acute inflammation _ robbins basic pathology _ inflammation & repair

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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

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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

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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.

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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