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