1. Dr. Hiba Wazeer Al Zou’bi
Chronic Inflammation
Dr. Hiba Wazeer Al Zou’bi

4. Chronic Inflammation
Inflammation of prolonged duration (weeks to years).
Characterized by:
Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells
Tissue destruction, by the products of the inflammatory cells
Repair

5. Chronic Inflammation Under what circumstances, does it develop?
Progression from acute inflammation.
Persistent microbial infections that are difficult to eradicate
Mycobacterium Tuberculosis, Treponema Pallidum, certain viruses and fungi.
Immune mediated inflammatory disease (Hypersensitivity disease)
Rheumatoid arthritis, Inflammatory bowel disease, Psoriasis
Prolonged exposure to potentially toxic agent
Silica, Cholesterol crystals.

6. Macrophages and mononuclear phagocyte system
Macrophages (Dominant cells of chronic inflammation):
Derived from circulating blood monocytes
Scattered in tissues:
Kupffer cells (liver),
sinus histiocytes (spleen & Lymph node),
alveolar macrophages (lung)
microglia (CNS)

8. How do Macrophages Accumulate at Sites of Chronic Inflammation?
Recruitment of monocytes from circulation by chemotactic factors to the site of injury within hours.
When reach to extravascular tissue transform into macrophages.
Macrophages are larger, have a longer lifespan and a greater capacity for phagocytosis than do blood monocytes.

10. Lymphocytes B and T lymphocytes (CD4 and CD8)
Mobilized in the setting of:
Any specific immune stimulus (i.e., infections)
Non–immune-mediated inflammation (e.g., due to ischemic necrosis or trauma)
In the tissues:
B lymphocytes may develop into plasma cells, which secrete antibodies
CD4+ T lymphocytes are activated to secrete cytokines.

11. Three subsets of CD4+ helper T cells :
TH1 cells: produce the cytokine IFN-γ, which activates macrophages in the classical pathway.
TH2 cells: secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.
TH17 cells: secrete IL-17 and other cytokines that induce the secretion of chemokines responsible for recruiting neutrophils and monocytes .

12. Macrophage-lymphocyte interaction

13. Eosinophils:
Characteristic in:
A. Inflammatory sites around Parasitic infections
Allergic diseases such as asthma
- Eosinophil granules contain major basic protein, a highly charged cationic protein that is toxic to parasites but also causes epithelial cell necrosis.
Mast cells:
- Source of histamine early in allergic reactions

14. An important point:
Although the presence of neutrophils is the hallmark of acute inflammation, many forms of chronic inflammation may continue to show extensive neutrophilic infiltrates, as a result of either persistent microbes or necrotic cells, or mediators elaborated by macrophages.
Such inflammatory lesions are sometimes called “acute on chronic”.

15. Complete Resolution of Inflammation

16. Granuolmatous Inflammation
A distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages with scattered lymphocytes
Tuberculosis is the prototype of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified.

17. Formation of a granuloma effectively “walls off” the offending agent and is therefore a useful defense mechanism.
However, granuloma formation does not always lead to eradication of the causal agent, which is frequently resistant to killing or degradation
Granulomatous inflammation with subsequent fibrosis may be the major cause of organ dysfunction in some diseases, such as tuberculosis.

18. Examples of Granulomatous Inflammation
Bacterial
Mycobacterium tuberculosis
Mycobacterium Leprae (Leprosy)
Trepnema pallidum (Syphilis)
Parasitic
Shcistosomiasis
Fungal
Histoplasmosis
Foreign body
Suture material
Immune mediated
crohn disease
Unknown
Sarcoidosis

19. Histopathology of Granuloma
Epithelioid cells (activated macrophages)
The aggregates of epithelioid macrophages are surrounded by a collar of lymphocytes.
Multinucleate giant cells 40 to 50 μm in diameter (from the fusion of multiple activated macrophages)
Older granulomas may have a rim of fibroblasts and connective tissue

20. In granulomas associated with certain infectious organisms (most classically the tubercle bacillus), a combination of hypoxia and free radical injury leads to a central zone of necrosis.
- Gross examination: Granular, cheesy appearance ( caseous necrosis).
- Microscopic examination: Eosinophilic amorphous, structureless, granular debris, with complete loss of cellular details.

21. The granulomas associated with Crohn disease, sarcoidosis, and foreign body reactions tend to not have necrotic centers and are said to be “noncaseating.”
Healing of granulomas is accompanied by fibrosis that may be quite extensive.

22. Histopathology of Granuloma

23. Histopathology of Granuloma

24. Caseating Granuloma

25. AFB Stain in Caseating Granuloma

26. Systemic Effects of Inflammation (Acute phase reactions)

27. Systemic Acute-phase Reactions

28. The acute-phase response of inflammation
A. Fever,:
- Elevation of body temperature
Produced by substances called pyrogens that act by stimulating prostaglandin synthesis in vascular and perivascular cells in hypothalamus
Bacterial products, such as lipopolysaccharide (LPS) (called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens), which increase the levels of cyclooxygenases that convert AA into prostaglandins

29. B- Elevated plasma levels of acute-phase proteins.
- These proteins are synthesized in the liver, stimulated by IL6:
1. C-reactive protein (CRP)
- Binds to microbial cell walls, and they may act as opsonins and fix complement, thus promoting the elimination of the microbes.
2. Fibrinogen,
- Binds to erythrocytes and causes them to form stacks (Rouleaux) that sediment more rapidly than individual erythrocytes and this is the basis for measuring the erythrocyte sedimentation rate (ESR)
- ESR is a simple test for the systemic inflammatory response,
3. Serum Amyloid A (SAA)

30. C. Leukocytosis:
- Common feature of inflammatory reactions, especially those induced by bacterial infection
The leukocyte count usually climbs to 15,000 to 20,000 cells/mL, but in some cases it may reach 40,000 to 100,000 cells/mL. called leukomoid reaction
The leukocytosis occurs initially because of accelerated release of cells (under the influence of cytokines, including TNF and IL-1) from the bone marrow
Prolonged infection also stimulates production of colony-stimulating factors (CSFs), which increase the bone marrow output of leukocytes, thus compensating for the consumption of these cells in the inflammatory reaction

31. - Most bacterial infections induce an increase in the blood neutrophil count (neutrophilia)
Viral infections, such as infectious mononucleosis, and mumps, german measles associated with increase numbers of lymphocytes (lymphocytosis).
Bronchial asthma and parasite infection cause increase in the number of eosinophils
Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) are paradoxically associated with a decreased number of circulating white cells (leukopenia), because of cytokine-induced sequestration of lymphocytes in lymph nodes.

32. Other:
Increase heart rate and blood pressure
Anorexia
Malaise
Rigor (shivering)
Chills (perception of being cold )