Acute inflammation = short duration, few minutes to few days,

neutrophils predominate, usually occurs with protein exudate.

Chronic inflammation = duration of days to years, mainly
lymphocytic and macrophage infiltrate, fewer neutrophils
Acute Inflammation processes:
1. vasodilation (leads to calor, rubor)
2. increased permeability of vessels (leads to tumor)
3. emigration of leukocytes
Dolor and functio laesa are also features of acute inflammation.
Vasodilation occurs early and is considered the first response
leading to redness and heat in the area (note this sometimes
follows brief vasoconstriction). Alteration of normal hydrostatic
pressure leads to a transudate fluid that begins edema
formation. Permeability of the vessels gets triggered by many
mediators, especially histamine and leukotrienes. Permeability
is achieved via contraction of endothelial cells, interruption of
junctions between endothelial cells, direct injury, and injury to
endothelium mediated by leukocytes and transcytosis across
the endothelial cell. A proteinaceous exudate forms in the
interstitium leading to further edema.
1. Endothelial cell contraction occurs only in the venules and
occurs within minutes and lasts for 15-30 minutes.
2. Junctional retraction occurs in response to cytokines and
begins 4-6 hours after injury, lasting mores than 24 hours.
3. Direct injury to EC cells can happen via infections, burns or
from leukocyte mediated injury. This response begins
immediately (except for leukocyte mediated form) and can
persist for days.
4. Increased transcytosis involves increased size of channels
across the EC cytosol that allows for increased transport,
especially in response to VEGF.

EXTRAVASATION:
Following the increase in permeability,
1. Blood flow in vessels slows (stasis) and leukocytes
marginate to the vessel walls. Leukocytes normally travel
towards the vessel wall with RBCs in a central column in
normal laminar blood flow.
2. Leukocytes can cover an area of the vessel wall, called
pavementing.
3. Along the vessel wall, the leukocytes are grabbed by
sticky receptors of selectins including E-selectin on
endothelial cells (previously called ELAM-1) and P-selectin
on platelets and endothelium. These receptors become
more abundant through redistribution mediated by
histamine or thrombin (previously in Weibel-Palade bodies
in ECs) and/or via upregulation within minutes of local
injury; E-selectin is induced by IL-1 and TNF. The selectins
bind only weakly, and the leukocytes roll along the vessel
edge being bound and released by subsequent receptors.
4. Integrins (LFA-1) on the leukocyte surface eventually
change conformation so that they bind more tightly to the
endothelium receptors such as ICAM-1(intercellular
adhesion molecule 1, VCAM = vascular), a process called
adhesion. Integrins are normally expressed but only
function following activation by chemotactic agents.
5. Leukocytes then migrate through the endothelial cell layer
via intercelleular junctions, secrete collagenases to
degrade the BM and arrive at the site of injury via
chemotaxis. This process, leukocyte diapedesis, occurs
mainly in the venules. Neutrophils are always the first line
of defense and can be found with 6-24 hours at the injury
site. Within 24-48 hours monocyte/macrophage cells
predominate at the injury.
Basic process: endothelial activation (mediators increase
expression of selectins), rolling, adhesion, transmigration.

After transmigration, leukocytes will migrate towards the injury

via chemotaxis (movement along a chemical gradient).
Chemotactic agents for leukocytes include bacterial peptides,
C5a, LTB4, IL-8. These mediators also help to activate
leukocytes which causes them to produce AA metabolites,
secrete lysosomal enzymes, and regulate expression of surface
receptors. Leukocytes move by extending a pseudopod and
moving towards that via filament contraction with actin and
myosin.
Phagocytosis: basically recognize, attach, engulf, and kill.
Recognition occurs with opsonin coating with Fc portion of IgG
and C3b fragment of complement.
Binding triggers engulfment. Killing works through activated
oxygen in the oxidative burst: 2 O2 + NADPH --> 2O2 activated
+ NADP + H+. They also use myeloperoxidase and halide to
form bleach with HOCl radical, which is the most effective killer.
Even without oxidative burst, certain enzymes can kill such as
lysozyme, defensins (poke holes in membranes). Following
phagocytosis, neutrophils die through apoptosis and are taken
up by macrophages or lymphatics.
Note that leukocyte enzymes may be released into the ECM
during inflammation, leading to local tissue damage. Chemical
mediators may be released which further amplify the
inflammatory response.
Some diseases that involve defective leukocyte function:
Chediak-Higashi syndrome involves abnormal phagocytosis due
to poor organelle release of enzymes, and chronic
granulomatous disease from decreased ability to generate an
oxidative burst due to low levels of NADHP oxidase.

MEDIATORS OF INFLAMMATION:
General principles: mediators come from plasma in precursor
forms that are activated. Cell bound mediators are in granules
and released or newly synthesized, usually from mast cells,
platelets, neutrophils, or monocytes. Most are short lived and
decay, often within seconds.

Histamine: preformed in mast cells in tissues, circulating

basophils and platelets. It is released from any trauma,
complement C3a and C5a, cytokines IL-1 and IL-8. Causes
arteriolar dilation and increased vascular permeability of
venules via H1 receptors.
Serotonin: Preformed, similar to histamine in effects, comes
from platelet dense body granules.
Prostaglandins: Synthesized from arachidonic acid from the
cyclooxygenase pathway in leukocytes, platelets, and
endothelial cells in response to induction from mediators. AA is
membrane bound component of phospholipids, released via
activation of phospholipases or from C5a. Cyclooxygenase
produces PGs and TXAs from AA. Lipo-oxygenases produce LTs
from AA. PGI2 is a potent inhibitor of platelet aggregation and a
vasodilator. TXA2 works contrary to PGI2 and promotes platelet
aggregation and vasoconstriction. PGD2, PGE2, and PGF2 are
vasodilators. PGs contribute to pain and fever in inflammation.
NOTE: platelets mostly produce TXA2 via thromboxane
synthetase. ECs mostly produce PGI2 via prostacyclin
synthetase.
Leukotrienes: Synthesized from arachidonic acid in leukocytes
in the lipooxygenase pathway, especially in neutrophils. These
play many roles, but particularly important is LTB4 for
chemotaxis of neutrophils. LTC4, LTD4, and LTE4 cause
vasoconstriciton, bronchospasm and increase permeability.
Lipoxins are a new discovery of AA produced products formed
by platelet interaction with leukocytes.
Nitric Oxide: Synthesized by macrophages and ECs and very
short-lived with many potential effects, especially vasodilation.
NO can be toxic to infectious organisms and also reduces
platelet aggregation and adhesion. Increased production in
response to IL-1 and TNF and IFN. General effect is to reduce
leukocyte migration to site of inflammation and thus serves to
minimize the inflammatory response.
Platelet Activating Factor: produced by most inflammatory cell
types. Causes vasoconstriction and bronchoconstriction, but at

very low doses instead vasodilates and increases permeability

effectively (better than histamine). Tobacco smoke may induce
PAF and thus cause inflammation.
Cytokines: these are chemical mediators mainly produced by
activated lymphocytes and macrophages which act locally
(paracrine, autocrine) or systemically (endocrine). Some of the
most important ones include:
IL-1 produced by activated macrophages in response to injury
can activate ECs so that they produce different receptors on
their surface. It (and IL-6) is associated with fever systemically
and signs of malaise.
IFN, produced by T cells, works to cause systemic symptoms of
fever and malaise. IFN-gamma activates macrophages.
TNF (tumor necrosis factor) is produced by activated
macrophages (alpha) and T cells (beta). It also activates ECs
and leads to fever, neutrophil aggregation and NO synthesis. It
induces proliferation of fibroblasts. TNF-alpha regulates body
mass and when it increases, cachexia can result.
TGF-beta (transforming growth factor) is produced by
macrophages, T cells, endothelium and generally works as a
growth inhibitor of epithelial cells. It stimulates collagen
production and seems to be important in chronic inflammation
and fibrosis.
Bradykinin causes pain, vasodilation and increases vascular
permeability. Kallikrein, in the Hageman factor cascade that
produces bradykinin, activates Hageman factor itself, setting
up potential autocatalysis.
Hageman factor (Factor XII, active form Factor XIIa): produced
by liver and found in plasma. Crucial initiator of kinin cascade,
clotting cascade (producing thrombin that splits fibrinogen to
fibrin), fibrinolytic system (producing plasmin that degrades
fibrin) and complement cascade.
Complement: Present in plasma, activated via the Hageman
factor cascade, the classic pathway of presentation of antigenantibody complexes, or alternative pathway of microbial

polysaccharides, or collectin binding to bacterial carbohydrates

can activate via C1 and C3. Plasma proteins undergo cleavage
to active products including C3a and C5a which cause
degranulation of mast cells and anaphylaxis. C5a also plays a
role in chemotaxis of leukocytes and activation of AA pathway.
C3b opsonizes bacteria for phagocytosis. C5-C9 forms the
membrane attack complex.

SUMMARY OF MEDIATORS BY FUNCTION:

Increase vascular permeability: histamine, C3a, C5a, PAF,
bradykinin, LTC, LTD, LTE
Chemotaxis: C5a, LTB4, chemokines
Vasodilation: NO, PGI2
Systemic signs: TNF, IL-1, IL-6
Pain: bradykinin, prostaglandins
Tissue Destruction: leukocyte lysosomal enzymes, NO, reactive
O2
Outcomes of Acute Inflammation:
Resolution = return to normal architecture and removal of dead
cellular debris
Organization = scar formation with loss of original architecture
from more significant injury. Fibrosis denotes connective tissue
replacement of functional tissue and occurs with serious protein
exudates, lots of fibrin exudation from plasma, areas where
exudate cannot be adequately absorbed.
Abscesses may form in some bacterial infections.
Acute inflammation can continue and progress to chronic
inflammation.
Chronic Inflammation: occurs where tissue destruction is too
massive to be resolved, if acute inflammation continues with
ongoing injury, some viral infections.

Consists of infiltration of mononuclear cells, including

macrophages, plasma cells, and lymphocytes along with tissue
destruction, repair with new vessels and fibrosis. Classic
examples include atherosclerosis, TB, and autoimmune
conditions like rheumatoid arthritis.
Major Cell Types in Chronic Inflammation:
Macrophages become activated by cytokines (especially IFNgamma) and release proteases that cause tissue destruction.
They play a role in secreting some factors in complement, NO,
AA metabolites, and cytokines, especially IL-1 and TNF. Many of
these recruit more monocytes or stimulate macrophage division
in the tissues. They may also induce local tissue destruction in
addition to attacking the source of inflammation. Half life in
tissues is several months. Giant cell formation is induced by IL4 and IFN-gamma.
Lymphocytes migrate to area via chemokines. T lymphocytes
mutually stimulate macrophages and may set up an ongoing
inflammation. Macrophages present antigen to T cells to
stimulate them and release IL-1 and TNF that recruit
lymphocytes. T cells release IFN-gamma to activate
macrophages.
Eosinophils are associated with parasitic infections and IgE
allergic reactions, mediated by the chemokine eotaxin.
Lymphatics: Lymphatics offer help in both defenses against
infection and in responding to and resolving an inflammatory
response. They are valvular, very thin channels without
muscular wall layers. Local lymph flow increases in response to
local inflammation. Lymph nodes may become enlarged and
reactive in local inflammation, which is termed lymphadenitis. If
the lymphatic channels are involved, this is called lymphangitis.
The lymphatic system can help to spread disease (infection or
cancer) if the local nodes fail to contain the infection and the
lymph channels will eventually return to venous circulation,
allowing overwhelming infection to occur.
Patterns of Inflammation:

Granulomas may form in sites of chronic inflammation caused

by certain specific infections (TB, syphilis, cat-scratch disease)
or foreign bodies. Granulomas consist of activated epithelioid
macrophages surrounded by lymphocytic infiltrate. Giant cells,
multinucleated enlarged and fused macrophages, may be
present.
Tuberculous granulomas tend be caseating, meaning that there
is an area of central necrosis.
Serous inflammation: fluid transudate from inflammatory cells
or lining mesothelium
Fibrinous inflammation: fibrin accumulates due to vascular
permeability
Suppurative or purulent inflammation: Pus forms of necrotic
cells, neutrophils, edema. Abscesses are foci of purulent
inflammation.
Ulceration: local area of necrotic tissue sloughs off
Systemic effects of fever, anorexia, increased sleep are
mediated mainly by IL-1, IL-6, and TNF that can enter the BBB.
Note that IL-6 stimulates hepatic production of fibrinogen which
cause erythrocytes to agglutinate and increases ESR
(erythrocyte sedimentation rate), a nonspecific test of systemic
inflammation.
TNF-alpha affects appetite and can cause anorexia and
cachexia when levels increase. Typically in systemic infection,
prostaglandins act on the hypothalamus to increase
temperature and white cell counts increase to 15-20,000 per
microliter. This is usually accompanied by a "left shift" with
increased numbers of immature neutrophils present. Certain
infections such as typhoid fever occur with leukopenia, which
also occurs when the body is overwhelmed by disease as in
advanced cancer or TB.