1. Dr.ROOPA Premed 3 Pathophysiology
Inflammation
Dr.ROOPA
Premed 3
Pathophysiology

2. Introduction: “Inflame” – to set fire.
“Inflammation is a reaction of a tissue and its microcirculation to a pathogenic insult. It is characterized by the generation of inflammatory mediators and movement of fluid & leukocytes from the blood into extravascular tissues.”
“dynamic response of vascularised tissue to injury.”
Is a protective response.
Serves to bring defense & healing mechanisms to the site of injury.

3. Naming of inflammatory diseases:
[prefix] + ‘itis’
(exceptions exist)
crohn’s disease

4. Types of Inflammation
Acute
Chronic

5. Acute Inflammation Acute inflammation is a rapid response to an injurious agent that serves to deliver mediators of host defense—leukocytes and plasma proteins—to the site of injury. Acute inflammation has three major components: (1) alterations in vascular caliber that lead to an increase in blood flow; (2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation; and (3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent

6. Acute inflammatory reactions are triggered by a variety of stimuli: • 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)

7. Acute Vs Chronic Flush, Flare & Wheal
Acute inflammatory cells - Neutrophils
Vascular damage
More exudation
Little or no fibrosis
Little signs - Fibrosis,
Chronic inflammatory cells – Lymphocytes
Neo-vascularisation
No/less exudation
Prominent fibrosis

8. Table 5–1. Differences between Acute and Chronic Inflammation.
Acute
Chronic
Duration
Short (days)
Long (weeks to months)
Onset
Insidious
Specificity
Nonspecific
Specific (where immune response is activated)
Inflammatory cells
Neutrophils, macrophages
Lymphocytes, plasma cells, macrophages, fibroblasts
Vascular changes
Active vasodilation, increased permeability
New vessel formation (granulation tissue)
Fluid exudation and edema + –
Cardinal clinical signs (redness, heat, swelling, pain)
Tissue necrosis
– (Usually)
+ (Suppurative and necrotizing inflammation)
+ (ongoing)
Fibrosis (collagen deposition)
Operative host responses
Plasma factors: complement, immunoglobulins, properdin, etc; neutrophils, nonimmune phagocytosis
Immune response, phagocytosis, repair
Systemic manifestations
Fever, often high
Low–grade fever, weight loss, anemia
Changes in peripheral blood
Neutrophil leukocytosis; lymphocytosis (in viral infections)
Frequently none; variable leukocyte changes, increased plasma immunoglobulin

10. Cardinal Signs of Inflammation
Rubor : Redness – Hyperaemia.
Calor : Warm – Hyperaemia.
Dolor : Pain – Nerve, Chemical med.
Tumor: Swelling – Exudation
Loss of Function: Eg.

11. The 5 Cardinal Signs of
Heat Redness Swelling Pain Loss Of Func.

13. Inflammation - Mechanism
Vaso dilatation
Exudation - Edema
Emigration of cells
Chemotaxis

14. Mechanism of Inflammation:

15. 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

16. PRINCIPAL CELL EFFECTORS
1st 24 hours: NEUTROPHILS
Bacterial infections, infarction
Come from the bone marrow reserve pool
Band neutrophils: less mature cells 16

17. Neutrophils
-- the key cell type of the acute inflammatory response

18. 2nd-3rd day: neutrophils are replaced by monocytes-macrophages
Tuberculosis, salmonellosis

19. Eosinophils
Allergic reactions
Parasitic infections
Hodgkin lymphoma

20. Mast cells and basophils
Chronic myelogenous leukemia
Myeloproliferative diseases
histamine

21. Cellular response of leukocytes
Emigration
Margination
Pavementing
Rolling/Tumbling
Adhesion
Transmigration
Chemotaxis
Phagocytosis
Opsonization
Intracellular microbial killing
Oxygen-dependent
Oxygen-independent

22. 22

25. MARGINATION
THE ENDOTHELIAL CELLS ARE ACTIVATED, ATTRACT THE SURFACE GLYCOPROTEINS ON NEUTROPHILS 25

26. INSINUATION OF THE NEUTROPHILS THRU THE ENDOTHELIAL CELLS
DIAPEDESIS
INSINUATION OF THE NEUTROPHILS THRU THE ENDOTHELIAL CELLS
BASEMENT MEMBRANE
EXTRAVASCULAR TISSUES 26

27. NEUTROPHIL DIRECT ITS MIGRATION TOWARDS THE CHEMOATTRACTANT
CHEMOTAXIS
NEUTROPHIL DIRECT ITS MIGRATION TOWARDS THE CHEMOATTRACTANT 27

28. FORMATION OF PHAGOSOME LYSOSOME PHAGOLYSOSOME
PHAGOCYTOSIS
FORMATION OF PHAGOSOME
LYSOSOME
PHAGOLYSOSOME 28

30. Intracellular microbial killing:
Oxygen-dependent killing is the MOST important microbial process
Phagocytosis activates HMP shunt
oxidative burst
suppplies electrons to NADPH oxidase
superoxide anion
Hydrogen peroxide

31. Hydrogen peroxide Oxides microbial proteins and disrupts cell walls
Myeloperoxidase-halide system of bacterial killing

33. After killing and eliminating the microbes, the activated leukocytes play other functions
1.Macrophages produce GF(growth factor) that stimulate endothelial cell proliferation and fibroblasts.
2.Synthesis of collagen
3,Aids in the process of repair.

34. THE TOXIC SUBSTANCES MAY CAUSE LOSS OF FUNCTION (FUNCTIO LAESA)
DEGRANULATION
THE TOXIC SUBSTANCES MAY CAUSE LOSS OF FUNCTION (FUNCTIO LAESA) 34

35. INCREASED BLOOD FLOW DUE TO RELAXATION OF THE TERMINAL ARTERIOLES
RUBOR AND CALOR 35

36. CONTRACTION OF CAPILLARY ENDOTHELIAL CELLS
INCREASED VASCULAR PERMEABILITY
SWELLING 36

37. TUMOR MILDEST: EXTRAVASATION OF WATER, LOW MOLECULAR WEIGHT PROTEINS
MODERATE: + HMW(high molecular weight) PROTEINS
SEVERE: + BLOOD CELLS 37

38. 38

39. MEDIATORS OF ACUTE INFLAMMATION
Exogenous:
microbial products
Endogenous:
1. vasoactive amines
histamine
serotonin
2. Arachidonic acid metabolites
cyclooxygenase pathway
lipooxygenase pathway
3. Cytokines
4. Kinin system
5. Complement system

41. Histamine increase capillary permeability
contracts postcapillary venules
Source: basophils, mast cells,platelets
Stimuli: binding of IgE
binding of C3a and C5a:”anaphylotoxins”
heat, cold
Interleukin-1

42. Serotonin 5-hydroxytryptamine Action: similar to histamine
Source: platelets

44. Arachidonic acid metabolites
Cyclooxygenase pathway
Enzymes:COX-1,COX-2
Products:
Platelet TxA2
-vasoconstrictor,platelet aggregator
2. Endothelial prostacyclin
-vasodilator,inhibits platelet aggregation
Lipooxygenase pathway
Products: hydroperoxyeicosatetraenoic acid (HPETE)
5-HPETE
-leukotrienes

45. Important leukotrienes
LTB4: chemotactic for neutrophils
LTC4,LTD4,LTE4
“slow reacting substance of anaphylaxis”
vasocontriction
bronchospasm (bronchcontriction)
increase capillary permeability

46. Cytokines Soluble proteins
Secreted by numerous cells(monocytes-macrphages)
Act as “effector molecules”
IL-1 and TNF
“acute phase response”
Fever, increase WBC: systemic
Synthesis of C-reactive proteins, complement components, fibrinogen, prothrombin
Synthesis of adhesion molecules
Neutrophil degranulation

47. Kinin system
Formed during active secretion in sweat glands, salivary glands, pancreas, kidneys
End product: bradykinin
Actions: vascular permeability
arteriolar dilation
pain

48. Complement system 20 Plasma proteins
HEPATOCYTES,MACROPHAGES, GIT CELLS
Action: cell lysis

49. COMPLEMENT CASCADE
classical pathway
alternative pathway 49

50. ACTIVATE PMN, MACROPHAGES REGULATES AB RESPONSE
OPSONIZE BACTERIA
ACTIVATE PMN, MACROPHAGES
REGULATES AB RESPONSE
CLEARS AWAY IMMUNE COMPLEXES
INFLAMMATION, TISSUE DAMAGE
ANAPHYLAXIS 50

51. MAC

52. Classical pathway vs alternative pathway
Starts with C1 + antigen-antibody
Ends with the membrane attack complex
Bacterial surface activates the pathway
Works in the absence of antibodies
Less efficient 52

53. C3b: opsonin
C3a and C5a: anaphylotoxins
C5b-C9: “MAC”
membrane attack complex

54. Inflammation Outcome Acute Inflammation Resolution
Chronic Inflammation
Abscess
Sinus
Fistula
Fibrosis/Scar
Ulcer
Injury

56. ABSCESS Cavity filled with pus
Pus: neutrophils, monocytes and cellular debris
Fibrous wall
Inaccessible to circulation
Bacterial infections, especially staphylococci

59. Ulcer
Involves epithelial surfaces
Loss of surface epithelium

60. Fistula Abnormal communication between 2 organs or
between an organ and a surface

61. Scar Final result of tissue destruction Distortion of structure
Altered function

71. Patterns of chronic inflammation
Chronic nonspecific inflammation
Granulomatous inflammation

72. Chronic nonspecific inflammation
Proliferation of fibroblasts and new vessels
Increased macrophages, lymphocytes, plasma cells
Macrophage+antigen B lymphocyte activation antibody-producing plasma cells
Scarring and distortion of tissue architecture

78. Most characteristic: CASEOUS NECROSIS
Multinucleated giant cells
TB, fungal infections, Syphyllis, cat-scratch fever, foreign bodies