1. ACUTE AND CHRONIC INFLAMMATION
Morphologic Patterns
Defect in leukocyte function
Complement deficiency
Systemic manifestation

5. Acute Inflammation CELLULAR EVENTS: LEUKOCYTE EXTRAVASATION AND PHAGOCYTOSIS

7. 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

8. Objectives Patterns of Acute Inflammation
Outcomes of Acute Inflammation
Patterns of chronic Inflammation
Defect in leukocyte function
Complement deficiency
Systemic manifestation

9. Objectives Patterns of Acute Inflammation
Outcomes of Acute Inflammation
Patterns of chronic Inflammation
Defect in leukocyte function
Complement deficiency
Systemic manifestation

10. Morphologic Patterns of Acute Inflammation
Several types of inflammation vary in their morphology and clinical correlates. Why?
The severity of the reaction
specific cause
the particular tissue
site involved

11. Morphologic Patterns of Acute Inflammation
SEROUS INFLAMMATION
FIBRINOUS INFLAMMATION
SUPPURATIVE OR PURULENT INFLAMMATION
ULCERS

12. Patterns of Acute Inflammation
SEROUS INFLAMMATION:
Serous inflammation is marked by the outpouring of a thin fluid
e.g. the skin blister resulting from a burn or viral infection represents a large accumulation of serous fluid

15. Morphologic Patterns of Acute Inflammation
FIBRINOUS INFLAMMATION
more severe injuries and more greater vascular permeability, larger molecules such as fibrinogen pass the vascular barrier, and fibrin is formed and deposited

16. Morphologic Patterns of Acute Inflammation FIBRINOUS INFLAMMATION
A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium and pleura

17. Morphologic Patterns of Acute Inflammation
FIBRINOUS INFLAMMATION
Fibrinous exudates may be removed by fibrinolysis
But when the fibrin is not removed, it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring (organization)

18. Morphologic Patterns of Acute Inflammation SUPPURATIVE OR PURULENT INFLAMMATION
characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils, necrotic cells, and edema fluid
Certain bacteria (e.g., staphylococci) produce this localized suppuration and are therefore referred to as pyogenic (pus-producing) bacteria

19. Suppurative inflammation
Suppurative inflammation. A, A subcutaneous bacterial abscess with collections of pus. B, The abscess contains neutrophils, edema fluid, and cellular debris.

20. Purulent inflammation

21. Morphologic Patterns of Acute Inflammation SUPPURATIVE OR PURULENT INFLAMMATION
Abscesses : localized collections of purulent inflammatory tissue caused by suppuration buried in a tissue, an organ, or a confined space

22. Brain Abscess

23. Liver abscess

24. Removal of the dead tissue leaves behind a scar
Localized liquefactive necrosis liver abscess
Removal of the dead tissue leaves behind a scar

25. Morphologic Patterns of Acute Inflammation
ULCERS
An ulcer is a local defect of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflammatory necrotic tissue

26. Morphologic Patterns of Acute Inflammation
ULCERS
encountered in:
inflammatory necrosis of the mucosa of the mouth, stomach, intestines, or genitourinary tract
subcutaneous inflammation of the lower extremities in older persons who have circulatory disturbances

27. Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface
Epithelial Defect
Necrotic base
Fibrinopurulent exudates
Granulation tissue
Fibrosis

28. Objectives Outcomes of Acute Inflammation
Patterns of Acute Inflammation
Outcomes of Acute Inflammation
Patterns of chronic Inflammation
Defect in leukocyte function
Complement deficiency
Systemic manifestation

29. Outcomes of Acute Inflammation
Acute inflammation may have one of the four outcomes:
Complete resolution
Healing by connective tissue replacement (fibrosis)
Progression of the tissue response to chronic inflammation
Abcess formation

30. Outcomes of Acute Inflammation
Complete resolution
When?
the injury is limited or short-lived
there has been little tissue destruction
the damaged parenchymal cells can regenerate

31. Outcomes of Acute Inflammation
Complete resolution
Mechanism:
Neutralization and removal of chemical mediators
Normalization of vascular permeability
halting of leukocyte emigration
Clearance of edema (lymphatic drainage) , inflammatory cells and necrotic debris (macrophages).

32. Events in the resolution of inflammation

33. Outcomes of Acute Inflammation
Healing by connective tissue replacement (fibrosis):
This occurs after substantial tissue destruction
the inflammatory injury involves tissues that are incapable of regeneration
there is abundant fibrin exudation.
The destroyed tissue is resaorbed and eventually replaced by fibrosis.

34. 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

36. A 36-year-old man has had midepigastric abdominal pain for the past 3 months. An upper gastrointestinal endoscopy shows a 2-cm, sharply demarcated, shallow ulceration of the gastric antrum. A biopsy specimen of the ulcer base shows angiogenesis, fibrosis, and mononuclear cell infiltrates with lymphocytes, macrophages, and plasma cells. Which of the following terms best describes this pathologic process? (A) Acute inflammation (B) Serous inflammation (C) Granulomatous inflammation (D) Fibrinous inflammation (E) Chronic inflammation

37. Objectives Patterns of chronic Inflammation
Patterns of Acute Inflammation
Outcomes of Acute Inflammation
Patterns of chronic Inflammation
Defect in leukocyte function
Complement deficiency
Systemic manifestation

38. Chronic Inflammation or inflammation of prolonged duration
weeks or months
Mixture of active inflammation, tissue destruction, and attempts at repair
it may follow:
acute inflammation
begins insidiously,
as a low-grade,
often asymptomatic
response. or
This is the cause of tissue damage in some of the most common and disabling human diseases, such as rheumatoid arthritis, atherosclerosis, tuberculosis, and chronic lung diseases

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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?!!..

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

46. 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

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

49. 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.

50. Eosinophils
are abundant in immune reactions mediated by IgE and in parasitic infections
respond to chemotactic agents derived largely from mast cells
Granules contain major basic protein: toxic to parasites and lead to lysis of mammalian epithelial cells

51. 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

52. 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

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

55. 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

56. 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)

57. Objectives Defect in leukocyte function Patterns of Acute Inflammation
Outcomes of Acute Inflammation
Patterns of chronic Inflammation
Defect in leukocyte function
Complement deficiency
Systemic manifestation

58. Defects in Leukocyte Function
Genetic
Acquired
lead to increased vulnerability to infections

59. Genetic Defects in Leukocyte Function
A. Defect in leukocyte adhesions:
- 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)
B. Defect of phagocytosis (Chédiak-Higashi syndrome)
An autosomal recessive condition characterized by neutropenia (decreased numbers of neutrophils), defective degranulation, and delayed microbial killing
C. Defect of bactericidal activity (Chronic granulomatous disease)
Patients susceptible to recurrent bacterial infection. Chronic granulomatous disease results from inherited defects in the genes encoding several components of NADPH oxidase, which generates superoxide.

60. Acquired Defects in Leukocyte Function
Thermal injury, diabetes, malignancy, sepsis, immunodeficiencies
Chemotaxis
Hemodialysis, diabetes mellitus
Adhesion
Leukemia, anemia, sepsis, diabetes, neonates, malnutrition
Phagocytosis and microbicidal activity

61. Objectives Complement deficiency Patterns of Acute Inflammation
Outcomes of Acute Inflammation
Patterns of chronic Inflammation
Defect in leukocyte function
Complement deficiency
Systemic manifestation

62. Complement deficiency

63. Complement deficiency
hereditary deficiency of C3 results in an increased susceptibility to infection with pyogenic bacteria.
Deficiencies of the late components of the classical complement pathway (C5-C8) result in recurrent infections by Neisseria
Inherited deficiencies of C1q, C2, and C4 increase the risk of immune complex-mediated disease (e.g., SLE)

64. Complement deficiency
hereditary deficiency of complement components, especially C3 (critical for both the classical and alternative pathways), results in an increased susceptibility to infection with pyogenic bacteria.
Inherited deficiencies of C1q, C2, and C4 do not make individuals susceptible to infections, but they do increase the risk of immune complex-mediated disease (e.g., SLE), possibly by impairing the clearance of apoptotic cells or of antigen-antibody complexes from the circulation.
Deficiencies of the late components of the classical complement pathway (C5-C8) result in recurrent infections by Neisseria (gonococci, meningococci) but not by other microbes.

65. Complement disturbance
Lack of the regulatory protein C1 inhibitor allows C1 activation, with the generation of down-stream vasoactive complement mediators
The result is hereditary angioedema, characterized by recurrent episodes of localized edema affecting the skin and/or mucous membranes.

66. Objectives Systemic manifestation Patterns of Acute Inflammation
Outcomes of Acute Inflammation
Patterns of chronic Inflammation
Defect in leukocyte function
Complement deficiency
Systemic manifestation

67. Systemic effects of Inflammation
Acute phase reaction/response
- IL-1 and TNF
- Fever
- Malaise
- Anorexia
Bone marrow
- leukocytosis
- IL-1 + TNF
Lymphoid organs
Liver
-IL-6, IL-1, TNF
-Acute phase proteins
C-reactive protein
Lipopolysaccharide binding protein
Serum amyloid A
a-2 macroglobulin
Haptoglobin
Ceruloplasmin
fibrinogen

68. Systemic Effects of Inflammation Fever
Fever is produced in response to Pyrogens
What are pyrogens?
act by stimulating prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus.
Bacterial products (called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens) that increase the enzymes (cyclooxygenases) that convert AA into prostaglandins.

69. Fever
In the hypothalamus, the prostaglandins, especially PGE2, stimulate the production of neurotransmitters such as cyclic AMP, which function to reset the temperature set-point at a higher level.
NSAIDs, including aspirin , reduce fever by inhibiting cyclooxygenase and thus blocking prostaglandin synthesis.
fever may induce heat shock proteins that enhance lymphocyte responses to microbial antigens.

70. 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,

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

72. Acute inflammation is marked by an increase in inflammatory cells
Acute inflammation is marked by an increase in inflammatory cells. Perhaps the simplest indicator of acute inflammation is an increase in the white blood cell count in the peripheal blood, here marked by an increase in segmented neutrophils (PMN's).

73. An experiment introduces bacteria into a perfused tissue preparation
An experiment introduces bacteria into a perfused tissue preparation. Leukocytes then leave the vasculature and migrate to the site of bacterial inoculation. The movement of these leukocytes is most likely to be mediated by which of the following substances? (A) Bradykinin (B) Chemokines (C) Histamine (D) Prostaglandins (E) Complement C3a

74. A 32-year-old woman has had a chronic cough with fever for the past month. On physical examination, she has a temperature of 37.5°C, and on auscultation of the chest, crackles are heard in all lung fields. A chest radiograph shows many small, ill-defined nodular opacities in all lung fields. A transbronchial biopsy specimen shows interstitial infiltrates with lymphocytes, plasma cells, and epithelioid macrophages. Which of the following infectious agents is the most likely cause of this appearance?
(A) Staphylococcus aureus (B) Plasmodium falciparurn (C) Candida albi cans (D) Mycobacteriurn tuberculosis (E) Klebsiella pneumo nine (F) Cytomegalovirus

76. Thank you

77. Acute inflammation Time 4-6 hours to 3-5 days Vascular involvement
Active hyperemia
Edema, occ.fibrin thrombi
Neutrophils
Cardinal signs of inflammation
Lymphatics
Role to remove exudate
Can lead to inflammation.
Lymphangitis
Lymphadenitis