2. Intro
• Inflammation is a response of vascularized tissues to infections and
tissue damage
• It brings cells and molecules of host defense from the circulation to
the sites where they are needed, to eliminate the offending agents
• It serves to rid the host of both the initial cause of cell injury (e.g.,
microbes, toxins) and the consequences of such injury (e.g., necrotic
cells and tissues).
• The mediators of defense include phagocytic leukocytes, antibodies,
and complement proteins
3. Intro
• The typical inflammatory reaction develops through a series of
sequential steps:
• The offending agent, which is located in extravascular tissues, is
recognized by host cells and molecules.
• Leukocytes and plasma proteins are recruited from the circulation to
the site where the offending agent is located.
• The leukocytes and proteins are activated and work together to
destroy and eliminate the offending substance.
• The reaction is controlled and terminated.
4. Inflammation: acute and chronic
• The initial, rapid response to infections and tissue damage is called
acute inflammation
• It typically develops within minutes or hours and is of short duration,
lasting for several hours or a few days
• Its main characteristics are the exudation of fluid and plasma proteins
(edema) and the emigration of leukocytes, predominantly neutrophils
• When acute inflammation achieves its desired goal of eliminating the
offenders, the reaction subsides and residual injury is repaired.
• But if the initial response fails to clear the stimulus, the reaction
progresses to a protracted type of inflammation that is called chronic
inflammation
8. CAUSES OF INFLAMMATION
• Infections and microbial toxins are among the most common and
medically important causes of inflammation
• Tissue necrosis elicits inflammation regardless of the cause of cell
death
• Foreign bodies (splinters, dirt, sutures) may elicit inflammation by
themselves or because they cause traumatic tissue injury or carry
microbes
• Immune reactions (also called hypersensitivity) are reactions in which
the normally protective immune system damages the individual’s own
tissues
9. RECOGNITION OF MICROBES AND DAMAGED
CELLS
• The first step in inflammatory responses is the recognition of
microbes and necrotic cells by cellular receptors and circulating
proteins
• The cells and receptors that recognize invaders and the responses
they trigger are critical for survival
• The best defined of these receptors belong to the family of Toll-like
receptors (TLRs), which are named for the founding member, Toll, a
gene that was discovered in Drosophila
• TLRs are located in plasma membranes and endosomes, so they are
able to detect extracellular and ingested microbes.
• TLRs recognize motifs common to many microbes, often called
pathogen-associated molecular patterns (PAMPs)
10. RECOGNITION OF MICROBES AND DAMAGED
CELLS
• All cells have cytosolic receptors that recognize molecules that are
liberated or altered as a consequence of cell damage
• And are hence appropriately called damage-associated molecular
patterns (DAMPs)
• A circulating protein called mannose-binding lectin recognizes
microbial sugars and promotes ingestion of microbes and activation
of the complement system.
• Other proteins called collectins also bind to microbes and promote
their phagocytosis.
• The complement system reacts against microbes and produces
mediators of inflammation
11. ACUTE INFLAMMATION
Acute inflammation has three major components:
(1) Dilation of small vessels, leading to an increase in blood flow
(2) Increased permeability of the microvasculature, enabling plasma
proteins and leukocytes to leave the circulation
(3) Emigration of the leukocytes from the microcirculation, their
accumulation in the focus of injury, and their activation to eliminate the
offending agent
14. Lymphatic Vessels and Lymph Nodes
• The system of lymphatics and lymph nodes filters and polices the
extravascular fluids.
• In inflammation, lymph flow is increased to help drain edema fluid that
accumulates because of increased vascular permeability.
• In addition to fluid, leukocytes and cell debris, as well as microbes, may
find their way into lymph.
• Lymphatic vessels, like blood vessels, proliferate during inflammatory
reactions to handle the increased load.
• The lymphatics may become secondarily inflamed (lymphangitis), as may
the draining lymph nodes (lymphadenitis).
• This constellation of pathologic changes is termed reactive, or
inflammatory, lymphadenitis
15. Leukocyte Recruitment
• Leukocytes that are recruited to sites of inflammation perform the
key function of eliminating the offending agents.
• The most important are the ones capable of phagocytosis, namely,
neutrophils and macrophages.
• Neutrophils are produced in the bone marrow and rapidly recruited
to sites of inflammation.
• Macrophages are slower responders.
• These leukocytes ingest and destroy bacteria and other microbes, as
well as necrotic tissue and foreign substances
20. Phagocytosis
Phagocytosis involves three sequential steps:
(1) recognition and attachment of the particle to be ingested
(2) engulfment, with subsequent formation of a phagocytic vacuole
(3) killing or degradation of the ingested material
• The efficiency of phagocytosis is greatly enhanced when microbes are
opsonized (coated) by specific proteins (opsonins)
21. Intracellular Destruction
• The killing of microbes and the destruction of ingested materials are
accomplished by reactive oxygen species (ROS)
• Mainly derived from nitric oxide (NO), and lysosomal enzymes
• ROS are produced by the rapid assembly and activation of a
multicomponent enzyme, phagocyte oxidase reduces oxygen to the
superoxide anion (O2)
• This is the final step in the elimination of infectious agents and necrotic
cells
• Neutrophils and monocytes contain granules packed with enzymes and
anti-microbial proteins that degrade microbes and dead tissues and may
contribute to tissue damage
22.
23. Leukocyte-Mediated Tissue Injury
• Leukocytes are important mediators of injury to normal cells and
tissues under several circumstances
• As part of a normal defence reaction against infectious microbes
tissues at or near the site of infection suffer collateral damage.
• In some infections that are difficult to eradicate, such as tuberculosis
and certain viral diseases such as hepatitis, the prolonged host
response contributes more to the pathology than does the microbe
itself
• In autoimmune diseases and “hyper-reacts” against usually harmless
environmental substances
24. Termination of the Acute Inflammatory
Response
• Such a powerful system of host defense, with its inherent capacity to
cause tissue injury, needs tight controls to minimize damage
• In part, inflammation declines after the offending agents are removed
simply because the mediators of inflammation are produced in rapid
bursts, have short half-lives, and are degraded after their release
• In addition, as inflammation develops, the process itself triggers a
variety of stop signals that actively terminate the reaction
26. Vasoactive Amines: Histamine and Serotonin
• The two major vasoactive amines, so named because they have
important actions on blood vessels
• They are stored as preformed molecules in cells and are therefore
among the first mediators to be released during inflammation
• The richest sources of histamine are mast cells, which are normally
present in the connective tissue adjacent to blood vessels
• Histamine also is found in blood basophils and platelets.
• Serotonin (5-hydroxytryptamine) is a preformed vasoactive mediator
present in platelets and certain neuroendocrine cells
27. Arachidonic Acid Metabolites
• The lipid mediators prostaglandins and leukotrienes are produced from
arachidonic acid present in membrane phospholipids,
• And they stimulate vascular and cellular reactions in acute inflammation
• Most cellular arachidonic acid is esterified and incorporated into
membrane phospholipids.
• Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a)
trigger the release of arachidonic acid from membranes by activating
cellular phospholipases,
• Once freed from the membrane, arachidonic acid is rapidly converted to
bioactive mediators. These mediators, also called eicosanoids
• Synthesized by two major classes of enzymes: cyclooxygenases (which
generate prostaglandins) and lipoxygenases (which produce leukotrienes
and lipoxins)
29. Prostaglandins
• Prostaglandins (PGs) are produced by mast cells, macrophages,
endothelial cells, and many other cell types, and are involved in the
vascular and systemic reactions of inflammation
• They are generated by the actions of two cyclooxygenases called COX-
1 and COX-2.
• Prostaglandins are named based on structural features coded by a
letter (e.g., PGD, PGE, PGF, PGG, and PGH) and a subscript numeral
(e.g., 1, 2), which indicates the number of double bonds in the
compound
• The most important prostaglandins in inflammation are PGE2, PGD2,
PGF2a, PGI2 (prostacyclin), and TXA2 (thromboxane A2)
32. Complement System
• The complement system is a collection of soluble proteins
• Complement proteins are present in inactive forms in the plasma, and
many of them are activated to become proteolytic enzymes that
degrade other complement proteins, thus forming an enzymatic
cascade capable of tremendous amplification
• They function in both innate and adaptive immunity for defence
against microbial pathogens
• In the process of complement activation cause increased vascular
permeability, chemotaxis, and opsonization
