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20/8/2014 Acute Inflammation | Robbins Basic Pathology | Inflammation & Repair
https://www.inkling.com/read/robbins-basic-pathology-kumar-abbas-aster-9th/chapter-2/acute-inflammation 1/24
ACUTE INFLAMMATION
The acute inflammatory response rapidly delivers leukocytes and plasma proteins
to sites of injury. Once there, leukocytes clear the invaders and begin the process of
digesting and getting rid of necrotic tissues.
Acute inflammation has two major components
(Fig. 22 ):
Vascular changes: alterations in vessel caliber
resulting in increased blood flow (vasodilation)
and changes in the vessel wall that permit plasma
proteins to leave the circulation (increased
vascular permeability). In addition, endothelial
cells are activated, resulting in increased adhesion
of leukocytes and migration of the leukocytes
through the vessel wall.
Cellular events: emigration of the leukocytes from
the circulation and accumulation in the focus of
injury (cellular recruitment), followed by
activation of the leukocytes, enabling them to
eliminate the offending agent. The principal
leukocytes in acute inflammation are neutrophils
(polymorphonuclear leukocytes).
Stimuli for Acute Inflammation
Acute inflammatory reactions may be triggered by a variety of stimuli:
Infections (bacterial, viral, fungal, parasitic) are among the most common and
medically important causes of inflammation.
Trauma (blunt and penetrating) and various physical and chemical agents (e.g.,
thermal injury, such as burns or frostbite; irradiation; toxicity from certain
environmental chemicals) injure host cells and elicit inflammatory reactions.
Figure 22 Vascular
and cellular reactions of
acute inflammation. The
major local
manifestations of
acute
20/8/2014 Acute Inflammation | Robbins Basic Pathology | Inflammation & Repair
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Tissue necrosis (from any cause), including ischemia (as in a myocardial infarct)
and physical and chemical injury
Foreign bodies (splinters, dirt, sutures, crystal deposits)
Immune reactions (also called hypersensitivity reactions) against
environmental substances or against self tissues. Because the stimuli for these
inflammatory responses often cannot be eliminated or avoided, such reactions
tend to persist, with features of chronic inflammation. The term immune-
mediated inflammatory disease is sometimes used to refer to this group of
disorders.
Although each of these stimuli may induce reactions with some distinctive
characteristics, in general, all inflammatory reactions have the same basic
features.
In this section, we describe first how inflammatory stimuli are recognized by
the host, then the typical reactions of acute inflammation and its morphologic
features, and finally the chemical mediators responsible for these reactions.
Recognition of Microbes, Necrotic Cells, and Foreign Substances
A fundamental question relating to activation of the host response is how cells
recognize the presence of potentially harmful agents such as microbes in the
tissues. It was postulated that microbes and dead cells must elicit some sort of
danger signals that distinguish them from normal tissues and mobilize the host
response. It is now established that phagocytes, dendritic cells (cells in connective
tissue and organs that capture microbes and initiate responses to them), and
many other cells, such as epithelial cells, express receptors that are designed to
sense the presence of infectious pathogens and substances released from dead
cells. These receptors have been called pattern recognition receptors because
they recognize structures (i.e., molecular patterns) that are common to many
microbes or to dead cells. The two most important families of these receptors are
the following:
Toll-like receptors (TLRs) are microbial sensors that are named for the founding
member called Toll, which was discovered inDrosophila. There are ten
mammalian TLRs, which recognize products of bacteria (such as endotoxin and
bacterial DNA), viruses (such as double-stranded RNA), and other pathogens
(Fig. 23, A ). TLRs are located in plasma membranes and endosomes, so they
20/8/2014 Acute Inflammation | Robbins Basic Pathology | Inflammation & Repair
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are able to detect extracellular and ingested microbes. They are complemented
by cytoplasmic and membrane molecules, from several other families, that also
recognize microbial products. TLRs and the other receptors recognize products
of different types of microbes and thus provide defense against essentially all
classes of infectious pathogens. Recognition of microbes by these receptors
activates transcription factors that stimulate the production of a number of
secreted and membrane proteins. These proteins include mediators of
inflammation, antiviral cytokines (interferons), and proteins that promote
lymphocyte activation and even more potent immune responses. We return to
TLRs in Chapter 4 , when we discuss innate immunity, the early defense
against infections.
The inflammasome is a multi-protein cytoplasmic complex that recognizes
products of dead cells, such as uric acid and extracellular ATP, as well as crystals
and some microbial products. Triggering of the inflammasome results in
activation of an enzyme called caspase-1, which cleaves precursor forms of the
inflammatory cytokine interleukin-1 (IL-1) into its biologically active form
(Fig. 23, B ). As discussed later, IL-1 is an important mediator of leukocyte
recruitment in the acute inflammatory response, and the leukocytes phagocytose
and destroy dead cells. The joint disease, gout, is caused by deposition of urate
crystals, which are ingested by phagocytes and activate the inflammasome,
resulting in IL-1 production and acute inflammation. IL-1 antagonists are
effective treatments in cases of gout that are resistant to conventional anti-
inflammatory therapy. Recent studies have shown that cholesterol crystals and
free fatty acids also activate the inflammasome, suggesting that IL-1 plays a role
in common diseases such as atherosclerosis (associated with deposition of
cholesterol crystals in vessel walls) and obesity-associated type 2 diabetes. This
finding raises the possibility of treating these diseases by blocking IL-1.
20/8/2014 Acute Inflammation | Robbins Basic Pathology | Inflammation & Repair
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The functions of these sensors are referred to throughout the chapter. We now
proceed with a discussion of the principal reactions of acute inflammation.
Vascular Changes
The main vascular reactions of acute inflammation are increased blood flow
secondary to vasodilation and increased vascular permeability, both designed to
bring blood cells and proteins to sites of infection or injury. While the initial
encounter of an injurious stimulus, such as a microbe, is with macrophages and
other cells in the connective tissue, the vascular reactions triggered by these
interactions soon follow and dominate the early phase of the response.
Changes in Vascular Caliber and Flow
Changes in blood vessels are initiated rapidly after infection or injury but evolve at
variable rates, depending on the nature and severity of the original inflammatory
stimulus.
Figure 23 Sensors of microbes and dead cells: Phagocytes,
dendritic cells, and many types of
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After transient vasoconstriction (lasting only for seconds), arteriolar vasodilation
occurs, resulting in locally increased blood flow and engorgement of the down-
stream capillary beds (Fig. 22 ). This vascular expansion is the cause of the
redness (erythema) and warmth characteristic of acute inflammation, and
mentioned previously as two of the cardinal signs of inflammation.
The microvasculature becomes more permeable, and protein-rich fluid moves
into the extravascular tissues. This causes the red cells in the flowing blood to
become more concentrated, thereby increasing blood viscosity and slowing the
circulation. These changes are reflected microscopically by numerous dilated
small vessels packed with red blood cells, calledstasis.
As stasis develops, leukocytes (principally neutrophils) begin to accumulate
along the vascular endothelial surfacea process called margination. This is the
first step in the journey of the leukocytes through the vascular wall into the
interstitial tissue (described later).
Increased Vascular Permeability
Increasing vascular permeability leads to the movement of protein-rich fluid and
even blood cells into the extravascular tissues (Fig. 24 ). This in turn increases
the osmotic pressure of the interstitial fluid, leading to more outflow of water from
the blood into the tissues. The resulting protein-rich fluid accumula