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  • 20/8/2014 Acute Inflammation | Robbins Basic Pathology | Inflammation & Repair 1/24


    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


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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


    Although each of these stimuli may induce reactions with some distinctive

    characteristics, in general, all inflammatory reactions have the same basic


    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


    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


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