synthesized mainly in liver
Kinin system
Factor XII = coagulation system (Hageman factor) activation
Coagulation system
Plasma proteins
C3a
C5a
C3b
C5b-C9
anaphylatoxins
Complement activation
opsonin
MAC

32. 1) Histamine: secreted from mast cells, basophiles & platelets.
Chemical Mediators of Inflammation
A/ Vasoactive Amines
1) Histamine: secreted from mast cells, basophiles & platelets.
2) Serotonin: secreted from platelets, enterochromaffin cells.
Effects: arteriolar vasodilatation & increase vascular permeability.

33. AA present in the cell membrane phospholipids.
B/ Arachidonic Acid (AA) Metabolites
AA present in the cell membrane phospholipids.
Release from phospholipids through the action of phospholipase enzyme by mechanical, chemical & physical stimuli.
AA metabolism proceeds along one of two pathways
Cyclo-oxygenase pathway--- Postoglandins (PG)
Lipo-oxygenase pathway------Leukotriens (LT)

34. Arachidonic Acid Metabolites
Cyclo-oxygenase pathway
Thromboxane A2
Vasoconstriction
Platelet aggregation
Protacyclin (PGI2)
Vasodilatation
Inhibits Platelet aggregation
PGD2, PGE2 & PGF2
VD & edema
PGE2:
Fever
Pain
Lipo-oxygenase pathway
5-HETE:
Chemotaxis
LTB4:
Aggregation of neutrophils
LTC4, LTD4, LTE4
Vasoconstriction
Bronchospasm
Increase vascular permeability

35. C/ Platelet-Activating Factor (PAF)
Synthesized from membrane phospholipids through the action of phospholipase A2 in basophiles, endothelial cells & neutrophiles.
Effect:
Platelet aggregation.
V.D. & increase vascular permeability.
Chemotaxis.
Smooth muscle contraction.

36. Polypeptides produced by activated lymphocytes & macrophages.
D) Cytokines
Polypeptides produced by activated lymphocytes & macrophages.
It involved in cellular immunity & inflammatory responses.
IL-1 & TNF
Acute phase reaction including fever & Neutrophilia.
Promote endothelial secretion of PG & NO.
Induce fibroblastic proliferation & collagen synthesis.
IT-6
Acute phase reactions.
IT-8
Chemotactant & neutrophiles activating agent.

37. Effects of the Nitric Oxide:
E) Nitric Oxide (NO)
Soluble free radical gas synthesized by endothelial cells, macrophages & specific neurons in the brain.
Effects of the Nitric Oxide:
Vascular smooth muscle relaxation causing vasodilatation.
Decreased platelet aggregation & adhesion.
Microbicidal agent.

38. Effect: F) Lysosomal Constituents
Potentially act as inflammatory mediators when released from neutrophiles & macrophages.
Effect:
Destruction of ECM.
Direct cleavage of C3 & C5.

39. Effects: G) Oxygen Free Radicals Superoxide (O2-), OH-, H2O2 & NO
Endothelial cell damage causing increase vascular permeability.
Activation of proteinases.
Injury to surrounding cells.

40. Present as inactive form in the plasma
H/ Plasma Proteases
1)Complement System
Present as inactive form in the plasma
Vascular effect (anaphylotaxins):
C3a, C5a & C4a causing V.D. & increase vascular permeability.
Leukocyte adhesion, chemotaxis & activation: C5a
Phagocytosis: C3b & C3b1 act as opsonin.

41. Activated by activation of Hageman factor (XII)
2) Kinin System
Activated by activation of Hageman factor (XII)
Bradykinin: increase vascular permeability , V.D., pain & smooth muscle contraction.
Kallikrein: has chemotactic activity.

42. 3) Clotting System
A cascade activated by Hageman factor (XII) resulting in conversion of fibrinogen to fibrin.
Fibrinopeptides: increase vascular permeability & chemotaxis.

43. 4) Fibrinolytic System:
Plasmin: lyses fibrin clots, degrades fibrin to fibrin degradation products.
Fibrin degradation products: Increase vascular permeability.

44. Microscopic appearance of acute inflammation
Congestion of blood vessels.
Exudation of fluid.
Exudation of inflammatory cells mainly neutrophiles.

47. 3. Suppurative (Purulent)
Macroscopic types of acute inflammation
1. Cattarhal
Acute inflammation + mucus hypersecretion of mucus membrane (common cold).
2. Serous
Low protein content, low cellular fluid (pleural effusion).
3. Suppurative (Purulent)
Pus: creamy yellow or blood stained fluid consist of N, M.O., & tissue debris (acute appendicitis).
Abscess: localized collection of pus material.
Empyema: Collection of pus in the hallow organ.
4. Fibrinous
Accumulation of thick exudate rich in fibrin, which may resolve by fibrinolysis or organize into thick fibrous tissue. Fibrinous inflammation –bread &butter appearance to the inflamed serous membrane.

48. Morphologic patterns of acute inflammation
Serous inflammation:
Tissue fluid accumulation indicating a modest increase in vascular permeability
Pleura, pericardium,
peritoneum: effusion
,Blister in burns

50. Fibrinous inflammation:
More marked increase in vascular permeability, with exudates containing large amounts of fibrinogen
Involvement of serosal surfaces ( pericardium or pleura) : fibrinous pericarditis or pleuritis

52. Suppurative or purulent inflammation:
Production of purulent exudates consisting of leukocytes and necrotic cells.

54. What’s the fates (outcomes) of acute inflammation?
Depending on the nature of lesion, site & response of the host.
The followings are the outcome of acute inflammation:
1-Complete resolution: restoration of site of acute inflammation to normal. It involve:
removal of the exudate, fibrin & debris.
reversal of the microvascular changes.
regeneration of lost cells.

55. Complete resolution

56. 4-Progression to chronic inflammation:
Fates (outcomes) of acute inflammation (cont.)
2-Healing & organization: replacement of dead tissue by granulation tissue which mature in to fibrous tissue.
It is seen in chronic inflammation, In excessive tissue damage & excessive fibrin deposition.
3-Suppuration It may be diffuse in tissue, localized in tissue (abscess) , on the surface of a wound, or in serous cavity.
4-Progression to chronic inflammation:
Acute inflammation progress in to chronic inflammation when there is persistent infection, when there is foreign body…………….

57. Ulcer:
Local erosions ( Loss of continuity ) of epithelial surfaces produced by sloughing of inflamed necrotic tissue.

58. Role of lymphatic system in inflammation
The local inflammatory reaction may fail in containing the injurious agent
Secondary lines of defense
Lymphatic system; causing
lymphangitis (lymphatic vessels inflammation)
lymphadenitis (lymph nodes inflammation)
Monocytic-phagocytic system; involve
phagocytic cells of spleen, liver & Bone marrow.

59. What’s the effects of Acute Inflammation
BENIFITIAL effect
Dilution of toxins
Entry of antibodies
Drug transport
Fibrin formation
Delivery of nutrient & O2
Stimulation of immune system
HARMFUL effect
Digestion of normal tissue
Swelling & pain
Inappropriate inflammatory response.