2. Objectives
This lecture provides an understanding of
Cells involved, etiologies, cellular
constituents, general histologic features,
of chronic inflammation
Granulomatous inflammation
Role of lymphatics in the inflammation

3. Learning outcomes
At the end of the lecture ,student will be able to
Identify and distinguish the cells involved in chronic
inflammation
List various causes of chronic inflammation
Describe the morphological features of chronic
inflammation
Define chronic granulomatous inflammation
List examples of diseases with granulomatous
inflammation
Describe the morphology of granulomatous inflammation
Describe the role of lymphatics in the inflammation

4. Tissue response to an injury

5. Definition of chronic inflammation
an inflammatory response of prolonged
duration (weeks – months - years)
provoked by the persistence of the causative
stimulus
simultaneous presence of active
inflammation, tissue destruction and repair

6. DEFINITION
Inflammation of prolonged duration
( weeks or months) in which
- active inflammation
- tissue destruction and
- attempts at healing
proceed simultaneously

7. Chronic Inflammation arrives in 3 ways:
1.May follow acute inflammation
e.g pneumonia -> chronic lung abscess
2. Repeated bouts of acute inflammⁿ
e.g cholecystitis , pyelonephritis
3. Begin insiduously as a low grade
smouldering reponse

8. Chronic inflammation arises in the
following settings: (CAUSES)
Persistent infections
Immune-mediated inflammatory
diseases
Prolonged exposure to non-degradable
but potentially toxic substances

9. Persistent infections by microbes
that are difficult to eradicate
Eg: mycobacteria,
Treponema pallidum (causative organism
of syphilis)
certain viruses, fungi and parasites

10. Immune-mediated inflammatory diseases
autoimmune diseases
(under certain conditions, immune reactions
develop against the individual's own tissues)
Eg:rheumatoid arthritis, multiple sclerosis
allergic diseases
hypersensitivity reaction that are caused by excessive
and inappropriate activation of the immune system)
Eg:bronchial asthma

11. Prolonged exposure to toxic substances
(non-degradable)
– Exogenous (asbestos, silicon)
– Endogenous
(chronically elevated plasma lipid components which
may contribute to atherosclerosis)

12. Cells of Chronic Inflammation
macrophages
lymphocytes
plasma cells
eosinophils
neutrophils

13. Maturation of Mononuclear Phagocytes

14. Macrophage
• Mononuclear Phagocyte System (MPS)
Circulating blood monocytes →Tissue
macrophages
↓
Kupffer cells (liver)
Sinus Histiocytes (spleen)
Microglia (CNS)
Alveolar Macrophages (lung)

15. Macrophage
During chronic inflammation
macrophages serve to eliminate
injurious agents and initiate repair
however, they are as well responsible
for much of the tissue injury that
occurs

16. Tissue macrophage
Activated T cell or NK cell
Non Immune activation: IFN-g
Endotoxins,
fibronectin,
chemical mediators
Activated macrophage
Fibrosis (Scaring)
Growth factors involved
in fibroblast proliferation
(PDGF,TGFb,FGF)
Tissue injury Angiogenesis factors
Toxic oxygen metabolites (FGF,VEGF)
Metallo-proteases Collagen deposition
Coagulation factors (IL-13 and TGFb)
AA metabolites and NO

17. Macrophage:
component of MPS
transformed from monocytes
prime cell of chr: inflammⁿ
Activated by
lymphokines
bact: endotoxin
Activated macrophages
secrete:
Enzymes
O2 metabolites , cytokines
growth factors
NO , PAF,IFN α
resulting
t/s destruction
neovascularisation
 fibrosis

18. In chronic inflammation
macrophage accumulation persists by
different mechanisms
Continued recruitment of monocytes
from the circulation
Local proliferation
Prolonged survival and immobilization

20. Lymphocytes:
Naive lymphocytes encounter antigen-presenting
cells and become antigen-specific lymphocytes
Activated T lymphocytes
Regulate macrophage activation and recruitment
by secreting specific mediators cytokines
(lymphokines) (IFN-γ)
Modulate anti-body production and cell-mediated
cytotoxicity and maintain immunologic memory

22. Plasma cells:
develop from activated B lymphocytes
produce antibody directed either against
persistent antigen in the inflammatory site
or against altered tissue components

24. Mast Cells:
- Widely distributed in connective tissues and
participate in both acute and persistent
inflammatory reactions
- Binds the Fc portion of the IgE antibody

25. Cells of Chronic Inflammation
Eosinophils:
- parasitic infections
- Mediated by IgE
- Eotaxin – a chemokine that has the ability to
prime eosinophils for chemotaxis
- have granules that contain major basic protein,
a highly cationic protein that is toxic to
parasites but also causes lysis of mammalian
epithelial cells

26. Chronic inflammation is characterized by
Infiltration with mononuclear cells
(including macrophages, lymphocytes, and plasma cells)
indicates persistent reaction to injury
Tissue destruction
(largely induced by the products of the inflammatory cells)
Repair (Healing)
(involving new vessel proliferation (angiogenesis) and fibrosis)
Attempt to replace lost tissue

27. Chronic inflammation in the lung
howing all three characteristic histologic features:
1) collection of chronic inflammatory cells
2) destruction of parenchyma
normal alveoli are replaced by spaces lined by cuboidal epithelium
3) replacement by connective tissue (fibrosis)

28. Chronic ulcer such as
chronic peptic ulcer of the stomach with
breach of the mucosa, a base lined by
granulation tissue and with fibrous tissue
extending through the muscle layers of the
wall

29. Chronic abscess cavity for example
osteomyelitis, empyema thoraccis
Thickening of the wall of a hollow viscus by
fibrous tissue in the presence of a chronic
inflammatory cell infiltrate, for example
Crohn's disease, chronic cholecystitis

30. Fibrosis
The most prominent feature of the chronic
inflammatory reaction when most of the
chronic inflammatory cell infiltrate has
subsided. This is commonly seen in
chronic cholecystitis
'hour-glass contracture' of the stomach, lead to acquired
pyloric stenosis
the strictures that characterise Crohn's diseas

31. Gallbladder showing chronic cholecystitis
The wall is greatly thickened by fibrous tissue

32. Chronic inflammation in the wall of a gallbladder
that has experienced previous episodes of acute cholecystitis
Aggregates of lymphocytes and ingrowing fibroblasts

33. Chronic peptic ulcer of the stomach
Continuing tissue destruction and repair
cause replacement of the gastric wall muscle layers by fibrous tissue
As the fibrous tissue contracts
permanent distortion of the gastric shape may result

34. CHRONIC GRANULOMATOUS
INFLAMMATION
A distinctive pattern of chronic inflammation
characterized by focus of chronic
inflammation consisting of a microscopic
aggregation of macrophages that are
transformed into epithelium-like cells,
surrounded by a collar of mononuclear
leukocytes, principally lymphocytes and
occasionally plasma cells fibroblasts

36. CHRONIC GRANULOMATOUS
INFLAMMATION
A distinctive pattern of chronic
inflammation characterised by
granulomas which are small nodular
collections in which the predominant
cell is the activated macrophage with
epithelial like (epitheloid) appearance
with abundant pink cytoplasm

37. MORPHOLOGY
Granuloma:
A granuloma is a focus of chronic
inflammation consisting of
a microscopic aggregation of macrophages
that are transformed into epithelium-like
cells (epitheloid cells) surrounded by a
collar of mononuclear leukocytes,
principally lymphocytes and occasionally
plasma cells

38. Epitheloid cell:(Activated
Macrophage)
-pale pink granular cytoplasm
-indistinct cell boundary
-oval or elongated nucleus +/- folding of
nuclear membrane
-may fuse to form giant cells

39. Giant cells:
- 40 to 50 µ in diam
- abundant cytoplasm
Langhans' type - 20 or more nuclei in
periphery ( horse shoe pattern)
Foreign body type - nuclei scattered in
cytoplasm

40. Caseous necrosis
Grossly - this has a granular, cheesy
appearance
Microscopically - appears as amorphous,
structureless, granular debris, with
complete loss of cellular details

41. central caseous necrosis
Epitheloid Cells

43. Typical tuberculous granuloma showing
an area of central necrosis surrounded by
multiple Langhans-type giant cells, epithelioid cells, and lymphocytes.
lymphocytes
central necrosis
Langhans-type giant cells

44. Granuloma with caseous necrosis

45. Scattered granulomas
The lung of a patient with miliary tuberculosis
1 to 2 mm granulomas are scattered around like millet seeds
(millet is a type of cereal grain)
With poor immune response
extensive spread of infection with the production of
a "miliary" pattern of granulomas

46. Types of granuloma:
1. Foreign body granuloma
2. Immune granuloma
(a) indigestible particles or organisms
(b) T cell mediated Immune Response
3. Toxic granuloma – due to silicon,
beryllium

47. In tuberculosis, granuloma is
referred
to as tubercle,
• Hard tubercle
• Soft tubercle – characterized by presence
of central caseous necrosis; caseation
necrosis is rare in other granulomatous
disease

48. Examples of Diseases with
Granulomatous Inflammation
 Tuberculosis
 Leprosy
 Syphillis
 Cat – scrath disease
 Sarcoidosis
 Crohn disease (inflammatory bowel
disease)

49. Examples of Chronic Granulomatous
Inflammation:
Bacterial
TB, leprosy, syphilis,
Parasitic
Schistosomiasis
Fungal
Cryptococcosis,Histoplasmosis,Blastomycosis,
Unknown
Sarcoidosis

50. Common Causes of Epithelioid Cell Granulomas.
Disease Causes
Immunologic response
Tuberculosis Mycobacterium tuberculosis
Leprosy (tuberculoid type) Mycobacterium leprae
Histoplasmosis Histoplasma capsulatum
Coccidioidomycosis Coccidioides immitis
Q fever Coxiella burnetii (rickettsial
organism)
Brucellosis Brucella species
Syphilis Treponema pallidum
Sarcoidosis2 Unknown
Crohn's disease2 Unknown
Berylliosis3 Beryllium (? +protein)
Nonimmunologic response
Foreign body (eg, in intravenous drug Talc, fibers (? +protein)

52. COMPARISON OF ACUTE AND
CHRONIC INFLAMMATION
FEATURE ACUTE CHRONIC
INFLAMMATION INFLAMMATION
Onset &duration Immediate & Delayed &
Transient (few weeks,months, years
days)
Pathogenesis Microbial pathogens, Persistent acute inflammation,
foreign bodies (e.g., silicone,
trauma, burns glass), autoimmune disease,
certain types of infection (e.g.,
tuberculosis, leprosy)

53. COMPARISON OF ACUTE AND
CHRONIC INFLAMMATION
FEATURE ACUTE INFLAMMATION CHRONICINFLAMMATION
Primary cells Neutrophils Monocytes/macrophages
cells), B and T
lymphocytes
plasma cells, fibroblasts
Necrosis Present Less prominent
Scar tissue Absent Present
Outcome Complete resolution, Scar tissue formation
disability, amyloidosis
progression to
chronic inflammation
abscess formation

54. Differences between Acute and Chronic Inflammation
Acute Chronic
Duration Short (days) Long (weeks to months)
Onset Acute 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) + (ongoing)
+ (Suppurative and necrotizing inflammation)
Fibrosis (collagen – +
deposition)
Operative host responses Plasma factors: complement, immunoglobulins, properdin, Immune response, phagocytosis, repair
etc; neutrophils, nonimmune phagocytosis
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

55. In acute inflammation the lymphatic channels
become dilated & drain away the oedema fluid of
the inflammatory exudate
This drainage tends to
limit the extent of oedema in the tissues
carry large molecules and some particulate matter
&
antigens are carried to the regional lymph nodes
for recognition by lymphocytes