Acute and Chronic inflammation

1. INFLAMMATION

2. DEFINITION AND CAUSES.
• Inflammation is defined as the local response of living mammalian
tissues to injury due to any agent.
• It is a body defense reaction in order to eliminate or limit the spread
of injurious agent, followed by removal of the necrosed cells and
tissues
• Inflammation is intended to contain and isolate injury, to destroy
invading microorganisms and inactivate toxins, and to prepare the
tissue for healing and repair

3. Causes
1. Infective agents like bacteria, viruses and their toxins, fungi, parasites.
2. Immunological agents like cell-mediated and antigen-antibody reactions.
3. Physical agents like heat, cold, radiation, mechanical trauma.
4. Chemical agents like organic and inorganic poisons.
5. Inert materials such as foreign bodies

4. Characterization of Inflammation
• Two main components—a vascular wall response and an inflammatory cell response
Effects mediated by circulating plasma proteins and by factors produced locally by the
vessel wall or inflammatory cells
• Termination when the offending agent is eliminated and the secreted mediators are
removed; active anti-inflammatory mechanisms are also involved
• Tight association with healing; even as inflammation destroys, dilutes, or otherwise
contains injury it sets into motion events that ultimately lead to repair of the damage
• A fundamentally protective response; however, inflammation can also be harmful, for
example, by causing life-threatening hypersensitivity reactions or relentless and
progressive organ damage from chronic inflammation and subsequent fibrosis (e.g.,
rheumatoid arthritis, atherosclerosis)
• Acute and chronic patterns:

5. Signs of Inflammation
4 cardinal signs of inflammation as:
rubor (redness) Erythema (Latin: rubor) due to vascular dilation and congestion
tumor (swelling); Edema (Latin: tumor) due to increased vascular permeability
calor (heat); Warmth due to vascular dilation
dolor (pain) due to mediator release
To these, fifth sign functio laesa (loss of function) was
later added by Virchow. Loss of function (Latin: functio laesa) due to pain, edema,
tissue injury, and/or scar

6. Types of Inflammation
1. Acute inflammation
 Is of short duration (lasting less than 2 weeks) and represents the early
body reaction, resolves quickly and is usually followed by healing.
 The main features of acute inflammation are:
1. accumulation of fluid and plasma at the affected site
2. intravascular activation of platelets
3. polymorphonuclear neutrophils as inflammatory cells.
Sometimes, the acute inflammatory response may be quite severe and is
termed as fulminant acute inflammation

7. 2. Chronic inflammation
Is of longer duration and occurs either after the causative agent of acute
inflammation persists for a long time, or the stimulus is such that it induces
chronic inflammation from the beginning.
 A variant, chronic active inflammation, is the type of chronic inflammation
in which during the course of disease there are acute exacerbations of
activity.
The characteristic feature of chronic inflammation is presence of chronic
inflammatory cells such as lymphocytes, plasma cells and
macrophages, granulation tissue formation, and in specific situations as
granulomatous inflammation

8. Acute Inflammation
Acute inflammation has three major components:
• Alterations in vascular caliber, leading to increased blood flow
• Structural changes in the microvasculature, permitting plasma proteins and
leukocytes to leave the circulation to produce inflammatory exudates
• Leukocyte emigration from blood vessels and accumulation at the site of
injury with activation

9. I. Vascular Events (Reactions of Blood Vessels in Acute Inflammation)
• Alteration in the microvasculature (arterioles, capillaries and venules) is
the earliest response to tissue injury. Two important things which are:
• haemodynamic changes and changes in vascular permeability
Haemodynamic Changes
1. Immediate vascular response is of transient vasoconstriction of
arterioles. With mild form of injury, the blood flow may be re-established in
3-5 seconds while with more severe injury the vasoconstriction may last for
about 5 minutes.

10. 2. Next is persistent progressive vasodilatation which involves mainly the
arterioles, but to a lesser extent, affects venules and capillaries.
Vasodilatation results in increased blood volume in microvascular bed of the
area, causing redness and warmth at the site of acute inflammation.
3. Progressive vasodilatation, in turn, may elevate the local hydrostatic
pressure resulting in transudation of fluid into the extracellular space. This
is responsible for swelling at the local site of acute inflammation.
4. Slowing or stasis of microcirculation follows which causes increased
concentration of red cells, and thus, raised blood viscosity.

11. 5. Stasis or slowing is followed by leucocytic margination or peripheral
orientation of leucocytes (mainly neutrophils) along the vascular
endothelium.
• The leucocytes stick to the vascular endothelium briefly, and then move
and migrate through the gaps between the endothelial cells into the
extravascular space. This process is known as emigration

12. 2. Increased Vascular Permeability
Induced by several different pathways
a) Contraction of venule endothelium to form intercellular gaps:
Most common mechanism of increased permeability
Elicited by chemical mediators (e.g., histamine, bradykinin, leukotrienes, etc.)
Occurs rapidly after injury and is reversible and transient (i.e., 15 to 30 minutes),
hence the term immediate-transient response
A similar response can occur with mild injury (e.g., sunburn) or inflammatory
cytokines but is delayed (i.e., 2 to 12 hours) and protracted (i.e., 24 hours or more)

13. b) Retraction of Endothelial Cells
In this mechanism, there is structural re-organisation of the cytoskeleton of
endothelial cells that causes reversible retraction at the intercellular
junctions.
This change too affects venules and is mediated by cytokines such as
interleukin-1 (IL-1) and tumour necrosis factor (TNF)-α. The onset of
response takes 4-6 hours after injury and lasts for 2-4 hours or more
(somewhat delayed and prolonged leakage).

14. c) Direct endothelial injury
 Severe necrotizing injury (e.g., burns) causes endothelial cell necrosis
and detachment that affects venules, capillaries, and arterioles
 Recruited neutrophils may contribute to the injury (e.g., through
reactive oxygen species)
 Immediate and sustained endothelial leakage

15. d) Increased transcytosis(Endothelial injury mediated by leucocytes)
 Adherence of leucocytes to the endothelium at the site of inflammation may result in
activation of leucocytes.
The activated leucocytes release proteolytic enzymes and toxic oxygen species which
may cause endothelial injury and increased vascular leakiness.
This form of increased vascular leakiness affects mostly venules and is a late response.
 Vascular endothelial growth factor (VEGF) and other factors can induce vascular leakage
by increasing the number of these channels

16. e) Leakage from new blood vessels
Endothelial proliferation (under the influence of vascular endothelial
growth factor (VEGF) and capillary sprouting (angiogenesis) result in
leaky vessels
Increased permeability persists until the endothelium matures and
intercellular junctions form

17. Responses of Lymphatic Vessels
• Lymphatics and lymph nodes filter and “police” extravascular fluids. With the mononuclear
phagocyte system, they represent a secondary line of defense when local inflammatory
responses cannot contain an infection.
In inflammation, lymphatic flow is increased to drain edema fluid, leukocytes, and cell
debris from the extravascular space.
In severe injuries, drainage may also transport the offending agent; lymphatics may
become inflamed (lymphangitis, manifest grossly as red streaks), as may the draining
lymph nodes (lymphadenitis, manifest as enlarged, painful nodes). The nodal
enlargement is usually due to lymphoid follicle and sinusoidal phagocyte hyperplasia
(termed reactive lymphadenitis

18. II. Cellular Events (Reactions of Leukocytes in Inflammation)
• A critical function of inflammation is to deliver leukocytes to sites of injury, especially those cells
capable of phagocytosing microbes and necrotic debris (e.g., neutrophils and macrophages).
• After recruitment, the cells must recognize microbes and dead material and effect their removal.
• The type of leukocyte that ultimately migrates into a site of injury depends on the age of the inflammatory
response and the original stimulus.
• In most forms of acute inflammation, neutrophils predominate during the first 6 to 24 hours and are then
replaced by monocytes after 24 to 48 hours.
• There are several reasons for this sequence: neutrophils are more numerous in blood than monocytes, they respond
more rapidly to chemokines, and they attach more firmly to the particular adhesion molecules that are induced on
endothelial cells at early time points.
• After migration, neutrophils are also short-lived; they undergo apoptosis after 24 to 48 hours, whereas monocytes
survive longer.
• The process of getting cells from vessel lumen to tissue interstitium is called extravasation and is divided into three
steps
I. Margination, rolling, and adhesion of leukocytes to the endothelium
II. Transmigration across the endothelium
III. Migration in interstitial tissues toward a chemotactic stimulus

19. 1. Changes in the Formed Elements of Blood
• With stasis, changes in the normal axial flow of blood in the microcirculation
take place.
• Due to slowing and stasis, the central stream of cells widens and peripheral
plasma zone becomes narrower because of loss of plasma by exudation.
• This phenomenon is known as margination.
• As a result of this redistribution, the neutrophils of the central column come
close to the vessel wall; this is known as pavementing.

20. 2. Rolling and Adhesion
• Peripherally marginated and pavemented neutrophils slowly roll over the endothelial cells
lining the vessel wall (rolling phase).
• This is followed by the transient bond between the leucocytes and endothelial cells
becoming firmer (adhesion phase).
• Molecules that bring about rolling and adhesion phases:
i) Selectins are expressed on the surface of activated endothelial cells which recognise
specific carbohydrate groups found on the surface of neutrophils, the most important of which
is s-Lewis X molecule.
P-selectin (preformed and stored in endothelial cells and platelets) is involved in rolling
E-selectin (synthesised by cytokine activated endothelial cells) is associated with both
rolling and adhesion
L-selectin (expressed on the surface of lymphocytes and neutrophils) is responsible for
homing of circulating lymphocytes to the endothelial cells in lymph nodes

22. ii) Integrins on the endothelial cell surface are activated during the process of
loose and transient adhesions between endothelial cells and leucocytes. At the
same time the receptors for integrins on the neutrophils are also stimulated.
This process brings about firm adhesion between leucocyte and endothelium.
iii) Immunoglobulin gene superfamily adhesion molecule
such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion
molecule-1 (VCAM-1) allow a tighter adhesion and stabilize the interaction
between leucocytes and endothelial cells.
Platelet-endothelial cell adhesion molecule-1 (PECAM-1) or CD31 may also be
involved in leucocyte migration from the endothelial surface.

23. 3. Emigration
After sticking of neutrophils to endothelium, the neutrophils throw out cytoplasmic
pseudopods at suitable sites.
Subsequently, the neutrophils damage basement membrane locally with secreted
collagenases and escape out into the extravascular space; this is known as emigration.
Transmigration (also called diapedesis) is mediated by homotypic (like-like) interactions
between platelet-endothelial cell adhesion molecule-1 = CD31 (PECAM-1) on leukocytes
and endothelial cells.
Once across the endothelium and into the underlying connective tissue, leukocytes
adhere to the extracellular matrix via integrin binding to CD44.

24. 4. Chemotaxis of Leukocytes
• After emigrating through interendothelial junctions and traversing the
basement membrane, leukocytes move toward sites of injury along
gradients of chemotactic agents (chemotaxis).
• Chemotaxis involves binding of chemotactic agents to specific leukocyte
surface G protein–coupled receptors
• These trigger the production of phosphoinositol second messengers, in turn
causing increased cytosolic calcium and guanosine triphosphatase
(GTPase) activities that polymerize actin and facilitate cell movement.
• Leukocytes move by extending pseudopods that bind the extracellular
matrix and then pull the cell forward (front-wheel drive).

25. The following agents act as potent chemotactic substances or chemokines
for neutophils:
i) Leukotriene B4 (LT-B4), a product of lipoxygenase pathway of arachidonic
acid metabolites
ii) Components of complement system (C5a and C3a in particular)
iii) Cytokines (Interleukins, in particular IL-8)
iv) Soluble bacterial products (such as formylated peptides).

26. Phagocytosis
• Phagocytosis is defined as the process of engulfment of solid particulate
material by the cells (cell-eating)
• Phagocytes include
i) Polymorphonuclear neutrophils (PMNs) which appear early in acute
inflammatory response, sometimes called as microphages.
ii) Circulating monocytes and fixed tissue mononuclear phagocytes,
commonly called as macrophages.

27. • Neutrophils and macrophages on reaching the tissue spaces produce
several proteolytic enzymes—lysozyme, protease, collagenase, elastase,
lipase, proteinase, gelatinase, and acid hydrolases.
• These enzymes degrade collagen and extracellular matrix. The microbe
undergoes the process of phagocytosis by polymorphs and macrophages
and involves the following 3 steps
1. Recognition and attachment
2. Engulfment
3. Killing and degradation

28. A. Recognition of Microbes and Dead Tissues
• Leukocytes distinguish offending agents and then destroy them.
• To accomplish this, inflammatory cells express a variety of receptors that recognize pathogenic
stimuli, and deliver activating signals (see figure slide 27)
1. Receptors for microbial products: These include toll-like receptors (TLRs)
 Proteins that recognize distinct components in different classes of microbial pathogens
 TLRs participate in cellular responses to bacterial lipopolysaccharide (LPS) or
unmethylated CpG nucleotide fragments
 Whereas others respond to double-stranded RNA made by some viral infections.
 They function through receptor-associated kinases that in turn induce production of
cytokines and microbicidal substances.

30. 2. G protein–coupled receptors: These receptors typically recognize
bacterial peptides containing N-formyl methionine residues, or they are
stimulated by the binding of various chemokines, complement fragments, or
arachidonic acid metabolites (e.g., prostaglandins and leukotrienes).
 Ligand binding triggers migration and production of microbicidal
substances.
3. Receptors for opsonins: Molecules that bind to microbes and render them
more “attractive” for ingestion are called opsonins. These include
antibodies, complement fragments, and certain lectins (sugar-binding
proteins).
 Binding of opsonized (coated) particles to their leukocyte receptor leads to
cell activation and phagocytosis

31. 4. Cytokine receptors: Inflammatory mediators (cytokines) bind to cell
surface receptors and induce cellular activation.
One of the most important is interferon-gamma, produced by activated T
cells
and natural killer cells.
It is the major macrophage-activating cytokine.

32. B. Removal of the Offending Agents
1. Engulfment
This is accomplished by formation of cytoplasmic pseudopods around the
particle due to activation of actin filaments beneath cell wall, enveloping it in
a phagocytic vacuole.
Eventually, the plasma membrane enclosing the particle breaks from the
cell surface so that membrane lined phagocytic vacuole or phagosome lies
internalized and free in the cell cytoplasm.
The phagosome fuses with one or more lysosomes of the cell and form
bigger vacuole called phagolysosome.