Chapter 5: Innate Defense: Inflammation

Front 1

What is innate resistance?

Back 1

(also called natural or native immunity)

includes natural barriers (physical, mechanical, and biochemical) and inflammation

Front 2

What is the first line of defense?

Back 2

(1) Physical Barriers
(2) Mechanical Barriers
(3) Biochemical Barriers

Front 3

What is the second line of defense?

Back 3

Inflammation

Front 4

What is the third line of defense?

Back 4

Adaptive (acquired) immunity

Front 5

List the physical barriers of the first line of defense.

Back 5

(1) tightly associated epithelial cells of the skin and of the membranes of the gastrointestinal, genitourinary, and respiratory tract

Front 6

List some mechanical barriers of the first line of defense.

Back 6

(1) pathogens sloughed off with dead skin cells as they are routinely replaced
(2) pathogens expelled by coughing or sneezing
(3) pathogens vomited from the stomach
(4) pathogens flushed from the urinary tract by urine
(5) epithelial cells of the respiratory tract also produce mucus and have hairlike cilia that trap and move pathogens upward to be expelled by coughing or sneezing
(6) low temperature on the body's surface generally inhibits microorganisms, most of which routinely require temperatures near 37*C (98.6*F) for efficient growth

Front 7

List some biochemical barriers of the first line of defense.

Back 7

(1) mucus
(2) perspiration
(3) saliva
(4) tears
(5) earwax
(6) sebaceous glands in the skin secrete fatty acids and lactic acid that kill bacteria and fungi
(7) epithelial cells secrete antimicrobial peptides, that are toxic to certain bacteria, fungi, and viruses
(8) normal bacterial flora on body's surfaces produce chemicals (such as ammonia, phenols, indols, and other toxic chemicals) that inhibit colonization by pathogenic organisms

Front 8

What do perspiration, tears, and saliva contain and what does this molecule do?

Back 8

they contain an enzyme (lysozyme) that attacks the cell walls of gram-positive bacteria

Front 9

What do the sebaceous glands in the skin secrete?

Back 9

fatty acids and lactic acid that kill bacteria and fungi

Front 10

What do epithelial cells secrete that are toxic to certain bacteria, fungi, and viruses?

Back 10

antimicrobial peptides

Front 11

What is the normal bacterial flora and where does it reside?

Back 11

a spectrum of nonpathogenic bacteria that resides on the body's surfaces

Front 12

How do the microorganisms that colonize the lower gut help us?

Back 12

(1) help digest fatty acids, large polysaccharides, and other dietary substances
(2) produce vitamin K
(3) assist in the absorption of various ions, such as calcium, iron, and magnesium
(4) also produce chemicals (ammonia, phenols, indols, and other toxic substances) that inhibit colonization by pathogenic microorganisms

Front 13

What can prolonged antibiotic treatment do to the body?

Back 13

it can alter the normal intestinal flora, decreasing its protective activity, and lead to an overgrowth of pathogenic microorganisms, such as the yeast Candida albicans or the bacteria Clostridium difficile

Front 14

What is the bacterium Lactobacillus? What does it produce? What can diminished colonization by this bacteria cause?

Back 14

(1) The bacterium Lactobacillus is a major constituent of the normal vaginal flora in healthy women.
(2) It produces chemical (hydrogen peroxide, lactic acid, and other molecules) that help prevent infections of the vagina and urinary tract by other bacteria and yeast.
(3) Diminished colonization by this bacteria (such as, as a result of prolonged antibiotic treatment) increases the risk for urologic or vaginal infections, such as vaginosis.

Front 15

List the classic symptoms of inflammation.

Back 15

(1) Redness
(2) Swelling
(3) heat
(4) pain
(5) loss of function

Front 16

What are the characteristic microscopic changes of inflammation?

Back 16

(1) vasodilation
(2) increased vascular permeability and leakage of fluid out of the vessel, causing swelling (edema)
(3) white blood cell adherence to the inner walls of vessels and their migration through enlarged junctions between the endothelial cells lining the vessels into the surrounding tissue

Front 17

What does vasodilation cause?

Back 17

It increases the size of the blood vessels, which cuases slower blood velocity and increases blood flow to the injured site.

Front 18

What do increased vascular permeability and leakage of fluid out of the vessel cause?

Back 18

As plasma moves outward, blood in the microcirculation becomes more viscous and flows more slowly, and the increased blood flow and increasing concentration of red cells at the site of inflammation cuase locally increased warmth and redness.

Front 19

What do the vascular changes associated with inflammation do?

Back 19

Deliver leukocytes, plasma proteins, and other biochemical mediators to the site of injury, where they act in concert.

Front 20

List the benefits of inflammation.

Back 20

(1) Limits and controls tissue damage through the influx of plasma protein systems (e.g., clotting system) and white blood cells (e.g., eosinophils) that prevent the inflammatory response from spreading to areas of healthy tissue
(2) Prevents infection by contaminating microorganisms through the influx of fluid to dilute toxins produced by bacteria, the influx and acntivation of plasma protein systems that help destroy and contain bacteria (e.g., compelement system, clotting system), and the influx of white blood cells (e.g., neutrophils, macrophages) that "eat" and destroy infectious agents
(3) initiates the adaptive immune response through the influx of macrophages and lymphocytes and drainage of microbial antigens by lymphatic vessels to the lymph nodes, where they activate lymphocytes
(4) initiates healing through removal of bacterial products, dead cells, and other products of inflammation (e.g., by way of channels through the epithelium or drainage by lymphatic vessels) and activate mechanisms of repair

Front 21

What 3 phases can inflammation be divided into?

Back 21

(1) Acute
(2) Chronic
(3) Granulomatosus

Front 22

What cell is the most important activator of the inflammatory response?

Back 22

the Mast Cell

Front 23

What are mast cells filled with?

Back 23

filled with granules

Front 24

Where are mast cells located?

Back 24

in loose connective tissues close to blood vessels near the body's outer surfaces (i.e., in the skin and lining the gastrointestinal and respiratory tracts)

Front 25

Where are basophils found and what is their function?

Back 25

Basophils are found in the blood and probably function in the same way as tissue mast cells.

Front 26

What is the role of cells and proteins that move into an area of inflammation?

Back 26

(1) limit tissue damage
(2) prevent infection
(3) control blood loss

Front 27

What causes mast cell degranulation?

Back 27

Mast cell degranulation is caused by a stimulus that activates mast cells to release potent soluble inducers of inflammation.

Front 28

A great number of stimuli activate mast cells to release potent soluble inducers of inflammation. How are these released?

Back 28

(1) degranulation (the release of the contents of mast cell granules)
(2) synthesis (the new production and release of mediators in response to a stimulus)

Front 29

What are the preformed vasoactive amines and chemotactic factors that are released from mast cells?

Back 29

(1) vasoactive amines: histamine and serotonin
(2) chemotactic factors: neutrophil chemotactic factor and eosinophil chemotactic factor of anaphylaxis

Front 30

What is histamine?

Back 30

a small molecular weight molecule with potent effects on many other cells, particularly those that control the circulation

Front 31

What is histamine, along with serotonin, referred to as?

Back 31

a vasoactive amine

Front 32

What does histamine cause?

Back 32

(1) temporary, rapid constriction of smooth muscle and dilation of the postcapillary venules, which results in increased blood flow into the microcirculation
(2) also causes increased vascular permeability resulting from retraction of endothelial cells lining the capillaries and increased adherence of leukocytes to endothelial cells

Front 33

How does histamine affect cells?

Back 33

by binding to histamine H1 and H2 receptors on the target cell surface

Front 34

What are antihistamines?

Back 34

Drugs that block the binding of histamine to its receptors, resulting in decreased inflammation

Front 35

What do chemotactic factors do?

Back 35

They diffuse from a site of inflammation forming a gradient and causing directional movemement (chemotaxis) of cells toward inflammation

Front 36

What are neutrophils?

Back 36

the predominant cell needed to kill bacteria in the early stages of inflammation

Front 37

What are eosinophils?

Back 37

cells that help regulate the inflammatory response, releases toxic proteins, and acts directly on parasites.

Front 38

What factors can cause mast cell degranulation?

Back 38

(1) mechanical injuries
(2) chemicals
(3) IgE binding in response to allergens
(4) activated complement

Front 39

Activated mast cells begin new synthesis of other mediators of inflammation, which are released later than those in the granules. List the mediators that are synthesized by the mast cells.

Back 39

(1) Leukotrienes (slow-reacting substances of anaphylaxis [SRS-A])
(2) Prostaglandins
(3) Platelet-activating factor

Front 40

What are leukotrienes?

Back 40

sulfur-containing lipids that produce histamine-like effects: smooth muscle contraction and increased vascular permeability.

Front 41

Why are leukotrienes important in the later stages of the inflammatory response?

Back 41

because they stimulate slower and more prolonged responses than do histamines

Front 42

What do prostaglandins cause?

Back 42

(1) increased vascular permeability
(2) neutrophil chemotaxis
(3) pain by direct effects on nerves

Front 43

What are prostaglandins?

Back 43

long-chain, unsaturated fatty acids

Front 44

What are prostaglandins produced by?

Back 44

arachidonic acid production leads to the synthesis of prostaglandin precursors via the action of the cyclooxgenase enzymes. These precursors are then modified into several types of active prostaglandins (E2, A2, F2, D2, I2, B2)

Front 45

What are prostaglandins classified into?

Back 45

They are classified into groups (E, D, A, F, and B) according to their structure

Front 46

What do prostaglandins E1 and E2 cause?

Back 46

(1) increased vascular permeability
(2) smooth muscle contraction

Front 47

Which drugs block the synthesis of prostaglandins of the E series and other arachidonic acid derivatives, thereby inhibiting inflammation?

Back 47

(1) aspirin
(2) some other NSAIDS (nonsteroidal anti-inflammatory drugs)

Front 48

What is platelet-activating factor produced by?

Back 48

made directly from membrane phospholipids

by removal of a fatty acid chain from the plasma membrane phospholipid by phospholipase A2.

Front 49

What cells are the major source of PAF?

Back 49

mast cells, but they can also be produced during inflammation by neutrophils, monocytes, endothelial cells, and platelets.

Front 50

The biologic activity of PAF is virtually identical to what other molecule?

Back 50

Leukotrienes

Front 51

List the functions of PAF.

Back 51

(1) cause endothelial cell retraction to increase vascular permeability
(2) leukocyte adhesion to endothelial cells
(3) platelet activation to stop bleeding
(4) vasoconstriction
(5) bronchoconstriction

Front 52

At the site of tissue damage all the hallmarks of inflammation are caused by ______________.

Back 52

mast cell products

Front 53

What are the 3 key plasma protein systems?

Back 53

(1) Complement system
(2) Clotting (Coagulation) system
(3) Kinin system

Front 54

List the similarities of the 3 plasma protein systems.

Back 54

(1) each system consists of multiple proteins in the blood
(2) to prevent activation in unnecessary situations, each protein is normally in an inactive form.
(3) several of the proteins are enzymes that circulate in inactive forms called proenzymes
(4) each systems contains a few proteins that can be activated by products of tissue damage or infection
(5) activation of the first component results in sequential activation of the first components of the system, leading to a biologic function that helps protect the individual. This sequential activation is referred to as a cascade.
(6) in some cases, activation of a protein may require that it be enzymatically cut into two pieces of different size. Usually the larger fragment continues the cascade by activating the next component. The smaller fragment frequently has potent biologica activities to promote inflammation.

Front 55

What does the complement system consist of?

Back 55

a large number of proteins (sometimes called complement components) that together constitute about 10% of the total circulating serum protein.

Front 56

Why is the complement system important?

Back 56

because activated components can destroy pathogens directly and can activate or collaborate with virtually every other component of the inflammatory response. For these reasons, proteins of the complement system are among the body's most important defenders against bacterial infection.

Front 57

What is the most important portion of the complement cascade?

Back 57

activation of C3 adn C5

Front 58

What does the activation of C3 and C5 result in?

Back 58

a variety of subunits that are (1) opsonins
(2) chemotactic factors
(3) anaphylatoxins

Front 59

What are opsonins?

Back 59

Molecules that coat bacteria and increase their susceptibility to being eaten and killed by inflammatory cells, such as neutrophils and macrophages

Front 60

What are anaphylatoxins?

Back 60

Molecules that induce rapid degranulation of mast cells, thus increasing inflammation.

Front 61

What are the most potent complement products?

Back 61

(1) C3b (opsonin)
(2) C3a (anaphylatoxin)
(3) C5a (anaphylatoxin, chemotactic factor)

Front 62

What does opsonization mean?

Back 62

Means that complement C3b and C5b (along with antibodies) make it easier for phagocytes to ingest bacteria, especially those organisms that have capsules that make them difficult to phagocytose. Phagocytes have receptors on their surfaces for complement and antibodies and can thus "grab" onto the bacteria and pull them into the cell to be destroyed.

Front 63

What is chemotaxis?

Back 63

describes the chemical signaling that causes leukocytes to move toward an area of inflammation.

C3a and C5a are the complement components most involved in chemotaxis

Front 64

Which complement components induce mast cell degranulation (anaphylatoxins)?

Back 64

C3a and C5a, which cause mast cells to release vasoactive chemicals such as histamine and serotonin, which cause hyperemia and fluid exudation

Front 65

Which complement componenets make up the membrane attack complex?

Back 65

C5-C9

Front 66

What is the membrane attack complex?

Back 66

a group of complement components (C5-C9) that bind to the lipid bilayer of cell membranes, forming cylindrical pores (channels). These pores in the membrane of target cells allow water to pour in, leading to cell lysis and cell death.

Front 67

What are the 3 ways that complement activation can be accomplished?

Back 67

(1) Classical pathway
(2) Lectin Pathway
(3) Alternative pathway

Front 68

What activates the classical pathway?

Back 68

proteins of the acquired immune system (antibodies)

Front 69

What activates the lectin pathway?

Back 69

certain bacterial carbohydrates

Front 70

What activates the alternative pathway?

Back 70

gram-negative bacteril and fungal cell wall polysaccharides

Front 71

Describe the classical pathway.

Back 71

It is primarily activated by proteins of the acquired immune system, antibodies. Antibody must first bind with their targets, called antigens.

Antigens can be proteins or carbohydrates from bacteria or other infectious agents.

(1) the classic pathway of complement activation involves the binding of the Fc portions of antibodies to activated C1, which results in the complement molecule transforming into its subcomponents C2, C4, and C3.
(2) C3 is subsequently divided into 2 components, C3a and C3b
(3) C3b is then transformed to C5, which is subsequently divided into 2 subcomponents, C5a and C5b
(4) Finally, C5b is transformed to C5b plus C6, C7, C8, and C9, which form the membrane attack complex (MAC)

Front 72

List the 3 major groups of active complement components and what they do.

Back 72

(1) C3a and C3b: chemotaxis and degranulate mast cells (anaphylatoxins)
(2) C3b and C5b:opsonize encapsulated bacteria
(3) C5-C9: form the membrane attack complex (MAC)

Front 73

How does opsonization work?

Back 73

C3b and C5b bind to the surface of encapsulated bacteria (along with antibodies).

Phagocytes have complement receptors on their surfaces that allow them to "grab onto" the bacterium and ingest it.

Front 74

What is the result of the anaphylatoxin role of C3a and C5a?

Back 74

Mast cell degranulation results in release of the preformed vascular mediators histamine and serotonin, leading to hyperemia and fluid exudation

chemotactic factors are released that bring inflammatory cells to the area of injury

rapidly formed production of arachidonate metabolism (prostaglandins and leukotrienes) contribute to the inflammatory response.

Front 75

What does MAC do?

Back 75

C5 through C9 bind to membranes of target cells and create pores into the cells, leading to cell lysis and death

Front 76

Describe the alternative pathway.

Back 76

activated by several substances found on the surface of infectious organisms (e.g., lipopolysaccharides [endotoxin] on bacterial surface or yeast cell wall carbohydrates [zymosan]).

this pathway uses unique proteins (factor B, factor D, and properdin) to form a complex that activates C3.

C3 activation leads to C5 activation and convergence with the classical pathway.

Thus, the complement system can be directly activated by certain infectious organisms without antibody being present.

Front 77

Describe the lectin pathway.

Back 77

similar to the classic pathway but is independent of antibody.

it is activated by a plasma protein called mannose-binding lectin (MBL).

MBL is similar to C1 and binds to bacterial polysaccharides containing the carbohydrate mannose.

Thus, infectious agents that do not activate the alternative pathway may be susceptible to complement through the lectin pathway.

Front 78

What is the clotting system?

Back 78

a group of plasma proteins that, when activated sequentially, form a fibrinous meshwork at an injured or inflamed site.

Front 79

What are the functions of the coagulation (clotting) system?

Back 79

(1) forms a clot that stops bleeding
(2) traps infectious organisms and prevents their spread to adjacent tissues
(3) keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity
(4) provides a framework for future repair and healing

Front 80

What is the main substance in the fibrinous mesh produced by the clotting system?

Back 80

fibrin, an insoluble protein produced by the coagulation cascade

Front 81

Where does the coagulation cascade converge?

Back 81

at factor X, from that point on a common pathway results in fibrin formation.

Front 82

What can activate the coagulation cascade?

Back 82

many substances released during tissue destruction and infection, such as bacterial products (e.g., endotoxin), collagen, and cellular proteases

Front 83

What are released when fibrinogen is activated to produce fibrin?

Back 83

two low-molecular-weight peptides (fibrinopeptides A and B).

these two fibrinopeptides are chemotactic for neutrophils and increase vascular permeability

Front 84

Describe the kinin system.

Back 84

interacts closely with the coagulation system

both the clotting system and kinin system are activated trhough activated factor XII (factor XIIa).

Another name for factor XIIa is prekallikrein activator because it enzymatically activates the first component of the kinin system, prekallikrein.

the final product of the kinin system is a small-molecular-weight molecule, bradykinin, which is produced from a large precursor molecule, kininogen.

Front 85

What is bradykinin produced from?

Back 85

a large precursor molecule called kininogen

Front 86

What does bradykinin cause at low doses?

Back 86

(1) dilation of blood vessels
(2) acts with prostaglandins to produce pain
(3) causes smooth muscle cell contraction
(4) increases vascular permeability

Front 87

What are the two pathways of activation of the coagulation cascade?

Back 87

a. Extrinsic pathway--causes blood clotting in response to factors released from damaged tissue

b. Intrinsic pathway--causes blood clotting in response to contact with a foreign substance

c. Injured cells, bacterial products, and exposed collagen can begin the cascade of events leading to the production of a fibrin clot.

Front 88

Why is control of the plasma protein systems essential?

Back 88

a. Because it would be detrimental to the person if the systems continued producing potent proinflammatory molecules indefinitely.

Front 89

What are some of the important control systems for inflammation?

Back 89

(1) during clot formation the enzyme plasmin is produced from plasminogen. Plasmin limits clot formation by degrading fibrin and fibrinogen and also can activate the complement cascade through components C1, C3, and C5.

(2) anaphylatoxic activities of C3a and C5a are inactivate by the plasma enzyme carboxypeptidase.

(3) C1 esterase inhibitor binds to C1 to inhibit further activation of the classical pathway. It also binds to elements of the kinin and clotting systems to prevent or limit their activation.

Front 90

26. What is an example of a disease caused by inadequate controls of plasma inflammatory systems?

Back 90

Hereditary angioneurotic edema is an autosomal dominant disease characterized by a deficiency of C1 esterase inhibitor.

In individuals with this disease, emotional stress and other stimuli often cause recurrent edema in the GI tract, respiratory tract, and skin, with swelling around the larynx sometimes causing death.

The mechanism appears to be episodic, uncontrolled activation of plasmin, resulting in Hageman factor (XII) activation, bradykinin production, and C1 activation.

Front 91

What are the primary circulating white blood cells?

Back 91

granulocytes

Front 92

List the granulocytes.

Back 92

(1) neutrophils
(2) basophils
(3) eosinophils

Front 93

List other blood components.

Back 93

(1) platelets
(2) monocytes/macrophages
(3) various forms of lymphocytes
(4) natural killer cells

Front 94

27. What are the primary mechanisms by which phagocytes arrive at the area of injury?

Back 94

Biochemical mediators produced by mast cells or from activation of plasma protein systems or are released from dying cells

Front 95

28. How do neutrophils and macrophages differ with respect to their roles in inflammation?

Back 95

a. Primary roles of the neutrophil are removal of debris and dead cells in sterile lesions, such as burns, and phagocytosis of bacteria in nonsterile lesions. It is incapable of division and sensitive to acidic environments, it is short lived at the inflammatory site.

(b) Macrophages are better suited than neutrophils to long-term defense against infectious agents because macrophages can survive and divide in the acidic inflammatory site.

Front 96

Endothelial cells release nitric oxide, which has at least two effects on inflammation. List them.

Back 96

(1) NO causes vasodilation by inducing relaxation of vascular smooth muscle, a response that is local and short-lived.

(2) NO may suppress mast cell release of inflammatory molecules and decrease platelet adhesion and aggregation.

Front 97

What are neutrophils?

Back 97

a member of the granulocyte series of white blood cells and is named for the characteristic staining pattern of its granules as well as its multilobed nucleus

Front 98

What are the predominant phagocytes in the early inflammatory site? When do they arrive?

Back 98

(1) neutrophils

(2) arrive within 6 to 12 hours after the initial injury

Front 99

Which inflammatory mediators specifically and rapidly attract neutrophils from the circulation and activate them?

Back 99

some bacterial proteins

complement fragments C3a and C5a

mast cell neutrophil chemotactic factor

Front 100

Why is the neutrophil short-lived at the inflammatory site?

Back 100

because it is a mature cell that is incapable of division and sensitive to acidic environments

it becomes a component of the purulent exudate, or pus, which is removed from the body through the epithelium or via the lymphatic system

Front 101

List the primary roles of the neutrophil.

Back 101

(1) removal of debris and dead cells in sterile lesions, such as burns

(2) phagocytosis of bacteria in nonsterile lesions

Front 102

What are monocytes?

Back 102

the immature form of this white blood cell in the blood

Front 103

What are macrophages?

Back 103

the mature form of this white blood cell in tissues

Front 104

How are monocytes and macrophages different from the granulocytes?

Back 104

they have fewer and larger lysosomes in their cytoplasm than do granulocytes

Front 105

What are the largest normal blood cells and have a nucleus that is often indented or horseshoe shaped?

Back 105

monocytes

Front 106

Where are monocytes produced?

Back 106

in the bone marrow, where they then enter the circulation, migrate to the inflammatory site, and develop into macrophages

Front 107

What are the macrophages of the liver called?

Back 107

Kupffer's cells

Front 108

What are the macrophages of the brain called?

Back 108

microglia

Front 109

What are the macrophages of the lungs called?

Back 109

alveolar macrophages

Front 110

When do macrophages enter the site of inflammation?

Back 110

ater 24 hours or later, and gradually replace neutrophils

Front 111

Why do macrophages migrate to the area of inflammation after neutrophils?

Back 111

because they move more sluggishly and because many of the chemotactic factors that attract them, such as macrophage chemotactic factor, must first be released by neutrophils

Front 112

Why are macrophages better suited than neutrophils to long-term defense against infectious agents?

Back 112

because macrophages can survive and divide in the acidic inflammatory site

Front 113

What organisms can avoid being killed inside macrophages and why?

Back 113

a. Several bacteria are resistant to killing by granulocytes and can even survive inside macrophages:
(1) Mycobacterium tuberculosis (tuberculosis)
(2)Mycobacterium leprae (leprosy)
(3) Salmonella typhi (typhoid fever)
(4)Brucella abortus (brucellosis)
(5) Listeria monocytogenes (lysteriosis)

b. They can remain dormant or multiply inside the phagolysosomes of macrophages

c. For macrophages to kill certain infectious agents most effectively, they require activation by lymphokines produced from T helper cells, especially interferon. These lymphokines make the macrophage increase in size, have more phagocytic activity, and increase the number of lysosomes. When there is immune dysfunction such that the T helper cells do not secrete adequate lymphokines, certain infections may persist within macrophages for long periods of time (latency) without being killed. The organism may be contained for long periods by the formation of a granuloma.

Front 114

What are the functions of macrophages in the inflammatory response?

Back 114

(1) provide prolonged phagocytosis at the site of inflammation

(2) process and present antigens to the immune system

(3) release numerous cytokines that promote healing, including growth factors and angiogenesis factors (promote new blood vessel formation)

Front 115

What are the 2 specific functions of eosinophils?

Back 115

(1) serve as the body's primary defense against parasites

(2) help regulate vascular mediators released from mast cells

Front 116

What attracts eosinophils to the site of inflammation?

Back 116

eosinophil chemotactic factor-A produced by mast cells

Front 117

What do eosinophil lysosomes contain?

Back 117

several enzymes that degrade vasoactive molecules, thereby controlling the vascular effects of inflammation

these enzymes include histaminase, which mediates the degradation of histamine, and arlysulfatase B, which degrades some of the lipid-derived mediators produced by mast cells

Front 118

What are the roles of natural killer cells and platelets in inflammation?

Back 118

a. Natural killer cells--recognize and eliminate cells infected with viruses and abnormal host cells, specifically cancer cells

Platelets--activated after injury, which results in (1) their interaction with components of the coagulation cascade to stop bleeding and (2) degranulation, releasing biochemical mediators such as serotonin, which has vascular effects similar to those of histamine

Front 119

What is the main function of natural killer cells? How do these cells recognize target cells?

Back 119

to recognize and eliminate cells infected with viruses and abnormal host cells, specifically cancer cells.

Along with Toll-like receptors, NK cells have additional inhibitory and activating receptors that allow them to recognize differences between infected or tumor cells and normal cells. If the NK cell binds to a target cell through activating receptors, it produces several cytokines and toxic molecules that can kill the target.

Front 120

How do eosinophils contribute to tissue damage?

Back 120

through the release of toxic substances, such as major basic protein and eosinophil cationic protein

Front 121

How are eosinophils activated in allergies and asthma?

Back 121

by interleukin-5 produced by T helper 2 cells.

Front 122

How do eosinophils and their release to toxic substances contribute to acute allergic and asthmatic response?

Back 122

by denuding epithelial membranes and making them more vulnerable to noxious stimuli.

They also participate in chronic inflammatory changes that can lead to fibrosis and permanent changes in tissues.

Front 123

What are platelets?

Back 123

cytoplasmic fragments formed from megakaryocytes

Front 124

Platelets circulate in the bloodstream until vascular injury occurs. What happens after an injury?

Back 124

platelets are activated by many products of tissue destruction and inflammation, including collagen, thrombin, and platelet-activating factor.

Front 125

What does the activation of platelets result in?

Back 125

(1) their interaction with components the coagulation cascade to stop bleeding

(2) degranulation, releasing biochemical mediators such as serotonin, which has vascular effects similar to those of histamine

Front 126

What is phagocytosis?

Back 126

the process by which a cell ingests and disposes of foreign material, including microorganisms

Front 127

What are the two most important phagocytes?

Back 127

(1) neutrophils

(2) macrophages

Front 128

What are the steps involved in phagocytosis?

Back 128

a. Adherence of the phagocyte to its target

b. Engulfment (endocytosis)

c. Formation of a phagosome

d. Fusion of the phagosome with lysosomal granules within the phagocyte

e. Destruction of the target

Front 129

What is meant by pattern-recognition receptors?

Back 129

Groups of innate receptors that bind to unique molecular "patterns" on infectious agents or their products or products of cellular damage

Front 130

What is meant by margination, or pavementing?

Back 130

a process by which leukocytes adhere to the endothelial cells on the walls of capillaries and venules

Front 131

What is diapedesis?

Back 131

emigration of leukocytes through the endothelial junctions that have retracted in response to inflammatory mediators

Front 132

Once inside the tissues, leukocytes are attracted to the inflammatory site by chemotactic factors. List them.

Back 132

(1) many bacterial products

(2) neutrophil chemotactic factor from mast cells

(3) complement fragments C3a and C5a

(4) products of the clotting and kinin systems

Front 133

Most phagocytes can trap and engulf bacteria that have not been coated with an opsonin. How does adherence occur in this situation?

Back 133

through groups of innate receptors, pattern recognition receptors (PRRs), that bind to unique molecular "patterns" on infectious agents or their products (pathogen-associated molcular patterns [PAMPs]) or products of cellular damage.

Front 134

What are Toll-like receptors?

Back 134

a set of pattern recognition receptors expressed on the surface of phagocytes as well as many cells that have direct contact with potential pathogenic microorganisms.

These include mucosal epithelial cells, mast cells, neutrophils, macrophages, and some subpopulations of lymphocytes.

Front 135

What do Toll-like receptors do?

Back 135

recognize a large variety of chemicals located on the microorganism's cell wall or surface (e.g., bacterial lipopolysaccharide [LPS], peptidoglycans, lipoproteins, yeast zymosan, and viral coat proteins) and on other surface structures (e.g., bacterial flagellin)

Front 136

Phagocytosis using innate receptors is a relatively slow process. What enhances adherence by acting as a glue to tighten the affinity of adherences between the phagocyte and the target cell?

Back 136

opsonization

Front 137

What are the most efficient opsonins?

Back 137

antibody and C3b produced by the complement system

Front 138

The surface of phagocytes contains a variety of specific receptors that will strongly bind to opsonins. What do these include?

Back 138

(1) complement receptors that bind to C3b

(2) Fc receptors that bind to a site on antibody molecules

Front 139

How is engulfment (endocytosis) carried out?

Back 139

by small pseudopods that extend from the plasma membrane and surround the adherent microorganism forming an intracellular phagocytic vacuole, or phagosome.

After the formation of the phagosome, lysosomes converge, fuse with the phagosome, and discharge their contents, creating a phagolysosome.

Destruction of the bacterium takes place within the phagolysosome and is accomplished by both oxygen-dependent and oxygen-independent mechanisms.

Front 140

Describe the oxygen-dependent killing mechanisms.

Back 140

result from the production of toxic oxygen species.

phagocytosis is accompanied by a burst of oxygen uptake by the phagocyte; this is termed the respiratory burst and results from a shift in much of the cell's glucose metabolism to the hexose-monophosphate shunt, which produces nicotinamide adenine dinucleotide phosphate (NADPH).

A membrane-associated enzyme, NADPH oxidase uses NADPH to generate superoxide, hydrogen peroxide, and other reactive oxygen species that can be highly damaging to bacteria.

Hydrogen peroxide also can collaborate with the lysosomal myeloperoxidase and halide anions (Cl- and Br-) to form acids that can kill bacteria and fungi

Front 141

Describe the oxygen-independent killing mechanisms.

Back 141

(1) the acidic pH (3.5 to 4.0) of the phagolysosome
(2) cationic proteins that bind to and damage target cell membranes
(3) enzyme attack of the microorganism's cell wall by lysozyme and other enzymes
(4) inhibition of bacterial growth by lactoferrin binding of iron

Front 142

When a phagocyte dies at an inflammatory site, it frequently lyses and releases its cytoplasmic contents, including the lysosomal enzymes, into the tissue. What does this do to the tissues?

Back 142

These enzymes can digest the connective tissue matrix, causing much of the tissue destruction associated with inflammation.

Front 143

How are the destructive effects of many enzymes released by dying phagocytes minimized?

Back 143

by natural inhibitors found in the blood, such as alpha1-antitrypsin, a plasma protein produced by the liver.

Front 144

What does an inherited deficiency of alpha1-antitrypsin lead to?

Back 144

chronic lung damage and emphysema as a result of inflammation

Front 145

How do released lysosomal products also contribute to inflammation?

Back 145

(1) increasing vascular permeability
(2) attracting additional monocytes
(3) activating the complement and kinin systems

Front 146

What are the shared characteristics of inflammatory cytokines?

Back 146

a. Inflammatory cytokines are produced by the cells of inflammation (as well as some lymphocytes) and provide rapid and nonspecific responses to invaders. 

• Most cytokines enhance inflammation (proinflammatory) (TNF-alpha, IL-1, IL-6, interferons).

• A few are anti-inflammatory (IL-10).

• Most cytokines act on the cells and tissues in their immediate vicinity.

• When a significant inflammatory response is initiated, these cytokines may spill into the bloodstream and cause systemic manifestation such as fever (TNF-alpha, IL-1).

• Cytokines bind to receptors on inflammatory cells.

• Cytokine activity may vary depending on the target cell and its receptors.

• Cytokines may act synergistically or antagonistically.

• Some cytokines are more active in some stages of inflammation than others.

Front 147

For inflammation to occur, many different kinds of cells must cooperate. That cooperation is achieved by the secretion of a variety of proteins that affect other cells. What are these factors referred to as?

Back 147

cytokines and chemokines

Front 148

What are the majority of important cytokines classified as?

Back 148

as interleukins or interferons

Front 149

What is the major role of interleukin-1 (IL-1)?

Back 149

a. Fever-causing cytokine (endogenous pyrogen); reacts with receptors on cells of the hypothalamus and affects the body's thermostat resulting in fever.

b. It also activates phagocytes and lymphocytes, thereby also enhancing both the innate and acquired immunity, and acts as a growth factor for many cells.

c. Has several affects on neutrophils, inlcuding induction of proliferation (resulting in an increase in the number of circulating neutrophils), chemotaxis, increased cellular respiration, and increased lysosomal enzyme activity.

Front 150

What are interleukins produced predominantly by?

Back 150

macrophages and lymphocytes in response to their recognition of a pathogen or stimulation by other products of inflammation

Front 151

What is interleukin-1 produced primarily by?

Back 151

macrophages

Front 152

What is the main function of interleukin-1?

Back 152

as an endogenous pyrogen that reacts with receptors on cells of the hypothalamus and affects the body's thermostat resulting in fever.

It also activates phagocytes and lymphocytes, thereby enhancing both the innate and acquired immunity, and acts as a growth factor for many cells

Front 153

What are the effects of interleukin-1 on neutrophils?

Back 153

(1) induction of proliferation
(2) chemotaxis
(3) increased cellular respiration
(4) increased lysosomal enzyme activity

Front 154

What is the major role of interleukin-6 (IL-6)?

Back 154

a. Directly induces hepatocytes to produce many of the proteins needed in inflammation (acute-phase reactants).

b. Also stimulates growth and differentiation of precursors of blood cells in the bone marrow and the growth of fibroblasts.

c. Produced by macrophages and lymphocytes.

Front 155

What is interleukin-6 produced by?

Back 155

macrophages

lymphocytes

fibroblasts

other cells

Front 156

What does interleukin-6 do?

Back 156

directly induces hepatocytes (liver cells) to produce many of the proteins needed in inflammation (acute phase reactants)

also stimulates the growth and differentiation of precursors of blood cells in the bone marrow and the growth of fibroblasts

Front 157

Which interleukin is an example of an anti-inflammatory cytokine?

Back 157

interleukin-10

Front 158

What is the major role of interleukin-10 (IL-10)?

Back 158

a. Anti-inflammatory cytokine primarily produced by lymphocytes to down-regulate both the inflammatory response and acquired immune response.

b. Suppresses growth of lymphocytes and the production of proinflammatory cytokines by macrophages.

Front 159

What is interleukin-10 primarily produced by?

Back 159

lymphocytes

Front 160

What is the function of interleukin-10?

Back 160

to down-regulate both the inflammatory and acquired immune responses.

suppresses growth of lymphocytes and the production of proinflammatory cytokines by macrophages

Front 161

More than 30 interleukins have been identified. What are their various effects?

Back 161

(1) alteration of adhesion molecule expression on many types of cells
(2) induction of leukocyte chemotaxis
(3) induction of proliferation and maturation of leukocytes in the bone marrow
(4) general enhancement or suppression of inflammation

Front 162

What are interferons?

Back 162

a family of cytokines that protect against viral infections

Front 163

What interferons do macrophages and other cells produce?

Back 163

IFN-alpha and IFN-beta

Front 164

What interferons do lymphocytes release?

Back 164

IFN-gamma

Front 165

What is the function of IFN-alpha and IFN-beta?

Back 165

induce production of antiviral proteins, thereby conferring protection on uninfected cells

Front 166

What is the function of IFN-gamma?

Back 166

enhances the inflammatory response by increasing the microbiocidal activity of macrophages

also facilitates development of the acquired immune response against viral antigens on infected cells

Front 167

Other essential cytokines are needed to mount an efficient inflammatory response. What is one of the most important ones?

Back 167

tumor necrosis factor-alpha

Front 168

What do macrophages secrete TNF-alpha in response to?

Back 168

recognition of foreign materials by toll-like receptors.

Front 169

Besides macrophages, what other cells are sources of TNF-alpha?

Back 169

mast cells

Front 170

What does TNF-alpha induce?

Back 170

a multitude of proinflammatory effects, including enhancement of endothelial cell adhesion molecule expression, which results in increased adherence of neutrophils, and induction of chemokine production by both endothelial cells and macrophages

Front 171

When secreted in large amounts TNF-alpha has system effects. List them.

Back 171

(1) inducing fever by acting as an endogenous pyrogen
(2) causing increased synthesis of inflammation-related serum proteins by the liver
(3) causing muscle wasting (cachexia) and intravascular thrombosis in cases of severe infection and cancer

Front 172

What are very high levels of TNF-alpha responsible for?

Back 172

fatalities from shock caused by gram-negative bacterial infections

Front 173

What are transforming growth factors produced by?

Back 173

by many types of cells in response to inflammation, tumor growth, and cellular differentiation

Front 174

What do cytokines that are growth factors do?

Back 174

induce the cell division and differentiation of many cell types, such as hemopoietic blood cells

Front 175

What are colony-stimulating factors?

Back 175

cytokines that stimulate differentiation of blood cells

Front 176

What are chemokines?

Back 176

a family of low-molecular-weight peptides that primarily induce leukocyte chemotaxis

Front 177

What types of cells are chemokines synthesized by?

Back 177

many cell types, including macrophages, fibroblasts, and endothelial cells, in response to proinflammatory cytokines

Front 178

What types of cells are chemokines synthesized by?

Back 178

many cell types, including macrophages, fibroblasts, and endothelial cells, in response to proinflammatory cytokines

Front 179

List some examples of chemokines.

Back 179

monocyte/macrophage chemotactic factors (MCP-1, MCP-2, and MCP-3)

macrophage inflammatory proteins (MIP-alpha and MIP-beta)

interleukin-8

Front 180

What causes the local manifestations of acute inflammation?

Back 180

a. Vascular changes and the subsequent leakage of circulating components into the tissue

b. The symptoms of acute inflammation are due to the vasodilation with hyperemia and fluid exudation that occur in response to the release of vasoactive substances from the mast cell and the plasma protein systems.

c. In addition, prostaglandins and bradykinin stimulate pain fibers. Thus, the symptoms of acute inflammation are redness, heat, swelling, pain, and loss of function.

Front 181

What are the major types of inflammatory exudate?

Back 181

a. Serous exudate--in early or mild inflammation, the exudate is watery with very few plasma proteins or leukocytes. e.g., fluid in a blister

b. Fibrinous exudate--in more severe or advanced inflammation, the exudate may be thick and clotted, such as in the lungs of individuals with pneumonia.

c. Purulent (suppurative) exudate--if a large number of leukocytes accumulate, as in persistent bacterial infections, the exudate consists of pus. This exudate is characteristic of walled-off lesions (cysts or abscesses).

d. Hemorrhagic exudate--if bleeding occurs, the exudate is filled with erythrocytes

Front 182

What are the systemic manifestations of acute inflammation?

Back 182

a. Fever

b. Leukocytosis

c. Plasma protein synthesis

Front 183

What causes fever?

Back 183

a. Partially induced by specific cytokines (e.g., IL-1 released from neutrophils and macrophages), known as endogenous pyrogens, that act on they hypothalamus, the portion of the brain that controls the body's thermostat

b. TNF-alpha, IL-1, IL-6, prostaglandins

Front 184

How can a fever be beneficial?

Back 184

because some microorganisms (e.g., syphilis, gonococcal urethritis) are highly sensitive to small increases in body temperature

Front 185

Why might a fever have harmful side effects?

Back 185

because it may enhance the host's susceptibility to the effects of endotoxins associated with gram-negative bacterial infections

Front 186

What is meant by leukocytosis and a “left shift”?

Back 186

a. Leukocytosis is an increase in the number of circulating white blood cells.

b. During many infections, leukocytosis may be accompanied by a "left shift" in the ratio of immature to mature neutrophils, so that the more immature forms of neutrophils, such as band cells, metamyelocytes, and occasionally myelocytes, are present in relatively greater than normal proportions. This increases primarily from proliferation and release of granulocyte and monocyte precursors in the bone marrow, which is stimulated by several products of inflammation.

Front 187

What are the important plasma proteins that are synthesized in inflammation?

Back 187

a. Acute-phase reactants
i. IL-1 directly induces the synthesis of acute-phase reactants by increasing production of IL-6, which directly stimulates the synthesis of acute-phase reactants by liver cells.

b. Fibrinogen, C-reactive protein

Front 188

What are the characteristic cells of chronic inflammation?

Back 188

Dense infiltration of lymphocytes and macrophages

Front 189

What is a granuloma?

Back 189

a. A walled-off and isolated infected area produced by the body if macrophages are unable to protect the host from tissue damage

b. Lymphocytes and macrophages are the primary cells of chronic inflammation. Macrophages may differentiate into epithelioid cells (which are inefficient phagocytes) or fuse into giant cells (which are excellent phagocytes and can envelop large particles). These cells gather around foreign bodies or infectious agents and form what is called a granuloma. A granuloma consists of a wall of epithelioid cells surrounding the nidus (center) of persistent inflammation, often with necrotic tissue at its core. Fibrin deposition and calcification of the lesion may also occur.

Front 190

What are epithelioid cells, and what are giant cells?

Back 190

a. Epithelioid cells are differentiated macrophages that are incapable of phagocytosing large bacteria but are capable of taking up debris and other small particles. When macrophages differentiate into epithelioid cells, granuloma formation begins.

b. Giant cells are fused macrophages which are active phagocytes that can engulf very large particles--larger than can be engulfed by a single macrophage

c. These two types of differentiated macrophages form the center of the granuloma, which is surrounded by a wall of lymphocytes.

Front 191

What do the terms regeneration, resolution, and repair mean?

Back 191

a. The term regeneration refers to the process in which a tissue is able to stimulate new cell division that allows for the restoration of damaged tissue.

b. Resolution is the result of complete regeneration and restoration of normal tissue function and structure after injury.

c. Repair is the replacement of damaged tissue with scar which is mostly composed of collagen.

Front 192

How do healing by primary intention and secondary intention differ from one another?

Back 192

a. Wounds that heal under conditions of minimal tissue loss are said to heal by primary intention.

b. Wounds that are larger and open and take longer to heal are said to heal by secondary intention.

Front 193

What are the steps in the reconstructive phase of healing?

Back 193

a. Clotting
b. Debridement
c. Formation of granulation tissue
d. Epithelialization
e. Fibroblast proliferation
f. Collagen deposition
g.Early wound contraction

Front 194

What is granulation tissue?

Back 194

Tissue that grows into the wound from surrounding healthy connective tissue. It is filled with new capillaries (angiogenesis) derived from capillaries in the surrounding tissue, giving the granulation tissue a red, granular appearance. New lymphatic vessels also grow into the granulation tissue by a similar process.

Front 195

What is meant by the term debridement?

Back 195

Activation of the plasma fibrinolytic system and release of lysosomal enzymes from neutrophils begins dissolving the clot. Macrophages phagocytose residual debris.

Front 196

What is epithelialization, and how does it occur?

Back 196

Epithelialization is the process by which epithelial cells grow into the wound from surrounding healthy tissue. The cells migrate under the clot or scab using MMPs (matrix metalloproteinases that degrade extracellular matrix proteins, such as collagen and fibrin, at the site of injury). Migrating epithelial cells contact similar cells from all sides of the wound and seal it, thereby halting migration and proliferation. The epithelial cells remain active, undergoing differentiation to give rise to the various epidermal layers.

Front 197

What are the steps in collagen deposition?

Back 197

a. Fibroblasts secrete collagen and other connective tissue proteins, which are deposited in the debrided areas about 6 days after the fibroblasts have entered the lesion.

b. Collagen is the most abundant protein in the body. It contains high concentrations of the amino acids glycine, proline, and lysine, many of which are enzymatically modified. Modification of proline and lysine requires several cofactors and is absolutely necessary for proper collagen polymerization and function. These include: iron, ascorbic acid (vitamin C), and molecular oxygen; absence of any of these results in impaired wound healing.

c. As healing progresses, collagen molecules are cross-linked by intermolecular covalent bonds to form collagen fibrils that are further cross-linked to form collagen fibers.

d. The complete process takes several months.

Front 198

What is wound contraction?

Back 198

a. Is necessary for closure of all wounds, especially those that heal by secondary intention.

b. Contraction is noticeable 6 to 12 days after injury.

c. The granulation tissue contains myofibroblasts--specialized cells that are responsible for wound contraction.

d. Myofibroblasts have features of both smooth muscle cells and fibroblasts.

e. Wound contraction occurs as extensions from the plasma membrane of myofibroblasts establish connections between neighboring cells, contract their fibers, and exert tension on the neighboring cells while anchoring themselves to the wound bed.

Front 199

What is meant by the maturation phase of healing?

Back 199

A phase that can persist for years in which collagen matrix assembly, tissue regeneration, and wound contraction continue.
b. Scar tissue is remodeled and capillaries disappear, leaving the scar avascular.

Front 200

What are the mechanisms by which healing can become dysfunctional during the acute inflammatory response?

Back 200

a. prolonged bleeding
b. excessive fibrin
c. Hypovolemia (insufficient arterial blood supply)
d. anti-inflammatory drugs
e. immunocompromise
f. poor nutrition
g. diabetes
h. wound sepsis

Front 201

What can cause impaired collagen synthesis, and how might it present clinically?

Back 201

a. Most of the factors that interfere with the production of collagen in healing tissues are nutritional.

b. Scurvy, for example, is caused by lack of ascorbic acid--one of the cofactors required for collagen formation by fibroblasts. The results of scurvy are poorly formed connective tissue and greatly impaired healing.

c. Protein and other nutrients are required for collagen synthesis. These include iron, oxygen, ketoglutarate, manganese, copper, and calcium.

d. Dysfunctional collagen synthesis may also involve excessive production of collagen, causing surface overhealing leading to a keloid or a hypertrophic scar.
i. A keloid is a raised scar that extends beyond the original boundaries of the wound. It invades surrounding tissue and is likely to recur after surgical removal.
ii. A hypertrophic scar is raised but remains within the original boundaries of the wound and tend to regress over time.

Front 202

Why does hyponatremia prolong inflammation?

Back 202

because it impaire fibroblast proliferation

Front 203

What can cause impaired epithelialization, and how can it be prevented?

Back 203

a. Epithelialization can be suppressed by:
i. Anti-inflammatory steroids
ii. Hypoxemia
iii. Ionizing radiation
iv. Zinc deficiencies

b. Can be prevented by wound care technique (promote epithelial cell migration):
i. Dressing that debride and protect wounds healing by secondary intention
ii.Cleaning/irrigation of wounds by normal saline rather than iodine and hydrogen peroxide

Front 204

What are the key factors involved in wound dehiscence?

Back 204

a. Generally occurs when collagen synthesis is at its peak.

b. Approx. half of cases are associated with wound infection, but they also may be the result of sutures breaking because of excess strain.

c. Obesity increases the risk for dehiscence because adipose tissue is difficult to suture.

d. Usually heralded by increased serous drainage from the wound and a feeling that "something gave way."

e. Prompt surgical attention is required.

Front 205

What is a contracture, and how should it be managed?

Back 205

a. A deformity that occurs when wound contraction becomes pathologic due to excessive contraction.
i. Burns are especially susceptible to contracture development.
ii. Internal contraction deformities include duodenal strictures caused by dysfunctional healing of an ulcer and esophageal strictures caused by lye burns.
iii. Contracture may occur in cirrhosis of the liver.
iv. Scar tissue that becomes contracted constricts vascular flow and contributes to the development of portal hypertension and esophageal varices.

b. Proper positioning and range-of-motion exercises and surgery are among the physical means used to overcome myofibroblast pull and prevent contractures.