1. Dr (Prof) Vishal Saxena MBBS, MD(Path), FICMR
CHRONIC INFLAMMATION
Dr (Prof) Vishal Saxena
MBBS, MD(Path), FICMR

2. Chronic inflammation
Inflammation of prolonged duration (weeks to months to years) in which :
Active inflammation, tissue destruction and attempts at repair proceed simultaneously.
Most often results from persistence of an injury causing agent.
Tissue destruction is hallmark.
Predominant cell type is mononuclear, which includes macrophages, lymphocytes and plasma cells.

3. Chronic inflammation Chronic inflammation: the characteristics:
Tissue destruction
Infiltration with mononuclear cells (Macrophages, lymphocytes and plasma cells)
Replacement of damaged tissue by connective tissue due to proliferation of fibroblasts and new vessels formation(fibrosis & angiogenesis).
Chronic inflammation Unlike acute inflammation has: Mononuclear cell infiltrate
Induration of affected tissue.
Less swelling (less exudate)
Less hyperemia
Induration-Any pathological hardening or thickening of tissue.

4. Chronic endometritis = Chronic inflammation of endometrium
In general, the inflammatory infiltrate of chronic inflammation consists mainly of mononuclear cells: lymphocytes, plasma cells, and macrophages.
Seen here is chronic endometritis with lymphocytes and plasma cells in the endometrial stroma.
Mononuclear
cells
Chronic endometritis = Chronic inflammation of endometrium

5. Causes of chronic inflammation
Following acute inflammation.
Infections with certain organisms
Viral infections
Mycobacteria (M. tuberculosis)
Treponema pallidum (syphilis)
Fungal infections
Parasitic infections
3. Prolonged exposure to toxic agents.
Silica (silicosis)
Lipids (atherosclerosis)
4. Autoimmune diseases
Rheumatoid arthritis
Multiple sclerosis

6. Cells of chronic inflammation
Different from acute inflammation!!
Monocytes – macrophages (most imp)
Lymphocytes
Plasma cells
Endothelial cells
Fibroblasts
Dominant cellular player in chronic inflammation is the macrophage
Belongs to the:
MONONUCLEAR PHAGOCYTE SYSTEM
Monocytes and / or macrophages are the primary cells in chronic inflammation.

7. Mononuclear Phagocyte System
Consists of :
Circulating blood monocytes and Tissue macrophages (2 types):
Fixed macrophages
Kupffer cells (liver)
Sinus Histiocytes (spleen)
Osteoclasts (Bone)
2. Wandering macrophages
Microglia (CNS)
Alveolar Macrophages (lung)
Remember that tissue macrophages are derived from blood monocytes.

8. IFN gamma by CD4 T cells Bacterial endotoxins
During inflammation macrophages are recruited from the blood (circulating monocytes).
Chemotactic factors: MCP-1.
At the site of injury monocyte transforms in to a larger cell-the macrophage: capable of phagocytosis.
These can become activated macrophages
Due to action of cytokines
Activated macrophages
Greater ability to kill ingested organisms
larger in size
Increased lysosomal enzymes
Activation signal :
IFN gamma by CD4 T cells
Bacterial endotoxins
MCP-1 = monocyte chemoattractant protein-1.

9. Blood vessel Tissue Macrophage IFN γ Activated CD4 T cell
Endotoxin
IFN γ
Activated
CD4 T cell
Activated macrophage
Tissue injury
Fibrosis
Toxic oxygen metabolites
Acid and neutral proteases:
degrade elastic and
collagen fibers.
Growth factors:
PDGF, FGF, TGF beta
Angiogenesis factor

10. Other Functions Microbicidal activity Have superoxide free radicals
Secrete Nitric oxide: vasodilation
Act as Ag presenting cells
Scavenger cells
Secrete Cytokines: IL-1 and TNF

11. Lymphocytes : in chronic inflammation
Lymphocytes: Primary inflammatory cells in
Viral infections
Type IV reactions
Pertussis infection

12. Activated macrophage Activated Lymphocyte
IL-1, TNF
Activated
macrophage
Activated
Lymphocyte
Ag presentation
IFN γ
Activated macrophages present antigen to lymphocytes converting them to activated lymphocytes which secrete IFN-gamma which acts on macrophages to convert them into activated macrophages which secrete IL-1 and TNF which act on lymphocytes and the cycle repeats again and again.
Macrophage

13. Plasma cells :
derived from activated B cells
Functions:
Antibody production
IgM produced on first exposure in acute inflammation
IgG synthesized after days
IgG is the main immunoglobulin of chronic inflammation

14. Patterns of chronic inflammation
1. Chronic nonspecific inflammation
2. Granulomatous inflammation
Chronic nonspecific inflammation: Characterized by
Infiltration by mononuclear cells (e.g lymphocytes, macrophages and plasma cells).
Inflammatory response not specific for any particular etiological agent.

15. Granulomatous inflammation
Definition: specialized form of chronic inflammation characterized by formation of granulomas.
Granulomas: are localized collections of modified macrophages (epithelioid cells).
Two types:
Caseating and
Non-caseating

16. Composition of granulomas
Epithelioid cells
IFN gamma transforms macrophages  epithelioid cells (hallmark cell of granuloma)
Multinucleated giant cells
Formed by fusion of epithelioid cells
Langhan’s type giant cells (TB)
Foreign body type of giant cells
May be present; but not necessary
Lymphocytes, Plasma cells
Central caseous necrosis
Seen in granulomas due to tuberculosis & fungal infections.
Rare in other granulomatous diseases.

17. = activated macrophage
Blood vessel
INF γ
Epithelioid cell
= activated macrophage
Monocyte
Granuloma

18. Examples of granulomatous diseases
Cause
Reaction
Tuberculosis
M.tuberculosis
Caseating*
Leprosy
M.Leprae
Non-caseating
Syphilis
T.Pallidum
Gumma
Cat scratch disease
Gram negative bacillus
Stellate granuloma
Fungal infections
Histoplasma, Coccidioides
Schistosomiasis
S.hematobium
Silicosis,Berylliosis
Silica,beryllium
Foreign body
Suture, Breast prosthesis
Sarcoidosis
Unknown
Examples of granulomatous diseases
Bacterial
Tuberculosis
Leprosy
Syphilis
Cat scratch disease
Parasitic
Schistosomiasis
Fungal
Histoplasma capsulatum
Blastomycosis
Coccidioides immitis
Inorganic metal or dust
Silicosis
Berylliosis
Foreign body
Suture
Breast prosthesis
Unknown
Sarcoidosis

19. Grossly, a granuloma tends to be a focal lesion.
Seen here in a hilar lymph node is a granuloma and a granuloma below the pleura.
Granulomas due to infection by M. tuberculosis are often "caseating" because they have prominent caseous necrosis.

20. Multiple tuberculous granulomas
Multiple tuberculous granulomas in the lung.

21. Granuloma
Giant cells are a "committee" of epithelioid macrophages. Seen here is a Langhan’s type giant cell in which the nuclei are lined up around the periphery of the cell.

22. Granuloma Langhans Giant Cell Lymphocytic Rim Caseous Necrosis
Epithelioid
Macrophage

23. Two spherules of Coccidioides immitis
Granulomatous inflammation occurs in response to some agents which persist for a long time and require a more orchestrated immune response to fight them. The granuloma seen here demonstrates the typical rounded and focal nature of this type of inflammation. A couple of spherules of C. immitis are present in the giant cell in the center.

24. Foreign body type giant cell
vegetable material
Here is a foreign body type giant cell at the upper left of center adjacent to a segment of vegetable material aspirated into the lung. Such foreign body giant cells have nuclei scattered haphazardly about the cell.

25. Suture Foreign body material type giant cell
Two foreign body giant cells are seen just to the right of center where there is a bluish strand of suture material from a previous operation.

26. Granuloma Giant cell Sarcoidosis
Lung, sarcoid granuloma - High power  The characteristic noncaseating granulomas of sarcoidosis, containing multinucleated giant cells, are well illustrated in this image. As the sarcoid granulomas heal, they are replaced by fibrous tissue, giving the appearance of diffuse interstitial pulmonary fibrosis.
Are there extrapulmonary lesions in sarcoidosis? What organs are commonly involved? While almost any organ may be involved, common sites include eye, salivary glands, skin, spleen and liver.

27. Cat scratch disease
Bartonella henselae: bacteria responsible for cat scratch disease.

28. Outcomes of chronic inflammation
Development of secondary amyloidosis.
due to production of serum associated amyloid (SAA) protein by the liver
Chronic inflammation repair by fibrosis:
Intestinal obstruction by fibrous bands (adhesions)
Induction of cancer (scar cancer of lung)
Stricture (narrowing) formation.
4. Fistula (pathological communication
between two hollow organs) e.g.
colovesical fistula
Examples of secondary amyloidosis associated with chronic inflammation: tuberculosis, leprosy, rheumatoid arthritis etc.

29. Lymphatics and lymphnodes in inflammation
Filter the Extravascular fluid.
Represent a secondary line of defense.
Lymphatics:
Help to drain edema fluid during inflammation
Can get inflamed: lymphangitis
Lymphnodes:
May get inflamed = lymphadenitis
May get enlarged = lymphadenopathy
If fail to filter the microbes  circulation  bacteremia.

30. Lab test abnormalities associated with inflammation
Leukocyte alteration
Anemia of chronic disease
Erythrocyte sedimentation rate

31. Leukocyte alteration Acute inflammation (e.g. bacterial infection) :
Neutrophilic leukocytosis: ↑release of neutrophils from bone marrow.
Mediated by IL-1 and TNF
Left shift: >10% band neutrophils or the presence of earlier precursors (e.g. metamyelocytes).
Toxic granulation: prominence of azurophilic granules.
Cytoplasmic vacuolation: represent phagolysosomes

32. Leukemoid reaction: reactive increase in WBC count.
Usually occurs secondary to bacterial infection.
Neutrophilic leukocytosis secondary to bacterial infection.
WBC counts are high, hence can be confused with Chronic myeloid leukemia (also characterized by high WBC count)

33. To differentiate, use LAP score (leukocyte alkaline phosphatase stain).
High LAP score in Leukemoid reaction (since neutrophils are normal and contain the enzyme).
Low LAP score in Chronic myeloid leukemia since the neutrophils are neoplastic and do not contain the enzyme.

34. patient with bacterial sepsis
Coarse purple cytoplasmic granules (toxic granulations)
Peripheral blood
smear from
patient with bacterial sepsis

35. Cytoplasmic vacuolation

36. Anemia of chronic disease
Associated with chronic inflammation.
Reason:
Decreased availability of iron
(trapped in macrophages)

37. Erythrocyte sedimentation rate
ESR: is the rate of settling of RBCs in a vertical tube in mm/hr.
Increased in inflammation (acute and chronic).
Plasma factors or RBC factors that promote rouleaux formation increase ESR.
Plasma Factor:
Increased fibrinogen (acute phase reactant)  decreases negative charge in RBCs promoting rouleaux formation.
RBC factor:
Anemia promotes rouleaux formation.

38. ESR Normal range: 0-15mm/hr in men and 0-20mm/hr in women.
ESR increased:
acute/chronic inflammation
multiple myeloma
Best initial screen for temporal arteritis:
if normal, temporal arteritis unlikely.
if increased, start corticosteroids.

39. C-reactive protein Acute phase reactant.
An excellent marker for bacterial (increased) versus viral infections (normal).

40. Eosinophils
Play an important role in parasitic infections (invasive helminths) and
IgE mediated allergic reactions.
Eosinophil chemokine: eotaxin
Eosinophil granules contain major basic protein (MBP)
Toxic to parasites
Also causes epithelial cell lysis

41. Eosinophilia: increase in number of eosinophils in peripheral blood:
type I hypersensitivity reaction:
allergic rhinitis
bronchial asthma
drug allergies
response to invasive helminthic
infections
miscellaneous:
Hodgkin’s Lymphoma
Polyarteritis nodosa (PAN)

42. Basophils Tissue based basophils are called mast cells
Present in high numbers in lung and skin
Play an important role in IgE mediated reactions (allergies and anaphylaxis)
Release histamine