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Block 7 week 4 > Acute Phase Response and Fever - Hunter > Flashcards

Acute Phase Response and Fever - Hunter Flashcards

1
Q

How does the host response to microbes begin?

A

By recognition of pathogen associated molecular patterns -PAMPS - by pattern recognition receptors - PRR’s on macrophages and other innate immune cells.

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2
Q

What is elicited by microbes?

A

Damage associated molecular patterns - DAMPS. These are elicited by tissue damage caused by microbes.

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3
Q

What is the result of PRR’s binding to PAMPS?

A

A variety of inflammatory mediators (like TNF-a) are produced that orchestrate the initial response to infection or tissue damage.

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4
Q

What sort of effects do inflammatory mediators have?

A
  1. increase in vascular permeability
  2. vasodilation
  3. up regulation of adhesion molecules and clotting
    The main ‘job’ is to keep the pathogen localized and to recruit cells like macrophages and neutrophils to the site.
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5
Q

Are most responses to pathogens localized?

A

Yes, however they can be systemic too.

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6
Q

Are systemic responses to pathogens always negative?

A

No. Systemic responses such as sepsis and septic shock are negative towards the host but some such as the acute phase response and fever are positive.

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7
Q

Name some PRR’s and the microbes that have antigens they recognize.

A
  1. f-Met-Leu-Phe receptor on neutrophils recognizes f-Met-Leu-Phe antigen on bacteria
  2. mannose receptor on macrophages and dendritic cells recognizes mannose on bacteria, fungi and viruses
  3. scavenger receptors on macrophages recognize acetylated lipoproteins on bacteria
  4. Dectin-1-glucan receptor on macrophages recognizes beta-glucans on fungi
  5. LPS binding protein binds to LPS on the surface of gram-neg bacteria and binds to CD14 and TLR-4 on macrophages.
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8
Q

Describe a typical local response to microbes (inflammation).

A
  1. microbe invades and is detected by macrophage
  2. macrophage produces and releases cytokines
  3. cytokines cause local blood vessel dilation
  4. leukocytes move to periphery of blood vessel as a result of increased expression of adhesion molecules (caused by cytokines)
  5. leukocyte extravasates at site of local infection due to increased vascular permeability caused by cytokines
  6. blood clotting occurs in the micro vessels due to macrophage activation of tissue factor
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9
Q

Do proinflammatory cytokines released by macrophages in response to microbial products have both local and systemic effects?

A

Yes.

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10
Q

Name some cytokines released in inflammation.

A
  1. IL-6
  2. IL-1B
  3. TNF-a
  4. IL-12
  5. CXCL8
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11
Q

Which cytokines are primarily involved in systemic effects?

A
  1. IL-6 - the primary one
  2. TNF-a
  3. IL-1B
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12
Q

Which cytokines have local effects?

A
  1. TNF-a
  2. IL-1B
  3. IL-12
  4. CXCL8
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13
Q

What does TNF-a do?

A
  1. locally it activates vascular endothelium and increases vascular permeability, which leads to increased entry of complement and cells to tissues and increased fluid drainage to lymph nodes
  2. systemically - causes fever and mobilization of metabolites and can cause shock
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14
Q

What does IL-1B do?

A
  1. locally is activates the vascular endothelium, activates lymphocytes, increases access of effector cells and causes local tissue destruction
  2. systemically - causes fever and production of IL-6
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15
Q

What does IL-6 do?

A

IL-6 is the primary cytokine for systemic effects. It causes fever and induces acute-phase protein production by hepatocytes.

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16
Q

What does IL-12 do?

A

This cytokine acts locally to activate NK cells.

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17
Q

What does CXCL8 do?

A

It acts locally as a chemotactic factor that recruits neutrophils and basophils to the site of infection.

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18
Q

Which three cytokines are the principle cytokines that mediate the systemic effects of inflammation?

A
  1. IL-1 - involved in the induction of fever
  2. IL-6 - involved in the acute phase response in the liver
  3. TNF-a - involved in the induction of fever
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19
Q

What are the effects of IL-1/IL-6/TNF-a in the liver?

A
  1. production of acute phase proteins such as C-reactive protein and mannose-binding lectin
  2. activation of complement opsonization
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20
Q

What are the effects of IL-1/IL-6/TNF-a in the bone marrow endothelium?

A
  1. neutrophil mobilization for neutrophil phagocytosis
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21
Q

What is the effect of IL-1/IL-6/TNF-a on the hypothalamus?

A

Increased body temperature leading to decreased viral and bacterial replication

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22
Q

What is the effect of IL-1/IL-6/TNF-a in fat and muscle?

A
  1. protein and energy mobilization to generate increased body temperature. Increased body temperature leads to decreased viral and bacterial replication
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23
Q

What is the acute phase response?

A

An evolutionarily conserved and highly coordinated systemic reaction to disturbances in homeostasis caused by infection, tissue injury, trauma or surged, neoplastic growth, or immunological disorders.

24
Q

Describe some characteristics of the acute phase response.

A
  1. orchestrated by pro-inflammatory cytokines - IL-1,IL-6,TNF-a and other mediators produces by macrophages and other cells
  2. involves changes in plasma levels of acute phase protein - many of which are produced in the liver in response to IL-6
  3. positive acute phase proteins are increased and negative acute phase proteins are decreased in amounts
  4. proinflammatory mediators also induce metabolic, physiologic and behavioral changes
25
Q

Name some positive acute phase proteins and their functions.

A
  1. C-reactive protein - acts as an opsonin on microbes
  2. Mannan-binding lectin - associated with manna-binding pathway of complement activation
  3. fibrinogen, prothrombin, factor VIII,vWF - coagulation factors, trapping invading microbes in blood clots
  4. Ferritin - binding iron, inhibiting microbe iron uptake
  5. Hepcidin - prevents release of iron bound by ferritin, oxidizes iron, inhibiting microbial iron uptake
  6. Haptoglobin - binds hemoglobin, inhibiting microbe iron uptake
  7. plasminogen - degradation of blood clots
26
Q

What are the general function of positive acute phase proteins?

A
  1. opsonization and trapping of microbe
  2. activates complement
  3. coagulation and fibrinolysis
  4. scavenging free Hb and iron
  5. neutralizing enzymes
27
Q

What are some negative acute phase proteins and do they increase or decrease?

A

The neg. APP’s decrease in inflammation.

  1. albumin
  2. transferrin
  3. retinol-binding protein
  4. antithrombin
  5. transcortin
  6. transthyretin
28
Q

What are some characteristics of C-reactive protein?

A
  1. has 5 identical subunits - part of the pentraxin family
  2. binds phosphocholine molecules in the cell membranes of microbes, including LPS of gram-neg bacteria
  3. promotes opsonizaiton by binding C1q and triggering the classical pathway of complement activation, generating C3b
  4. present at low levels in plasma, CRP concentration can increase 50,000 fold during inflammation induces acute phase response
  5. measurement of CRP is used clinically as a good diagnostic marker of systemic inflammation
29
Q

Where is phosphocholine expressed?

A

On the outside of damaged cells.

30
Q

Describe the procoagulant effects of the acute phase response.

A
  1. coagulation begins when cytokines, TLR agonists or other stimuli induce tissue factor expression on the surfaces of monocytes and vascular endothelial cells, leads to an increase in thrombin (coagulation)
  2. increased concentrations of plasminogen activator inhibitor or PAI-1 prevent the formation of plasmin, decreasing fibrinolysis
  3. hepatic synthesis of protein C and antithrombin III decreases during acute phase response
  4. the end result is increased thrombin activity and decreased fibrinolysis, which promotes fibrin formation and thrombosis
31
Q

What are the systemic effects of the acute phase response?

A
  1. local infection causes secretion of inflammatory mediators such as cytokines, chemokines, kinins and prostaglandins
  2. the chemokine CXCL8 causes the production and recruitment of neutrophils from bone marrow to site of infection
  3. IL-6 causes hepatocytes to produce a variety of acute phase proteins that have strong antimicrobial effects
  4. circulating cytokines also communicate with brain centers through the cerebral endothelium, the vagal nerve and the circumventricular organs to affect local cytokine (TNF-a) and prostaglandin synthesis and produce sickness behavior and fever respectively
32
Q

What are an important set of molecules that are produced in the acute phase response?

A

Too much inflammation is harmful so the body also produces anti-inflammatory molecules in the acute phase response to ensure that the process won’t get out of hand.

33
Q

What are the anti-inflammatory mediators that are produced to keep the acute phase response in check?

A
  1. IL-1 receptor antagonists - inhibit binding of IL-1 to its receptors
  2. soluble TNF-a receptors - neutralize TNF-a that enters circulation
  3. neuroendocrine hormones such as cortisol, ACTH, epinephrine, a-MSH - down regulate immune responses
  4. protease inhibitors or antioxidants - neutralize potentially harmful molecules released from neutrophils and other inflammatory cells
34
Q

What is the inflammatory reflex?

A

It is how the nervous system interacts with the immune system in the acute phase response.

35
Q

Describe the inflammatory reflex.

A
  1. inflammatory mediators produced by infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve
  2. action potentials are generated that travel from the brainstem to the spleen and other organs
  3. synapses with T lymphocytes activate these cells to release the neurotransmitter acetylcholine
  4. acetylcholine binds to receptors on macrophages and stimulates an intracellular signaling pathway that blocks secretion of inflammatory mediators like TNF-a
36
Q

What part of the body controls body temperature?

A

The hypothalamus - specifically the pre optic anterior region and the posterior region.

37
Q

What types of signals does the hypothalamus receive in regards to body temperature?

A
  1. signal from peripheral nerves that transmits information from warmth/cold receptors in the skin
  2. signal from the area surrounding the temp control regions of the hypothalamus regarding temperature of the blood
  3. these signals are integrated by the thermoregulatory center of the hypothalamus to maintain the normal temp or hypothalamic set point
  4. the mean temp of adults 18-40 is about 98.2 plus or minus 0.7 degrees F - low temps occur at 6am and higher temps around 4-6 pm
38
Q

What is fever?

A

Defined as the temperature in the morning of greater than 98.9 or a temp greater than 99.9 degrees F in the afternoon. Fever is an elevation of normal body temperature caused by resetting of the hypothalamic set point.

39
Q

What happens once the hypothalamic set point is raised?

A

The neurons in the vasomotor center are activated and vasoconstriction commences.

40
Q

Where is the vasoconstriction notices first?

A

In the hands and feet - due to the shunting of blood away from the periphery to the internal organs - this decreases heat loss from the skin and the person feels cold.

41
Q

Why does shivering or chills occur with fever?

A

Shivering increases heat production form the muscles - this happens because blood is shunted away from the periphery and the person feels cold.

42
Q

How much does body temperature increase for most fevers caused by infections?

A

1-2 degrees C

43
Q

What is a pyrogen?

A

Term used to describe any substance that causes fever.

44
Q

What are exogenous pyrogens?

A

Pyrogens that are derived from outside the patient such as microbial products, microbial toxins or whole microorganisms.

45
Q

What is the exogenous pyrogen of gram negative bacteria?

A

LPS or lipopolysaccharide, also called endotoxin. This is produced by all gram-neg bacteria.

46
Q

What are the pyrogenic compound of gram pos bacteria?

A
  1. enterotoxin of Staph aureus

2. enterotoxin of group A and B streps - also called superantigens

47
Q

Name some pyrogenic cytokines.

A
  1. IL-1
  2. IL-6
  3. TNF-A
  4. ciliary neurotropic factor
  5. interferon alpha and beta
48
Q

Bacteria induce pyrogens. Do fungi, viruses and parasites also induce pyrogenic cytokines?

A

Yes.

49
Q

What are some other causes of fever besides microbial infection?

A
  1. inflammatory processes
  2. trauma
  3. tissue necrosis
  4. antigen-antibody complexes
  5. fever of unknown origin
  6. these processes also trigger the hypothalamus to raise the set point to febrile levels
50
Q

How do pyrogenic cytokines and microbial products reset the hypothalamic thermal set point?

A
  1. pyrogenic cytokines mediate the coordinate induction of COX-2 and microsomal PGE synthase-1 (mPGES-1) in the endothelium of blood vessels in the pre optic hypothalamic area to form acrachidonic acid metabolite or PGE2
  2. PGE2 from the brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells (EP-3 receptors) and this stimulation results in the rapid release of cyclic AMP
  3. cAMP activates neuronal endings from the thermoregulatory center that extend into the area and mediates changes in the hypothalamic set point
  4. binding of these PAMPs and DAMPs also results in PGE2 production and up regulation of the set point
51
Q

How do antipyretic agents work?

A

Antipyretic drugs inhibit brain cyclooxygenase which is normally constitutively expressed and results in synthesis of PGE2.Reducing the level of PGE2 in the thermoregulatory center lowers the elevated hypothalamic set point.

52
Q

Name some antipyretics.

A
  1. aspirin
  2. other NSAIDS
  3. acetaminophen
  4. ibuprofen
  5. COX-2 inhibitors
  6. glucocorticoids - reduce PGE2 synthesis by inhibiting activity of phospholipase A2 which is needed to release arachadonic acid from the cell membrane. Also they block transcription of the mRNA for pyrogenic cytokines
53
Q

Can antipyretics effect normal body temperature?

A

No, they do not reduce normal core body temp. This means that PGE2 plays no role in regular thermogregulation.

54
Q

What are the benefits of fever to the body?

A
  1. a rise in temperature inhibits the growth of microorganisms
  2. antibody production increases when body temp is elevated
55
Q

What is hyperpyrexia?

A

This refers to extremely high temps - a rectal temp greater than 106.7 degrees F. This can develop in patients with severe infections but most commonly occurs in patients with CNS hemorrhages.

56
Q

At what temp does heat stroke develop?

A

When the temp is above 43 degrees F heat stroke develops and death is common.

Block 7 week 4 (6 decks)

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