Chapter 2 - Systemic Inflammatory Response

Question 1

1. What is the systemic inflammatory response syndrome?

Answer 1

• When response to infection and injury results in an incongruous and exaggerated systemic inflammatory reaction

Question 2

2. The activation of ________ is directly responsible for the development of clinical signs and symptoms of SIRS symptoms.

Answer 2

• Phagocytic activation of the monocyte/macrophage cell lineage

Question 2

3. Name 2 things that are most likely to cause a systemic inflammatory response

Answer 2

• Bacteria, their endotoxins, or both

Question 3

4. Name 3 things that can initiate Systemic Inflammatory response syndrome (SIRS) (3+7)

Answer 3

• Infection
• Endotoxemia
• Non-infectious insults
• Severe trauma
• Ischemia
• Immune-mediated disease
• Surgery
• Hypothermia
• Hyperthermia
• Intense hypoxemia (i.e. hemorrhagic shock)

Question 4

5. Name 7 non-infectious triggers of SIRS.

Answer 4

• Severe trauma
• Ischemia
• Immune-mediated disease
• Surgery
• Hypothermia
• Hyperthermia
• Intense hypoxemia (i.e. hemorrhagic shock)

Question 5

6. Name the 5 anti-inflammatory factors that can be secreted by the host to combat SIRS

Answer 5

• Cytokines
• Soluble cytokine receptors
• Receptor antagonists
• Prostaglandin E2
• Corticosteroids

Question 6

7. Define CARS. When does it occur?

Answer 6

• Compensatory Antiinflammatory Response Syndrome
• If there is over-recruitment of the anti-inflammatory processes, resulting in a state of anergy, increased susceptibility to infection, and inability to repair damaged tissues

Question 7

8. Name 3 possible undesirable effects of CARS

Answer 7

• A state of anergy
• Increased susceptibility to infection
• Inability to repair damaged tissues

Question 8

9. What do PAMP and DAMP stand for?

Answer 8

• Pathogen-Assoiciated Molecular Patterns
• Damage-Associated Molecular Patterns

Question 9

10. What is Multiple Organ Dysfunction Syndrome (MODS)?

Answer 9

• Presence of organ dysfunction associated with acute illness in which homeostasis cannot be restored without intervention

Question 10

11. The key event in the initiation and propagation of SIRS is ____

Answer 10

• Release of endogenous molecular substances by the host’s innate immune system

Question 11

12. What are cytokines?

Answer 11

• Protein substances that are the “early responders” to infectious agents or tissue damage

Question 12

13. Give examples of pro-inflammatory cytokines (5)

Answer 12

• Tumor necrosis factor, TNF
• Interleukin-1, IL-1
• Interleukin-6, IL-6
• Interleukin-8, IL-8
• Interferon-γ, IFN-γ

Question 13

14. What are the two universal sources of pro-inflammatory cytokines

Answer 13

• monocytes
• macrophages

Question 14

15. Name 8 cell types that can release proinflammatory cytokines

Answer 14

• Monocytes (universal)
• Macrophages (universal)
• Neutrophils (TNF)
• Endothelial cells (IL-1, IL-8)
• Fibroblasts (IL-1, IL-6)
• Keratinocytes (IL-1, IL-6)
• Lymphocytes (IL-1, IL-6)
• Natural killer cells (TNF, IFN-γ)

Question 15

17. What secretes TNF in SIRS?

Answer 15

• Neutrophils
• Natural Killer Cells

Question 16

16. Neutrophils can secrete what proinflammatory cytokine

Answer 16

• TNF (tumor necrosis factor)

Question 17

18. Endothelial cells secrete what proinflammatory cytokines(2)

Answer 17

• IL-1
• IL-8

Question 18

19. IL-1 and IL-6 are secreted by what 3 other cell types besides monocytes and macrophages

Answer 18

• Fibroblasts
• Keratinocytes
• lymphocytes

Question 19

20. Natural killer cells secrete what cytokine(s)

Answer 19

• TNF
• INF-γ

Question 20

21. Name main functions that TNF, IL-1, and IL-6 initiate (5)

Answer 20

• coagulation
• fibrinolysis
• complement activation
• the acute phase response
• neutrophil chemotaxis

Question 21

22. TNF and IL-1 induce ____ and ___

Answer 21

• Pyrogenic activities
• Augment further cytokine production

Question 22

23. What are the anti-inflammatory cytokines? (5)

Answer 22

• IL-4
• IL-10
• IL-11
• IL-13
• Transforming growth factor-β (TGF-β)

Question 23

24. What cells release anti-inflammatory cytokines?

Answer 23

• Monocytes
• Macrophages
• T-helper cells

Question 24

25. What do the anti-inflammatory cytokines inhibit? (5)

Answer 24

- Macrophage activation - Pro-inflammatory cytokine release - Antigen-presenting cells - chemotaxis

Question 25

26. Arachidonic acid is the parent molecule for ________ synthesis

Answer 25

- Eicosanoid synthesis

Question 26

27. ____ is the enzyme responsible for cleaving arachidonic acid from the cell membrane

Answer 26

- Phospholipase A2

Question 27

28. name 3 substances that stimulate the activity of phospholipase A2

Answer 27

- endotoxin - TNF - IL-1

Question 28

30. What are the 2 main prostanoids produced by the arachidonic acid cascade?

Answer 28

- Thromboxane A2 (TxA2) - Prostaglandins (PGs)

Question 28

29. Once released, arachidonic acid is either metabolized by _____ to form ____ or _____ to form ____

Answer 28

- Lipoxygenase * Family of leukotrienes - Cyclooxygenase * The prostanoids

Question 29

31. True/False: Thromboxane A2 and PGE 2 cause vasoconstriction

Answer 29

- False, PGF-2α causes vasoconstriction, PGE2 is a vasodilator

Question 30

32. Which 2 prostanoids cause vasoconstriction?

Answer 30

- Thromboxane A2 - PGF2α

Question 31

33. Which 2 prostanoids are vasodilators?

Answer 31

- PGI2 - PGE2

Question 32

34. True/False: PGE 2 and PGI 2 cause vasodilation

Answer 32

- True

Question 33

35. True/False: TxA2 inhibits platelet aggregation, PGI2 promotes platelet aggregation, and PGE2 is a pyrogen

Answer 33

- False, TxA2 promotes platelet aggregation and PGI2 inhibits platelet aggregation

Question 34

36. Which prostanoids is a pyrogen?

Answer 34

- PGE2

Question 35

37. What are the functions of leukotrienes (2)

Answer 35

- Chemoattractant - Increase vascular permeability

Question 36

38. Platelet activating factor is released from _____ by _____

Answer 36

- Cell membrane phospholipids - Phospholipase A2

Question 37

39. What are the biological effects of Platelet activating factor(PAF) (4)

Answer 37

- Vasodilation - Increased vascular permeability - Platelet aggregation - Recruitment and activation of phagocytes

Question 38

40. Define acute phase protein

Answer 38

- Any protein whose blood concentration significantly increases (or decreases) during an inflammatory response

Question 39

41. Where is the key site of production of acute phase protein?

Answer 39

- The liver

Question 40

42. What substances stimulate the production of and modulate the gene expression and transcription of acute phase proteins. (5)

Answer 40

- TNF - IL-1 - IL-6 - Glucocorticoids - Growth factors

Question 41

46. SAA values greater than _____ are suggestive of infective process in foals

Answer 41

- >100mg/L

Question 41

43. What are the major acute phase proteins?

Answer 41

- Serum amyloid A - C-reactive protein

Question 42

44. Name the 4 actions of C reactive protein

Answer 42

- Activate complement - Induce phagocytosis - Stimulate cytokine expression - Stimulate tissue factor expression

Question 43

45. What is the expected SAA concentration in a healthy adult horse and neonatal foals? - <27mg/L

Question 44

47. SAA nonspecifically increases due to _____ and ______ conditions

Answer 44

- Infectious - Non-infectious (but inflammatory)

Question 45

48. Name 4 effects of complement acute phase proteins

Answer 45

- Bacteriolysis - Increase vascular permeability - Chemotactic for neutrophils - Enhance opsonization of both microbes and damaged host cells

Question 46

49. What bacterial nutrient components can be bound by acute phase transport and scavenger proteins

Answer 46

- Copper - Iron

Question 47

57. What are the diagnostic criteria for SIRS in Adult horses?

Answer 47

- Rectal temperature <98.6°F or >101.3°F - Heart rate >52bpm - Respiratory rate >20bpm or PaCO2 <32mmHg - WBC count >12,500 cells/µL, <5,000 cells/µL, or >10% bands

Question 47

50. Oxygen derived toxic mediators commonly originate from ____ and _____ (think cells)

Answer 47

- Mononuclear phagocytes - Neutrophils

Question 48

51. Name 5 molecular consequences that can occur when ROS react with other molecules

Answer 48

- Loss of protein function - Cross-linking of DNA - Lipid peroxidation - Vasoconstriction - Pain

Question 49

52. Whatare the 3 main reactive oxygen species?

Answer 49

- Oxygen free radicals - Hydrogen peroxide (H2O2) - Nitric oxide (NO)

Question 50

53. Which reactive oxygen species do not contain unpaired electrons? (2)

Answer 50

- Hydrogen peroxide - Nitric oxide

Question 51

54. What effect do bradykinin and histamine have on the vasculature? - Vasodilators

Question 52

55. Name 4 substances involved in the inflammatory response that have vasoconstrictive effects

Answer 52

- Angiotensin - Endothelin - Thromboxane A2 - Leukotrienes

Question 53

56. Name 5 substances that promote vascular leakage

Answer 53

- Platelet Activating Factor - Leukotrienes - Complement components - NO - Bradykinin

Question 54

58. Define primary MODS

Answer 54

- Any disease process inducing a well-defined injury that affects the function of organs at the initial site of insult, not as a direct response to the insult, but as a consequence of the host’s response to that injury.

Question 55

59. Define secondary MODS

Answer 55

- Any disease process inducing a well-defined injury that affects the function of organs remotely positioned from the primary injury, not as a direct response to the insult, but as a consequence of the host’s response to the injury.

Question 56

60. What are the physiologic events that drive MODS (4)

Answer 56

- Immune-mediated inflammatory injury - Altered hemodynamics - Dysfunction of the autonomic nervous system - Reduced tissue perfusion

Question 57

61. name the 3 major elements that define dysfunction of the coagulation system associated with the development of MODS

Answer 57

- excessive procoagulation - loss of controlled fibrinolysis - loss of natural anticoagulant activities

Question 58

62. True/False: with prolonged or excessive thrombi formation, platelets, coagulation, anticoagulation, and fibrinolytic factors are consumed. Balance is lost and hemorrhage may occur. this is referred to as DIC

Answer 58

- True

Question 59

63. What products/items are consumed in the course of DIC? (4)

Answer 59

- Platelets - Coagulation factors - Anticoagulation factors - Fibrinolytic factors

Question 60

64. Name 2 primary ailments that can initiate DIC

Answer 60

- Endotoxemia - Sepsis

Question 61

65. True/False: the primary mechanism to initiate the hypercoagulable state of DIC is activated by the extrinsic coagulation cascade

Answer 61

- True

Question 62

66. True/False: in DIC, the extrinsic coagulation cascade is activated by decreased expression of membrane tissue factors

Answer 62

- False, via enhanced expression of membrane tissue factors

Question 63

69. Name 2 natural anticoagulants

Answer 63

- Antithrombin - Protein C

Question 63

67. T/F: membrane tissue factor is upregulated directly by cytokines or indirectly by the pathogen such as lipopolysaccharides

Answer 63

- False, indirectly by cytokines or directly by pathogens

Question 64

68. T/F: endotoxin appears to favor activation of plasminogen activator inhibitor over tissue plasminogen activator

Answer 64

- True

Question 65

70. Name 2 consequences of insufficient anti-thrombin and protein C

Answer 65

- Increased clot formation - Heightened inflammatory response

Question 66

71. Name 3 effects endotoxin can exert on the heart during cardiac dysfunction

Answer 66

- Reduced myocardial contractility - Increased heart rate - Reduced heart rate variability

Question 67

72. What is a unique manifestation of MODs in the horse?

Answer 67

- Laminitis

Question 68

73. In renal tubular necrosis, _______ leads to ______ which leads to cell death

Answer 68

- Systemic or local reduction in blood flow - Cellular hypoxia

Question 69

74. What are 5 combined effects of renal tubular necrosis and tubular obstruction on renal function?

Answer 69

- Loss of autoregulation of renal blood flow - Vasoconstriction - Fluid retention - Protein-losing nephropathy - Electrolyte derangement

Question 70

75. What two materials are recruited to replace damaged areas in the alveoli in ALI and ARDS

Answer 70

- type II pneumocytes - fibroblasts

Question 71

76. What are 5 likely triggers for the development of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS)?

Answer 71

- Sepsis - Aspiration of gastric contents - Smoke inhalation - Severe trauma - Transfusion reaction

Question 72

77. Name the 7 conditions that may indicate active DIC. An animal may be suspected of being in DIC if at least ____ of the criteria are met.

Answer 72

- Thrombocytopenia - Prolonged prothrombin - Activated partial thromboplastin time - Decreased fibrinogen concentration - Prolonged thrombin time - Increased fibrin degradation products or D-dimer concentrations - Decreased antithrombin activity - If 3 or more criteria are met

Question 73

78. Define sepsis

Answer 73

- A systemic inflammatory response to infection

Question 74

79. T/F: Septicemia is one of the most common causes of illness and death in neonatal foals and primarily involves gram-positive bacterial invasion

Answer 74

- False, gram-negative bacteria

Question 75

80. T/F: Infection is initially prevented by the innate immune system by pathogen associated molecular patterns (PAMPs) that are capable of interacting with microbial ligands on pattern recognition receptors (PRRs)

Answer 75

- True

Question 76

81. Give 4examples of PAMPs

Answer 76

- Endotoxin - Peptidoglycan - Lipoteichoic acid - Prokaryotic DNA

Question 77

82. T/F: The interaction of PRR with its PAMP can directly neutralize the PAMP or may activate other components of the host immune system

Answer 77

- True

Question 78

84. T/F: secreted PRRs are involved with phagocytosis and cell membrane PRRS involved in signal transduction are called defensins

Answer 78

- False, secreted PRRs are defensins. Cell membrane PRRs are involved in phagocytosis and signal transduction

Question 79

83. What are the 3 main types of PRRs

Answer 79

- Secreted PRRs (such as defensins) - Cell membrane PRRs, involved in phagocytosis - Cell membrane PRRs involved in signal transduction

Question 80

85. what is the main PRR that interacts with the PAMP endotoxin

Answer 80

- CD14-Toll like receptor

Question 81

86. T/F: endotoxin is a heat stable toxin consisting of lipopolysaccharide comprising approximately 75% of the outer membrane of gram positive bacteria

Answer 81

- False, gram-negative bacteria

Question 82

87. What are 4 common primary diseases that are associated with endotoxemia in mature horses?

Answer 82

- Colic - Septic metritis - Pleuropneumonia - Septic peritonitis

Question 83

88. Endotoxin has what 3 structural domains

Answer 83

- A highly variable ouer polysaccharide “O-antigenic” region - A core region consisting mostly of monosaccharides - Highly conserved toxic moiety, Lipid A

Question 84

89. T/F: Lipid A must enter circulation to fully manifest its pathological effects

Answer 84

- True

Question 85

90. T/F: lipopolysaccharide binding protein is an acute phase protein

Answer 85

- true

Question 86

91. T/F: CD-14 can both enhance and neutralize LPS (lipopolysaccharide)

Answer 86

- True

Question 87

92. T/F: CD14 can bind LPS and cross the cell membrane to deliver endotoxin to lysosomes that then degrade the endotoxin

Answer 87

- False. CD14 cannot cross the cell membrane and thus it must bind with a secondary protein, TLR, that contains a transmembrane portion

Question 88

93. ___ is the most important TLR isotype that recognizes endotoxin

Answer 88

- TLR-4

Question 89

94. ____ is the most important TLR isotype that recognizes gram positive bacteria

Answer 89

- TLR 2

Question 90

95. T/F: TRL 4 primarily recognized gram positive bacteria and TRL 2 recognizes endotoxin

Answer 90

- False, TLR-4 recognizes endotoxin and TLR-2 recognizes gram positive bacteria

Question 91

96. Translocation of ____ is a well characterized method of endotoxin induced cell signaling

Answer 91

- Nuclear factor KB (NFKB)

Question 92

97. T/F: most of deleterious effects of endotoxin are the result of overzealous endogenous synthesis of proinflammatory mediators and initiation of SIRS

Answer 92

True

Question 93

98. Name 3 things that are the culmination of events of endotoxemia

Answer 93

- Uncontrolled inflammation - Immunosuppression - Hemodynamic changes - Coagulopathy

Question 94

99. What is the gold standard for measurement of endotoxin?

Answer 94

- The limulus amebocyte lysate (LAL) assay

Question 95

100. Ileus noted in hyperdynamic phase of endotoxemia is most likely attributed to what molecule

Answer 95

- thromboxane A2

Question 96

1. What is one cardinal clinical pathology marker of endotoxemia?

Answer 96

- Profound neutropenia with toxic neutrophil morphology (basophilic cytoplasm, vacuolization, Dohle bodies)

Question 97

2. What items may be used in the treatment of endotoxemia? (4-6)

Answer 97

- Oral smectite (BioSponge) - Polymyxin B - Antiendotoxin antibodies - NSAIDs (flunixin meglumine) - Pentoxifylline - Lidocaine

Question 98

3. Name two commercially available products that directly bind endotoxin

Answer 98

- antiendotoxin antibodies polymyxin B