INFLAMMATION

Inflammation = tissue response to cell injury and infection, by delivery from the
vascular circulation and activation of inflammatory cells and host defense
molecules to remove both cause (e.g. microbes, toxins) and consequences (e.g.
necrotic cells) of cell injury
Causes of inflammation
• Infections: Most common cause. Different microbial organisms and toxins
elicit varying inflammatory responses from mild to severe or acute to chronic
reactions. Outcome depends largely on type of pathogen, host response and
host characteristics
• Tissue necrosis: Elicits inflammation regardless of the cause of cell death
(e.g. ischaemia, trauma, thermal/chemical injury)
• Foreign bodies: Can be due to their presence and/or the trauma they cause /
associated microbes. Can be endogenous e.g. urate crystal deposits in gout
• Immune reactions / hypersensitivity: When the normally protective immune
system is inappropriately directed against self-antigens or environmental
substances, damaging the individual’s own tissues e.g. autoimmune diseases
and allergies.

ACUTE INFLAMMATION
Involves both a vascular and cellular response: (I) Increased blood flow and
vascular permeability Vascular changes are designed to maximise exudation i.e.
the movement of plasma proteins and leucocytes (mediators of host defence)
out of the circulation and into the site of infection or injury.
Exudate = extravascular fluid with high protein concentration and contain
cellular debris. Implies presence of a process causing increased vascular
permeability o Pus = purulent exudate rich in leukocytes (mostly neutrophils),
dead cellular debris +/- microbes
• Transudate = extravascular fluid with low protein concentration (mostly
albumin), little/no cells and low specific gravity. Usually produced as a result of
osmotic or hydrostatic imbalance across the vessel wall without an increase in
vascular permeability
• Oedema = excess fluid in interstitial tissue; or serous cavities (effusion). Can
be either exudate or transudate Changes in vascular flow and caliber
(vasodilatation and stasis)
• Vasodilatation: One of the earliest manifestations of acute inflammation, first
involving arterioles and then opening of new capillary beds o Induced by
several mediators (histamine in particular) on vascular smooth muscle o
Resulting increased blood flow causes heat and redness (erythema)
• This together with the subsequent increased vascular permeability (and fluid
extravasation) leads to stasis i.e. engorgement of small vessels by increased
concentration of slowly moving red blood cells o Manifests as vascular
congestion and localized redness (erythema) o Blood leukocytes (primarily
neutrophils) marginate along the vascular endothelium and subsequently
migrate through the vascular wall into the interstitium (see “Leukocyte
recruitment to sites of inflammation”) Increased vascular permeability of post-
capillary venules (vascular leakage)
• Due to combination of varying degrees of both endothelial cell contraction
and injury
• Contraction of endothelial cells: Immediate transient response: occurs rapidly
after exposure to the mediator and usually short-lived (15-30 mins). Can also
be delayed (after 2-12 hrs) e.g. sunburn o Caused by histamine, bradykinin,
leukotrienes and other chemical mediators o Results in opening of
interendothelial gaps
• Endothelial injury: Usually immediate and sustained until damage is repaired
/ vessels thrombosed o Caused by direct physical damage (e.g. thermal burns),
induced by microbes/microbial toxins or adhering neutrophils that are
recruited and amplify the reaction.
(II) Recruitment of leukocytes to sites of inflammation Leukocyte influx into
tissues following the above vascular changes is important to eliminate the
offending agents, and usually involve leukocytes with phagocytic functions i.e.
neutrophils and macrophages that can ingest and destroy microbes as well as
necrotic tissue and foreign substances. While macrophages also produce
growth factors that help in repair, other leukocyte products can also injure
normal surrounding tissues and prolong the inflammatory reaction. The
process of leukocyte migration is multistep, mediated and controlled by
adhesion molecules and cytokines called chemokines:
1. Margination, rolling and adhesion to endothelium: Blood stasis causes
margination of more white cells (i.e. the white cells move peripherally and
more slowly along the endothelial surface). The white cells sense signals
from the endothelium, and then start rolling and adhering to the
endothelium via adhesion molecules, the expression of which is induced /
enhanced by cytokines e.g. tumour necrosis factor (TNF)
2. Migration across the endothelium and vessel wall: Leukocytes are
stimulated via chemokines to migrate through intact endothelium via
interendothelial gaps (transmigration / diapedesis), mainly in postcapillary
venules, along a chemotactic concentration gradient (i.e. towards the site
where the chemokines are produced). This is facilitated by adhesion
molecules present in the intercellular junctions between endothelial cells
such as CD31/PECAM-1.
3. The leukocytes then need to penetrate the endothelium basement
membrane (likely by secreting collagenases) to enter and accumulate in the
extravascular space 3. Migration in tissues towards chemotactic stimuli
(chemotaxis): Both exogenous and endogenous substances act as
chemoattractants to leukocytes e.g. bacterial products, cytokine
4. Leukocyte-mediated tissue injury and its regulation • Activated leukocytes
cause injury to normal tissues (pathologic vs physiologic consequence of
inflammation) via the above mechanisms in several situations: 1. As part of
normal defense reaction against infections, especially if infections are
difficult to eradicate e.g. tuberculosis 2. Inappropriate direction of
inflammatory response against normal tissue e.g. autoimmune diseases 3.
Excessive response against usually harmless environmental substances e.g.
allergies
Outcomes of acute inflammation
Typically 3 possible outcomes ensue:
1. Complete resolution: Ideal outcome. Usually only if injury is limited or
short-lived with little tissue destruction, allowing removal of cellular debris
and microbes by macrophages, resorption of oedema fluid and
regeneration of damaged cells.
2. Scarring / fibrosis: Healing by connective tissue replacement
(organization). Occurs after substantial tissue destruction, the damaged
tissue cannot regenerate or fibrinous exudate cannot be cleared
adequately.
 3. Progression to chronic inflammation: Occurs when acute inflammatory
response cannot be resolved due to persistence of injurious agent.

CHRONIC INFLAMMATION
Prolonged host response (weeks or months) to persistent stimuli in which
inflammation, tissue injury and attempts at repair coexist in varying
combinations Causes of chronic inflammation May follow acute
inflammation, or begin insidiously as a low-grade response without
evidence of preceding acute inflammation:
• Persistent infections: Unresolved acute inflammation with persistent
infection can evolve into chronic inflammation e.g. chronic abscess.
• Hypersensitivity diseases: Excessive and inappropriate activation of the
body’s immune system results in chronic inflammation and tissue damage
e.g. rheumatoid arthritis, inflammatory bowel disease.
• Prolonged exposure to potentially toxic agents: Exogenous agents include
silica (can result in silicosis).
• Mononuclear cell infiltrate: Macrophages, lymphocytes, plasma cells
• Tissue destruction: From the offending agent or inflammatory cells
• Healing attempts: Connective tissue replacement of damaged tissue via
angiogenesis (proliferation of small blood vessels) and fibrosis (see Section
V. Tissue Repair)

Granulomatous inflammation
Form of chronic inflammation characterized by granulomas (aggregates of
activated macrophages, often with T lymphocytes and sometimes
associated with necrosis)
• Cellular attempt to contain a difficult to eradicate offending agent
• Different types of granulomas may be induced by different causes: o
Foreign body granulomas: incited by inert (non-immunogenic) foreign
bodies (e.g. talc, sutures) too large for phagocytosis, in the absence of T-cell
mediated immune response o Immune granulomas: caused by any agent
(usually difficult to eradicate e.g. persistent microbe) capable of inducing a
persistent T-cell mediated immune response, which then activate
macrophages (e.g. via Th1 cells or Th2 cells) E.g. Mycobacterium
tuberculosis in tuberculosis, Troponema pallidum in syphilis E.g. immune
reaction against intestinal bacterial ?self-antigens in Crohn disease o
Sarcoid granulomas: unknown etiology; tends to be non-caseating and
‘naked’ i.e. not surrounded by lymphocytes As only a limited number of
conditions cause granulomatous inflammation, recognition of granulomas
and exclusion of treatable conditions (e.g. tuberculosis) is important.
Ancillary investigations include special stains for organisms (Ziehl-Neelson
stain for acid-fast bacilli), cultures, molecular techniques and serology
• Microscopy: Activated macrophages in granulomas may have abundant
cytoplasm resembling epithelial cells (epithelioid histiocytes) and fuse
(multinucleated giant cells). The macrophage aggregates may be
surrounded by a collar of lymphocytes or fibroblasts. Granulomas may have
a central zone of necrosis (classically seen in Mycobacterium tuberculosis
infection) which appears as amorphous eosinophilic granular debris.