INFLAMMATION & REPAIR
Lecture Chronic Inflammation
Winter 2013
Chelsea Martin Special thanks to Drs. Hanna and Forzan
Termination of the Acute Inflammatory Response
When the stimulus has been dealt with:
• mediators have short lives (degraded after release)
• produced in short bursts when stimulus is present
• switch to anti-inflammatory chemical mediators
TGF-β
Lipoxins
Termination of the Acute Inflammatory Response
If all goes well:
• return of normal vascular (im)permeability
• cessation of leukocyte infiltration and death of neutrophils in tissue
• removal of excess fluid, WBC’s, foreign material, necrotic debris
• repair of inflamed site
• return to normal structure and function
Outcome of Acute Inflammation
Resolution
• requires:
• cells which can repair (skin vs brain)
• minimal exudate
• mild tissue damage
Outcome of Acute Inflammation
Abscess Formation • pyogenic organisms
Arcanobacterium pyogenes
Streptococcus sp
Staph. aureus
Morph Dx:
Encephalitis, suppurative,
multifocal, chronic (chronic-
active), severe
Outcome of Acute Inflammation
Outcome of Acute Inflammation
Abscess Formation • pyogenic organisms
Arcanobacterium pyogenes
Streptococcus sp
Staph. aureus
Morph Dx:
Hepatitis, suppurative,
multifocal, chronic, severe
aka hepatic abscess
Morph Dx: Pleural fibrosis (adhesions), diffuse, severe
Outcome of Acute Inflammation
Fibrosis
• repair by CT replacement when:
substantial tissue destruction
tissue can not regenerate
abundant fibrin exudate
Masson Trichrome stain for CT
H&E stain
Outcome of Acute Inflammation
Chronic Inflammation
• inflammation of prolonged duration in
which inflammation, tissue injury and
attempts at repair coexist.
• characterized by:
mononuclear cell infiltrate
progressive tissue injury
repair by angiogenesis & fibrosis
Causes of Chronic Inflammation
Progression from acute inflammation
• unresolved acute process
persistence of agent
interference with normal healing
Some specific injurious agents
• some viral infections (eg CAE, PCV-2)
• some persistent microbial infections
Mycobacterium spp
Fungi
• prolonged exposure to some toxic agents
• autoimmune diseases
Gross Appearance of Chronic Inflammation
Cirrhosis
Renal Fibrosis
Histologic Features of Chronic Inflammation
• Mononuclear infiltrations
Macrophages
Epithelioid macrophages
Multinucleated giant cells
Lymphocytes
Plasma cells
• Tissue destruction
• Fibrosis / angiogenesis
• chronic inflammation with concurrent acute changes
esp abundant fibrin &/or neutrophils
Note, all chronic inflammatory lesions are still active, if not, they would be healed &/or scar tissue.
“Chronic-active” is only used when there are abundant neutrophils &/or fibrin in a chronic lesion.
Chronic-active Inflammation
Morph Dx (Cow):
Endocarditis, fibrinous, multifocal to coalescing,
chronic (chronic-active), severe, with fibrosis
Chronic-active Inflammation
Morph. Dx (horse):
Pericarditis, fibrinous, diffuse, chronic
(chronic-active), severe, with abundant
fibrosis
Chronic-active Inflammation
Fibrin Fibrosis
Acute inflammation of the lung
1) neutrophils fill the alveolar spaces
2) blood vessels are dilated (hyperemia)
3) fibrin may be present
Chronic vs Acute Inflammation
Chronic inflammation in the lung:
1) chronic inflammatory cells (*)
2) destruction of parenchyma (normal alveoli type 1
pneumocytes replaced by type 2 pneumocytes
(arrowheads)
3) replacement by fibrous connective tissue
(black arrows)
*
Pathogenesis of Chronic Inflammation
Persistent release of chemical mediators induces:
• tissue destruction
• persistent increase in blood flow
• increased vascular permeability
• recruitment of inflammatory cells
mostly macrophages, lymphocytes, plasma cells
• proliferation
parenchymal (epithelial) cells
supportive cells (fibroblasts & endothelial cells → granulation tissue)
Chronic Inflammation
• severity of chronic inflammation may not correlate with the onset of clinical signs.
• chronic lesion may develop as an insidious, low-grade, subclinical process without
history of a prior acute episode.
• eg, due to the high functional reserve of the liver and kidney it is common to find
severe chronic lesions in these organs in animals that die suddenly with no prior
clinical history disease.
Cells involved in Chronic inflammation Macrophage - “The WONDER CELL”
Bone marrow origin
• monocytes turn into macrophages in tissues
Macrophage - functions
• Phagocytosis
microbes, senescent cells, particles
• Sentinels for Immune System present Ag to lymphocytes
• When activated:
increase cell size
increase lysosomal enzymes
increase metabolism
increase ability to phagocytize, kill
and digest
Macrophage - types
Epithelioid macrophages
• abundant cytoplasm (epithelial-like)
• fewer receptors / less phagocytosis
• specialized in secretion of cytokines
• fuse into multinucleated giant cells
Multinucleated giant cells
• coalescence of macrophages
• due to IL-4, IFN-γ
• morphology varies
Langhans Foreign body
Touton
Langhans: peripheral nuclei; most types of chronic inflammation.
Foreign body: nuclei scattered throughout the cytoplasm.
Touton: rosette of nuclei at the centre, can be in tumours of
histiocytic (tissue macrophage) origin or xanthomas (masses
composed of lipids, foamy macrophages and giant cells;
associated with defects in lipid or triglyceride metabolism).
Multinucleated Giant Cells
Macrophage
• continued recruitment of monocytes from circulation (if persistent agent)
C5a, IL-8, PDGF, TGF-β
• can also increase due to local proliferation (replication).
• macrophages can be activated by microbial products (eg LPS), cytokines
(eg IFN-γ, IL-4) & other mediators.
• activated macrophages are immobilized at inflammatory sites (& long lived)
• Deleterious effects (tissue destruction – hallmark)
Participation in Chronic Inflammation
Actions of
Activated
Macrophages
Lymphocytes and Plasma Cells
Lymphocytes and Plasma Cells
• B cells plasma cells (antibody production)
• T cells: activated by MØ’s & then produce IFNγ activates MØ’s (amplification)
• MØ’s & lymphocytes continuously stimulate one another until Ag is removed
• +/- Eosinophils
• +/- Mast Cells
• +/- Neutrophils
Cells involved in Chronic inflammation Others
Cutaneous habronemiasis, skin, horse eosinophils
Granulomatous Inflammation
Definition = a chronic inflammatory reaction dominated by macrophages;
esp epithelioid macrophages &/or multinucleated giant cells.
• distinct pattern of chronic inflammation
• mechanism for dealing with indigestible substances
• macrophages predominate + some lymphocytes
Granulomatous Inflammation - Etiology
• Bacteria - eg Mycobacterium spp, Actinomyces, Actinobacillus
• Fungi - eg Aspergillus, Blastomyces, Cryptococcus, etc
• Parasites - eg ascarid larvae
Acid-fast +ve M. paratuberculosis
in Johne’s disease
Mature granuloma centered on an ascarid
larvae.
Granulomatous inflammation with
intralesional fungi (Blastomyces)
• Foreign material resistant to digestion, eg’s:
inert particles (silica, asbestos)
mineral oil
plant material (eg splinters, grass awns)
suture material
certain body substances (eg hair, keratin, sperm)
Granulomatous Inflammation - Etiology
Pyogranulomatous dermatitis with intralesional hair shaft Granulomatous inflammation with with intralesional plant
material.
• nodular / multinodular, firm lesions
with often central areas of caseous
necrosis
OR (less frequently)
diffuse (or locally extensive)
thickening of a tissue
Granulomatous Inflammation – Gross Appearance
Johne’s disease, bovine – locally extensive (segmental)
granulomatous enteritis due to M. paratuberculosis
Bovine tuberculosis – multifocal (to coalescing)
granulomatous lymphadenitis due to M. bovis
GRANULOMA
• certain pathogens cause a focal type of granulomatous inflammation with a
central aggregate of macrophages (often as epithelioid &/or giant cells)
• usually surrounded by a rim of lymphocytes & plasma cells
• fibrous connective tissue often surrounds granulomas
http://granuloma.homestead.com/files/granuloma_non_necrotizing78.jpg
GRANULOMAS
Simple granuloma: organized accumulation of
macrophages and epithelioid cells, often
rimmed by lymphocytes.
GRANULOMAS
Complex granuloma: granuloma with a
central area of necrosis (which may show
dystrophic calcification / mineralization).
Necrosis may be due to release of oxygen
free radicals &/or lysosomal enzymes or
ischemia.
GRANULOMAS
Pyogranuloma: core is rich in neutrophils;
often these neutrophils have undergone
degeneration.
GRANULOMAS
Foreign body granulomas: often
characterized by the abundance of foreign
body giant cells.
- inert particles (silica, asbestos, etc)
- lipids resistant to metabolism (mineral
oil)
- plant material (wood, grass awns)
- suture material, hair, keratin, sperm,
etc.
Do Not Confuse
GRANULOMATOUS INFLAMMATION with
GRANULATION TISSUE
It’s like confusing fibrinous inflammation with
fibrous connective tissue