1. INFLAMMATION .

2. Acute inflammation
Chronic inflammation
Repair
Resolution
Abscess
Injury

3. “Inflame” – to set fire.
Inflammation is “A dynamic response of vascularized tissue to injury.”
It is a protective response.
It serves to bring defense & healing mechanisms to the site of injury.

4. Definition
It is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult
It does it by
Diluting, destroying, or otherwise neutralizing harmful agents

5. Dysfunctions Inflammation may cause considerable harm to the body if:
The reaction is very strong (sever infection)
Prolonged (the agent resists eradication)
Inappropriate (Directed against self antigen in auto immune diseases.)
Or against usually harmless environmental antigens in allergic conditions

6. PLAYERS OF INFLAMMATION
Blood leukocytes
Plasma Proteins
Cells of vascular walls
Cells and extracellular matrix of the surrounding connective tissue

7. 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: rheumatoid arthritis.

8. Cardinal Signs of Inflammation
Redness (Rubor): Hyperaemia.
Warm (Calor): Hyperaemia.
Pain (Dolor): Nerve, Chemical mediators.
Swelling (Tumor): Exudation
Loss of Function: Pain

10. Time course Cell type Acute inflammation: Less than 48 hours
Chronic inflammation: Greater than 48 hours (weeks, months, years)
Cell type
Acute inflammation: Neutrophils
Chronic inflammation: Mononuclear cells (Macrophages, Lymphocytes, Plasma cells).

11. Increased blood flow (redness and warmth).
Pathogenesis: 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.

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

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

16. INCREASED VASCULAR PERMEABILITY
ACUTE INFLAMMATION
INCREASED VASCULAR PERMEABILITY
Increase in Permeability
Histamine (Mast Cells)
Serotonin (Platelets)
Time

17. Transudate: permeability of endothelium is usually normal.
An ultrafiltrate of blood plasma
permeability of endothelium is usually normal.
low protein content ( mostly albumin)

18. Exudate: permeability of endothelium is usually altered
A filtrate of blood plasma mixed with inflammatory cells and cellular debris.
permeability of endothelium is usually altered
high protein content.

19. Pus:
A purulent exudate: an inflammatory exudate rich in leukocytes (mostly neutrophils) and parenchymal cell debris.

20. Lymphatics in inflammation:
Lymphatics are responsible for draining edema.
Edema: An excess of fluid in the interstitial tissue or serous cavities; either a transudate or an exudate

21. Role of lymphatic and Lymph Nodes in Inflammation
Represents a second line of defense
Delivers antigens and lymphocytes to the central lymph nodes
Lymph flow is increased in inflammation
May become involved by secondary inflammation (lymphangitis, reactive lymphadenitis)

23. Acute Inflammation CELLULAR EVENTS: LEUKOCYTE EXTRAVASATION AND PHAGOCYTOSIS

24. Leukocytes Recruitment and Activation
Margination and Rolling
Adhesion and transmigration
Chemotaxis

25. Leukocytes Recruitment cont..
Margination and Rolling:
Leukocytes are pushed to the periphery as a result of Stasis, called Margination
Subsequently Leukocytes tumble on the endothelial surface, transiently sticking along the way, a process called Rolling

26. HEMOCONCENTRATION AND STASIS
ACUTE INFLAMMATION
HEMOCONCENTRATION AND STASIS
Normal flow
Stasis

27. Leukocytes Recruitment cont..
Rolling mechanism:
Endothelial complimentary molecules present on the surface of Endothelium and Leukocytes.
Selectins: P-selectin, E-selectin, L-selectins
Attached to mucine like glycoprotein on various cells.

28. Leukocytes Activation
Stimuli for activation:
Microbes
Products of necrotic cells
Chemical mediators

29. Leukocytes Activation conti..
Leukocytes Receptors:
Toll-like receptors (TLRs)for recognition of endotoxin (LPS) and other bacterial and viral products
G-protein coupled receptors for certain bacterial peptides and mediators produced in response to mediators
Other receptors

30. LIPOPOLYSACCHARIDE
peptidoglycan IM OM
lipid A

31. TOLL-LIKE RECEPTORS
single stranded
RNA
TLR8 .

32. Leukocytes Activation cont..
Leukocytes activation involves
Phagocytosis of particles
Production of substances that destroy phagocytosed microbes and remove dead tissues; These involves Lysosomal enzymes and reactive oxygen and nitrogen species.
Production of mediators that amplify the inflammatory reaction

33. Leukocytes Activation cont..
Phagocytosis
3 distinct steps
Recognition and attachment
Engulfment
Killing or degradation

35. LEUKOCYTES: ARSENAL REACTIVE OXYGEN PRODUCTS NUTRIENT-BINDING PROTEINS
PROTEASES
LYSOZYME
Bactericidal permeability-increasing proteins
Major Basic Proteins
MICROBICIDAL PEPTIDES
DEFENSINS
CATHELICIDINS

36. PHAGOCYTOSIS - ATTACHMENT
ACUTE INFLAMMATION
PHAGOCYTOSIS - ATTACHMENT

37. PHAGOCYTOSIS - ENGULFMENT
ACUTE INFLAMMATION
PHAGOCYTOSIS - ENGULFMENT

38. PHAGOCYTOSIS – KILLING AND DEGRADATION
ACUTE INFLAMMATION
PHAGOCYTOSIS – KILLING AND DEGRADATION

39. Role of Mediators in Different Reactions of Inflammation
Prostaglandins
Histamine
Nitric oxide
Vasodilation
Role of Mediators in Different Reactions of Inflammation
Vasoactive amines
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
Increased vascular permeability
C5a
Leukotriene B4
Chemokines
IL-1, TNF
Bacterial products
Chemotaxis, leukocyte recruitment and activation
Fever
IL-1, TNF
Prostaglandins
Prostaglandins
Bradykinin
Pain
Neutrophil and macrophage lysosomal enzymes
Oxygen metabolites
Nitric oxide
Tissue damage

41. VASOACTIVE AMINES
Increase Vascular Permeability and Vascular Permeability
Histamine and Serotonin
Mediators in the immediate active phase of increased permeability
Promotes contraction of smooth muscle
Stimulates to cells to produce eotaxins

42. Vasoactive Amines Releasing Stimulators .
Direct physical or chemical injury
Binding of IgE- Ag- complexes
Fragments of C3a and C5a
Histamine releasing factors (PMN’S )
Cytokines (IL-1, IL-8)
Neuropeptides

43. PLASMA PROTEASES
3 interrelated systems are active within this category
Kinin system
Highly vasoactive
Complement system
Vasoactive
Chemotactic
Clotting system
Cleaves C3

45. COMPLEMENT SYSTEM Plasma proteins - act against microbial agents
Products of activated complement
Vascular permeability
Chemotaxis
Opsonization
Lysis

47. COMPLEMENT SYSTEM . Important inflammatory mediators
C3a and C5a (anaphylatoxins)
Cause release of histamine from mast cells
Lysosomal enzyme release in inflammatory cells
C5a
Activates lipoxygenase pathway
Chemotactic many inflammatory cells
Increases adhesion of leukocytes .

48. KININ SYSTEM BRADYKININ Activated by Hageman factor (XIIa) Bradykinin
Generated from the plasma
Potent vasodilator
Increased vascular permeability
Contraction of smooth muscle
Produce pain
Stimulates release of histamine
Activates the arachidonic acid cascade

49. COAGULATION SYSTEM Plasma proteins
Clotting system
Plasma proteins
Can be activated by Hageman factor
Thrombin converts fibrinogen to fibrin
Fibrinopeptides are formed
↑vascular permeability
Chemotactic for leucocytes
Plasmin is important in lysing fibrin clots,
Activates Hageman factor (XII) ⇨ bradykinin
Cleaves C3 ⇨ C3a
"fibrin-split products" formed from fibrin breakdown
↑ vascular permeability

50. ARACHIDONIC ACID METABOLITES.
Via activation of cellular phospholipases
By mechanical, chemical and physical stimuli or by other mediators
2 major pathways
Cyclooxygenase pathway
Lipoxygenase pathway.
Roles in many biologic and pathologic processes
Inflammation
20-carbon polyunsaturated fatty acid
Derived directly from dietary sources or by conversion of essential fatty acid linoleic acid
Esterified in membrane phospholipids
Must first be released from phospholipids

51. .

52. CYCLOOXYGENASE PATHWAY
2 cyclooxygenase enzymes
COX-1
COX-2
3 important products
Thromboxane A2
Aggregates platelets and causes vasoconstriction
Prostacyclin (PGI2)
Endothelial cells inhibits platelet aggregation and causes vasodilation
Prostaglandins PGE2, PGF2 and PGD2
Variety of actions on vascular tone and permeability

53. LIPOXYGENASE PATHWAY Leukotrienes
Leukotriene B4 is a potent chemotactic agent
Leukotrienes C4, D4, E4
Potent vasoconstrictors
Potent mediators of increased vascular permeability on venules only
Up to 1000 times as potent as histamine in producing increased vascular permeability

54. .

55. PLATELET ACTIVATING FACTOR
Aggregate platelets
Bronchoconstriction
Vasodilatation and ↑ vascular permeability
↑ leukocyte adhesion
Leukocyte chemotaxis

56. CYTOKINES Transmitters for cell-to-cell chatting
Modulate cell function
Primarily from activated macrophages and lymphocytes
IL-1, IL-8, TNF

57. IL-I and TNF Origin Similar in action Endothelium Acute phase proteins
“Master Cytokines”
Origin
Monocytes
Macrophages
Similar in action
Endothelium
Acute phase proteins
Fibroblasts

58. Other Cytokines IL-5 IL-6 IL-8 Chemokines??? Eosinophils B and T cells
Neutrophils
Monocytes and eosinophils

60. HAGEMAN FACTOR Factor XII of intrinsic coagulation cascade
Dependent Factors
Factor XII of intrinsic coagulation cascade
Activated by
Negatively charged surfaces
Platelets
Proteases from inflammatory cells
Causes
Coagulation
Activation of fibrinolytic system
Produces bradykinin
Activates complement
Provides an amplification system

61. Events in the resolution of inflammation

62. Outcomes of Acute Inflammation
Progression of the tissue response to chronic inflammation:
occurs when the acute inflammatory response cannot be resolved WHY?
Due to: 1. the persistence of the injurious agent
2. some interference with the normal process of healing

64. CAUSES OF CHRONIC INFLAMMATION
Viral infection
Persistent infections by certain microorganisms, e.g. tubercle bacilli, Treponema pallidum, fungi, and parasites.
Prolonged exposure to potentially toxic agents, either exogenous or endogenous
e.g. of exogenous agent is particulate silica, when inhaled for prolonged periods, results in silicosis
e.g. of endogenous agent is atherosclerosis (a chronic inflammatory process of the arterial wall induced by endogenous toxic plasma lipid components)
Autoimmunity: immune reactions develop against the individual's own tissues
In these diseases, autoantigens evoke immune reaction that results in chronic tissue damage and inflammation e.g. rheumatoid arthritis and lupus erythematosus

65. MORPHOLOGIC FEATURES OF CHRONIC INFLAMMATION
Infiltration with mononuclear cells include
Macrophages
Lymphocytes
Plasma cells
Eosinophils
Tissue destruction
induced by the persistent offending agent or by the inflammatory cells.
Healing
by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis) and, in particular, fibrosis

66. MORPHOLOGIC FEATURES OF CHRONIC INFLAMMATION
MONONUCLEAR CELL INFILTRATION
Macrophages
the dominant cellular player in chronic inflammation
The mononuclear phagocyte system (sometimes called reticuloendothelial system) consists of closely related cells of bone marrow origin, including blood monocytes and tissue macrophages

67. mononuclear phagocyte system
monocytes begin to emigrate into extravascular tissues quite early in acute inflammation and within 48 hours they may constitute the predominant cell type

68. MONONUCLEAR CELL INFILTRATION Macrophages
Macrophages may be activated by a variety of stimuli, including
cytokines (e.g., IFN-γ) secreted by sensitized T lymphocytes and by NK cells
bacterial endotoxins
other chemical mediators
Activation results in
increased cell size
increased levels of lysosomal enzymes
more active metabolism
greater ability to phagocytose and kill ingested microbes.
Activated macrophages secrete a wide variety of biologically active products that, if unchecked, result in the tissue injury and fibrosis

69. Products of macrophages.
Products of macrophages
1.Acid and neutral proteases
2.Chemotactic factors
3.Reactive oxygen metabolites
4.Complement components
5. Coagulation factors
6.Growth promoting factors for fibroblasts, blood vessels and myeloid progenitor cells
7.Cytokines : IL-1, TNF
8.Other biologic active agents ( PAF, interferon, AA metabolites)
to eliminate injurious agents such as microbes
to initiate the process of repair
It is responsible for much of the tissue injury in chronic inflammation
Function?!!..

70. The roles of activated macrophages in chronic inflammation.
Acute
&
Chronic inflam. persist

71. Macrophages
In chronic inflammation, macrophage accumulation persists, this is mediated by different mechanisms:
Recruitment of monocytes from the circulation, which results from the expression of adhesion molecules and chemotactic factors
Local proliferation of macrophages after their emigration from the bloodstream
Immobilization of macrophages within the site of inflammation

73. OTHER CELLS IN CHRONIC INFLAMMATION
Lymphocytes
Both T & B Lymphocytes migrates into inflammation site

74. Lymphocytes and macrophages interact in a bidirectional way, and these reactions play an important role in chronic inflammation
Activated lymphocytes and macrophages influence each other and also release inflammatory mediators that affect other cells.

75. Mast cells are widely distributed in connective tissues
express on their surface the receptor that binds the Fc portion of IgE antibody ,
the cells degranulate and release mediators, such as histamine and products of AA oxidation

76. OTHER CELLS IN CHRONIC INFLAMMATION
GRANULOMATOUS INFLAMMATION
Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction characterized by focal accumulations of activated macrophages, which often develop an epithelial-like (epithelioid) appearance

77. Causes of Granulomatous Inflammations
Infections
Bacterial
Parasitic
Fungal
Inorganic dusts
Foreign bodeis
unknown

78. Examples of Diseases with Granulomatous Inflammations
Cause
Tissue Reaction
Tuberculosis
Mycobacterium tuberculosis
Noncaseating tubercle
Caseating tubercles
Leprosy
Mycobacterium leprae
Acid-fast bacilli in macrophages; noncaseating granulomas
Syphilis
Treponema pallidum
Gumma: wall of histiocytes; plasma cell
Cat-scratch disease
Gram-negative bacillus
Rounded or stellate granuloma
Sarcoidosis
Unknown etiology
Noncaseating granulomas
Crohn disease
Immune reaction against intestinal bacterial
dense chronic inflammatory infiltrate with noncaseating granulomas

79. Increased erythrocyte sedimentation rate
The rise in fibrinogen causes erythrocytes to form stacks (rouleaux) that sediment more rapidly at unit gravity than do individual erythrocytes. This is the basis for measuring the erythrocyte sedimentation rate (ESR) as a simple test for the systemic inflammatory response,

80. Inflammation Systemic Manifestations
Leukocytosis:
WBC count climbs to 15,000 or 20,000 cells/μl
most bacterial infection
Lymphocytosis:
Infectious mononucleosis, mumps,
measles
Eosinophilia: bronchial asthma,
hay fever, parasitic infestations
Leukopenia: typhoid fever,
infection with rickettsiae/protozoa

81. 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