INFLAMMATION II : CHRONIC
I.
---- Patrick C.J. Ward, M.D.
2008
CHRONIC INFLAMMATION: GENERAL PRINCIPLES
A. Weeks or months
B. Simultaneous

Active inflammation

Tissue destruction

Attempted repair
II.
CHRONIC INFLAMMATION: SPECIFIC EXAMPLES
A. Microorganisms

Tuberculosis

Syphilis

Certain fungi
B.
Exogenous or endogenous toxic agents
Silica

Atherosclerosis (toxic plasma lipid components)

C.
Microorganisms
D.
Autoimmune


III.
Rheumatoid arthritis
Lupus erythematosis
CHRONIC INFLAMMATION: HISTOLOGY
A. MONONUCLEAR CELLS
1. Macrophages (life span of several months)





Evolve from blood monocytes
Assume phagocytic roles
Activated by cytokines (from T-cells, bacteria)
Begin secreting, leading to injury, fibrosis
DISAPPEAR or ACCUMULATE
Fig. 2.28
B.
C.
Lymphocytes (B, T, ± memory)

lymphokines, e.g., IFN-
- activate macrophages to produce monokines

round robin
Plasma cells: secrete antibodies against
persistent antigens / irritants

altered tissue components

IV.
Other cells: eosinophils, mast cells may participate in certain immune
inflammatory reactions
A. FOREIGN-BODY GIANT CELLS
1. Seen in response to particulate material

particles generally small, engulfable

giant cells often work in pairs or groups
2. Attack is often ineffective
3. FBGCR IS NOT A GRANULOMATOUS REACTION
B. CHRONIC INFLAMMATION: SINUS TRACT FORMATION
1. 54 y/o female, a recovering alcoholic. Had right jaw infection (probably
actinomycotic) in October with severe cellulitis below the mandible.
Responded well to antibiotics but developed two residual sinus tracts in right
lower cheek area. Sinuses removed in early March.
V.
CONCEPT OF FOREIGNESS: Body reacts predictably to material considered nonself.
A. Animal
B. Mineral
C. Vegetable
VI.
FOREIGN BODY GIANT CELL REACTION
A. Usually follows an intrusion of foreign, inert or indigestible material
VII.
MENU OF GRANULOMATA
A. Foreign body---- Indigestible material
B. FOREIGN BODY GRANULOMA
1. Immune reaction to poorly soluble or particulate material

Particles embraced by macrophages

Presented to certain T-lymphocytes

Latter activated, produce cytokines as follows:
-
IL-2 activates other lymphocytes (perpetuation)
IFN- transforms Møs into:


multinucleated giant cells (e.g., Langhans)
epithelioid forms
2. Non-caseating ---- Sarcoidosis
3. Caseating ------a. Tubercle bacilli
b. Histoplasma
c. Coccidiodiomycosis
4. Necrotizing ---a. Cat-scratch
b. Tularemia
c. LGV
d. Brucellosis
VIII.
A.
B.
C.
D.
E.
F.
The Dissemination of Bacteria: from original arena to distal seeding sites
Bacteria Innoculation: Milestones
1st Line: innate defense system
2nd Line: monocyte/macrophage
3rd Line: Lymphatic system – Red Lines = move ass
1. Lymphatics – held open when tissue swells due to attachments on sides/walls
of lymphatic vessel. Pressure from swelling tissue actually pulls lymphatics
open more.
2. Lymphangitis
3. Lymphadenopathy
- Follicular hyperplasia
- Sinusoidal hyperplasia
- Paracortical (T-zone hyperplasia)
4. Lymphadenitis
4th Line: Reticuloendothelial System
1. Phagocytic cells of: German word = Grabenass
- Liver
- Spleen
- Lymph node
- Bone Marrow
5th Milestone: Bugs in blood (more likely to be seen in neutrophils or monocytes
in blood) Seeding of bugs elsewhere
1. Vacuoles in neutrophils from blood smear = move ass
Seeding: LBT’s, Cloud of blue bugs – micro abscesses of neutrophils
1. Heart
2. Meninges
3. Kidneys
4. Joints
IX. MORPHOLOGICAL PATTERNS IN INFLAMMATION
A. Serous: thinned, low specific gravity juice
B. Fibrinous
1. Cavities, lungs
2. Resolution
3. Organization
C. Suppaurative
1. Staphylococcus: deep seeding
2. Surround: attempted repair, walling off, abscess
D. Ulcerative:
1. Mucosal surfaces of many tubes – hollow viscera (stomach, intestine, oral
pharyinx, bronchi
a. Stomach ulcer on the “Magenstrasse”
- Smooth edges = benign
- Raised and rough edges = malignant
- If perforates, causes peritonitis. If hits artery = possibly lethal
b. Duodenal ulcer = (almost) never malignant
- Can perforate artery and be lethal
2. Skin
a. Lower extremities – induced by poor circulation
b. Bed sores – induced by unrelenting pressure
3. Both heal by scarring
X. DEFECTIVE FUNCTION/RESPONSE
A. PMN production
1. AML
2. Drugs: lots of drugs cause neutropenia so always check what medications
person is on
3. Irradiation
4. Chediak-Higashi
5. Mets
B. Adherence
1. Diabetes mellitus
2. EtOH
3. Steroids
4. beta-chain of integrins (LAD-I)
C. Chemotaxis
1. Diabetes mellitus
2. immunodeficiencies
D. Phagocytosis
1. Diabetes mellitus
2. Post splenectomy blood picture (decreased Ig, decreased Complement)
3. Chediak-Higashi
E. Killing
1. MPO deficiency
2. Chronic Granulomatous Disease
a. Defect in microbicidal activity
b. Recurrent bacterial infections
c. Inherited defects in genes encoding NADPH oxidase
- X-linked (membrane-bound component)
- Autosomal recessive (cytoplasmic components x2)
•
G-6-P + NADP+
Pentose + CO2 + NADPH
•
202 + NADPH
NADP+ + 2O2 + H+
+
•
202 + 2H
O2 + H2O2
•
2GSH + H2O2
GSSG + 2H2O
•
GSSG + NADPH
2GSH + NADP+
c. Nitro-Blue tetrazolium test: diagnostic for disease
•
In the metabolism of glucose through the pentose shunt:
 NADPH is generated from NADP
•
When NBT (colorless) is reduced to NBTH:

Formazan (a black pigment) is formed
•
Note: increased NBT reduction implies increased metabolic activity
in the shunt
d. CGD: Pathogenic organisms
- Staphylococci
- Enteric organisms, e.g.:
• E. coli
• Serratia
• Salmonella
- Fungi:
• Candida
• Aspergillus
e. CGD: Organs involved
- Membranes:
• Skin
• GIT
• Lungs
- RES, notably:
• Liver
f. CGD: Histopathology
- Suppurative inflammation with necrosis
- Necrotizing GRANULOMATOID lesions
3. Severe G6PD deficiency
a. Net effect same as CGD but later onset of infections
b. Defect is severe; hemolytic anemia is always present
c. Basic lesion:
- Deficiency of NADPH substrate for NADPH oxidase
d. Net result:
- Failure of respiratory burst
- Sharp reduction of O2 –dependent killing
XI. FEVER
A. Pyrogens:
1. Exogenous bacterial products lead to
2. Endogenous release of IL-1, TNF by WBC
a. Increase in cyclooxygenases (PGE2)
- Note: NSAIDS and aspirin inhibit cyclooxygenase (PGE2)
B. In hypothalamus:
1. PGE2 stimulates production of cyclic AMP
2. Latter resets temperature set-point
3. Pyrogens reach hypothalamus by:
a. Crossing blood brain barrier (BBB) and/or
b. Acquire access in regions lacking BBB
C. Initiation: set point increases
1. Vasoconstriction in skin
2. Shivering
D. Plateau: set point reached
1. Shivering stops
E. Resolution: set point decreases
1. Vasodilation in skin
2. Sweating
F. What does Fever do?
1. Helps Ward off bacterial infection
a. Increases efficiency of killing (?)
b. Impairs bacterial replication (?)
c. Induces HSPs, enhancing lymphocyte response (?)
XII.
ACUTE PHASE REACTION: GENERAL
A. Liver synthesis increased several hundred-fold
1. CRP – upregulated by IL-6
2. Fibrinogen – upregulated by IL-6
3. SAA – upregulated by IL-1 or TNF
B. CRP & SAA may act as opsonins for bacteria
C. Increased fibrinogen causes rouleaux formation (ESR)
D. Prolonged SAA production causes secondary amyloidosis
E. Increased CRP levels in blood may indicate:
1. Imminent MI I patients with CAD
2. Need for anti-inflammatory agents for same