Acute Inflammation

Question 1

Overview of Inflammation

Definitions and General Features

Answer 1

The major participants in the inflammatory reaction in tissues are blood vessels and leukocytes

Inflammation is a response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from the circulation to the sites where they are needed, in order to eliminate the offending agents

Question 2

Inflammatory reaction develops through a series of sequential steps

Answer 2

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.
The damaged tissue is repaired

Question 3

Causes of Inflammation

Answer 3

Infections (bacterial, viral, fungal, parasitic) 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, which may include ischemia (reduced blood flow, the cause of myocardial infarction), trauma, and physical and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to some environmental chemicals).

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.

Question 4

Recognition of Microbes and Damaged Cells

Answer 4

Cellular receptors for microbes

Sensors of cell damage

Other cellular receptors involved in inflammation

Circulating proteins

Question 5

Acute inflammation has three major components:

Answer 5

Dilation of small vessels leading to an increase in blood flow

Increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation

Emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent

Question 6

Reactions of Blood Vessels in Acute Inflammation

Answer 6

The vascular reactions of acute inflammation consist of changes in the flow of blood and the permeability of vessels, both designed to maximize the movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury

Question 7

Changes in Vascular Flow and Caliber

Answer 7

Vasodilation is induced by the action of several mediators, notably histamine, on vascular smooth muscle

Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich fluid into the extravascular tissues

The loss of fluid and increased vessel diameter lead to slower blood flow, concentration of red cells in small vessels, and increased viscosity of the blood.

As stasis develops, blood leukocytes, principally neutrophils, accumulate along the vascular endothelium.

Question 8

Increased Vascular Permeability (Vascular Leakage)

Answer 8

Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage.

Endothelial injury, resulting in endothelial cell necrosis and detachment.

Increased transport of fluids and proteins, called transcytosis, through the endothelial cell.

Question 9

Responses of Lymphatic Vessels and Lymph Nodes

Answer 9

The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis).

Inflamed lymph nodes are often enlarged because of hyperplasia of the lymphoid follicles and increased numbers of lymphocytes and macrophages. This constellation of pathologic changes is termed reactive, or inflammatory, lymphadenitis.

For clinicians the presence of red streaks near a skin wound is a telltale sign of an infection in the wound. This streaking follows the course of the lymphatic channels and is diagnostic of lymphangitis; it may be accompanied by painful enlargement of the draining lymph nodes, indicating lymphadenitis

Question 10

Cut with red streaks– what?

Answer 10

lymphangitis

Question 11

lymphangitis can lead to

Answer 11

inflammatory lymphadenitis, signs of early sepsis. Get on it!

Question 12

Leukocyte Recruitment to Sites of Inflammation

Answer 12

The changes in blood flow and vascular permeability are quickly followed by an influx of leukocytes into the tissue

Selectins- SLOW, or STOP the white cells.

Integrins- Cause attachment.

Question 13

The journey of leukocytes from the vessel lumen to the tissue is a multistep process that is mediated and controlled by adhesion molecules and cytokines called chemokines

Answer 13

In the lumen: margination, rolling, and adhesion to endothelium.

Vascular endothelium in its normal, unactivated state does not bind circulating cells or impede their passage.

In inflammation, the endothelium is activated and can bind leukocytes as a prelude to their exit from the blood vessels.
Migration across the endothelium and vessel wall
Migration in the tissues toward a chemotactic stimulus

Question 14

Leukocyte Adhesion to Endothelium

Answer 14

The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules on the two cell types whose expression is enhanced by cytokines

The two major families of molecules involved in leukocyte adhesion and migration are the selectins and integrins

Question 15

Leukocyte Migration through Endothelium

Answer 15

The next step in the process of leukocyte recruitment is migration of the leukocytes through the endothelium, called transmigration or diapedesis

Question 16

Chemotaxis of Leukocytes

Answer 16

After exiting the circulation, leukocytes move in the tissues toward the site of injury by a process called chemotaxis

Question 17

Phagocytosis and Clearance of the Offending Agent

Answer 17

Recognition of microbes or dead cells induces several responses in leukocytes that are collectively called leukocyte activation

Question 18

Phagocytosis

Answer 18

Recognition and attachment of the particle to be ingested by the leukocyte

Engulfment, with subsequent formation of a phagocytic vacuole

Killing or degradation of the ingested material.

Question 19

Intracellular Destruction of Microbes and Debris

Answer 19

Killing of microbes is accomplished by reactive oxygen species (ROS, also called reactive oxygen intermediates) and reactive nitrogen species, mainly derived from nitric oxide (NO), and these as well as lysosomal enzymes destroy phagocytosed debris

Question 20

Neutrophil Extracellular Traps

Answer 20

Neutrophil extracellular traps (NETs) are extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils

Question 21

Leukocyte-Mediated Tissue Injury

Answer 21

Leukocytes are important causes of injury to normal cells and tissues under several circumstances

As part of a normal defense reaction against infectious microbes, when adjacent tissues suffer collateral damage. In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases, the prolonged host response contributes more to the pathology than does the microbe itself.
When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases.
When the host reacts excessively against usually harmless environmental substances, as in allergic diseases, including asthma

Question 22

Termination of the Acute Inflammatory Response

Answer 22

Inflammation declines after the offending agents are removed simply because the mediators of inflammation are produced in rapid bursts, only as long as the stimulus persists, have short half-lives, and are degraded after their release

Question 23

Mediators of Inflammation

Answer 23

substances that initiate and regulate inflammatory reactions

Most important ones:

• vasoactive amines
• lipid products (prostaglandins and leukotrienes),
• cytokines (including chemokines)
• products of complement activation

Question 24

Plasma-derived mediators

Answer 24

e.g., complement proteins- produced mainly in the liver

present in the circulation as inactive precursors that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties

Question 25

Active mediators are produced only in response to various stimuli

Answer 25

• microbial products
• substances released from necrotic cells.

Some of the stimuli trigger well-defined receptors and signaling pathways,

The usual requirement for microbes or dead tissues as the initiating stimulus ensures that inflammation is normally triggered only when and where it is needed

Question 26

Most of the mediators are short-lived

Answer 26

They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited.

There is thus a system of checks and balances that regulates mediator actions.

Question 27

One mediator can stimulate the release of other mediators

Answer 27

products of complement activation –> histamine,

TNF acts on endothelial cells –> IL-1, and many chemokines.

The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying—or, in certain instances, counteracting—the initial action of a mediator.

Question 28

Vasoactive Amines:

Answer 28

Histamine and Serotonin

Histamine causes dilation of arterioles and increases the permeability of venules.

Question 29

Arachidonic Acid Metabolites

Answer 29

The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids, and stimulate vascular and cellular reactions in acute inflammation

Question 30

Prostaglandins

Answer 30

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 cyclooxgenases, called COX-1 and COX-2

Prostaglandins are involved in the pathogenesis of pain and FEVER in inflammation

Question 31

Leukotrienes

Answer 31

Leukotrienes are produced by leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment

Question 32

Lipoxins

Answer 32

Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes

Question 33

Do we want antagonists or agonists?

Answer 33

leukotriene antagonist
lipoxin agonist

to treat inflammation

Question 34

Pharmacologic Inhibitors of Prostaglandins and Leukotrienes

Answer 34

Cyclooxygenase inhibitors include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen

Lipoxygenase inhibitors. 5-lipoxygenase is not affected by NSAIDs, and many new inhibitors of this enzyme pathway have been developed. Pharmacologic agents that inhibit leukotriene production (e.g., Zileuton) are useful in the treatment of asthma

Leukotriene receptor antagonists block leukotriene receptors and prevent the actions of the leukotrienes. These drugs (e.g., Montelukast) are useful in the treatment of asthma

Question 35

corticosteroids

Answer 35

Corticosteroids are broad-spectrum antiinflammatory agents that reduce the transcription of genes encoding COX-2, phospholipase A2, proinflammatory cytokines (e.g., IL-1 and TNF), and iNOS

Question 36

cytokines

Answer 36

are proteins produced by many cell types (principally activated lymphocytes, macrophages, and dendritic cells, but also endothelial, epithelial, and connective tissue cells) that mediate and regulate immune and inflammatory reactions

Question 37

Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1)

Answer 37

TNF and IL-1 serve critical roles in leukocyte recruitment by promoting adhesion of leukocytes to endothelium and their migration through vessels

aspirin blocks IL-1

TNF augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates the microbicidal activity of macrophages, in part by inducing production of NO. IL-1 activates fibroblasts to synthesize collagen and stimulates proliferation of synovial and other mesenchymal cells. IL-1 also stimulates TH17 responses, which in turn induce acute inflammation.

IL-1 and TNF (as well as IL-6) induce the systemic acute-phase responses associated with infection or injury, including fever (described later in the chapter). They are also implicated in the syndrome of sepsis, resulting from disseminated bacterial infection. TNF regulates energy balance by promoting lipid and protein mobilization and by suppressing appetite. Therefore, sustained production of TNF contributes to cachexia, a pathologic state characterized by weight loss and anorexia that accompanies some chronic infections and neoplastic

Question 38

TNF antagonists in treatment

Answer 38

TNF antagonists have been remarkably effective in the treatment of chronic inflammatory diseases, particularly rheumatoid arthritis and also psoriasis and some types of inflammatory bowel disease

Question 39

Chemokines

Answer 39

Chemokines are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes

In acute inflammation
Inflammatory chemokines are the ones whose production is induced by microbes and other stimuli. These chemokines stimulate leukocyte attachment to endothelium by acting on leukocytes to increase the affinity of integrins, and they stimulate migration (chemotaxis) of leukocytes in tissues to the site of infection or tissue damage.
Maintenance of tissue architecture
Some chemokines are produced constitutively in tissues and are sometimes called homeostatic chemokines. These organize various cell types in different anatomic regions of the tissues, such as T and B lymphocytes in discrete areas of the spleen and lymph nodes

Question 40

Complement System

Answer 40

The complement system is a collection of soluble proteins and membrane receptors that function mainly in host defense against microbes and in pathologic inflammatory reactions

Question 41

The critical step in complement activation is the proteolysis of the third (and most abundant) component, C3. Cleavage of C3 can occur by one of three pathways:

Answer 41

The classical pathway, which is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen

The alternative pathway, which can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, cobra venom, and other substances, in the absence of antibody

The lectin pathway, in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1.

All three pathways of complement activation lead to the formation of an active enzyme called the C3 convertase, which splits C3 into two functionally distinct fragments, C3a and C3b

Question 42

The complement system has three main functions

Answer 42

Inflammation
C3a, C5a, and, to a lesser extent, C4a are cleavage products of the corresponding complement components that stimulate histamine release from mast cells and thereby increase vascular permeability and cause vasodilation. They are called anaphylatoxins because they have effects similar to those of mast cell mediators that are involved in the reaction called anaphylaxis.

Opsonization and phagocytosis
C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as opsonins and promote phagocytosis by neutrophils and macrophages, which bear cell surface receptors for the complement fragments.
Cell lysis
The deposition of the MAC on cells makes these cells permeable to water and ions and results in death (lysis) of the cells. This role of complement is important mainly for the killing of microbes with thin cell walls, such as Neisseria bacteria, and deficiency of the terminal components of complement predisposes to Neisseria infections.

Question 43

The activation of complement is tightly controlled by cell-associated and circulating regulatory proteins

Answer 43

C1 inhibitor (C1 INH) blocks the activation of C1, the first protein of the classical complement pathway. 
Inherited deficiency of this inhibitor is the cause of hereditary angioedema.

Decay accelerating factor (DAF) and CD59 are two proteins that are linked to plasma membranes by a glycophosphatidyl (GPI) anchor.
DAF prevents formation of C3 convertases and CD59 inhibits formation of the membrane attack complex. An acquired deficiency of the enzyme that creates GPI anchors leads to deficiency of these regulators and excessive complement activation and lysis of red cells (which are sensitive to complement-mediated cell lysis) in the disease called paroxysmal nocturnal hemoglobinuria (PNH)

Question 44

Morphologic Patterns of Acute Inflammation

Answer 44

The morphologic hallmarks of acute inflammatory reactions are dilation of small blood vessels and accu­mulation of leukocytes and fluid in the extravascular tissue

Question 45

Serous Inflammation

Answer 45

Serous inflammation is marked by the exudation of cell-poor fluid

Question 46

Types of exudates

Answer 46

serous
fibrinous
purulent
rotten
hemorrhagic

Question 47

fibrinous inflammation

Answer 47

A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus

Question 48

Purulent (Suppurative) Inflammation, Abscess

Answer 48

Purulent inflammation is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid

Abscesses are localized collections of purulent inflammatory tissue

Question 49

Ulcer

Answer 49

An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue

Question 50

Outcomes of Acute Inflammation

: complete resolution

Answer 50

In a perfect world, all inflammatory reactions, once they have succeeded in eliminating the offending agent, should end with restoration of the site of acute inflammation to normal. This is called resolution and is the usual outcome when the injury is limited or short-lived or when there has been little tissue destruction and the damaged parenchymal cells can regenerate. Resolution involves removal of cellular debris and microbes by macrophages, and resorption of edema fluid by lymphatics.

Question 51

outcomes of acute inflammation: healing by connective tissue replacement

Answer 51

(scarring, or fibrosis)

This occurs after substantial tissue destruction, when the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant fibrin exudation in tissue or in serous cavities (pleura, peritoneum) that cannot be adequately cleared. In all these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue, a process also called organization.

Question 52

Outcomes of Acute Inflammation: Progression of the response to chronic inflammation

Answer 52

Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, as a result of either the persistence of the injurious agent or some interference with the normal process of healing

Question 53

Summary of Acute Inflammation

Answer 53

The vascular and cellular reactions account for the signs and symptoms of the inflammatory response

The increased blood flow to the injured area and increased vascular permeability lead to the accumulation of extravascular fluid rich in plasma proteins, known as edema.

Circulating leukocytes, initially predominantly neutrophils, adhere to the endothelium via adhesion molecules, traverse the endothelium, and migrate to the site of injury under the influence of chemotactic agents. Leukocytes that are activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases extracellularly, causing tissue damage.

During the damage, and in part as a result of the liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain (dolor).