Hunter-Acute Phase Response & Fever Flashcards by michelle granstrom

The host response to invading microbes begins with what?

microbes begins with recognition of pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) on macrophages and other innate immune cells

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Microbes can cause tissue damage, eliciting what?

DAMPs: damage associated molecular patterns

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What changes do inflammatory mediators, like TNFalpha make to vascular endothelium?

Mediators like TNF-a change the properties of vascular endothelium, prompting an increase in vascular permeability, vasodilation, upregulation of adhesion molecules, and clotting

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When a local inflammatory response becomes systemic..is it helpful or harmful?

can be either.
Helpful: acute phase response & fever
Harmful: sepsis & septic shock

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What is an example of a highly conserved PAMP?

endotoxin on gram negative bacteria

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Give some examples of toll like receptors of various organisms.

f-Met-Leu-Phe receptor (bacteria)
Mannose receptor (bacteria, fungi, viruses)
Scavenger receptors (acetylated lipoproteins on bacteria)
Dectin-1 glucan receptor (fungi)
LPS binding protein and CD14 detected by TLR-4 (bacteria)

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T/F Local coagulation in microvessels is a natural part of inflammation.

True!

This helps keep the microorganisms in a local region.

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What are some of the pro inflammatory cytokines released by macrophages in an inflammatory response?

IL-6
TNFalpha
IL-1beta
CXCL8
IL-12

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IL-6 has what effects?

Systemic:
fever
induces acute phase protein production by hepatocytes

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TNF alpha has what effects?

Local:
activates vascular endothelium & increases vascular permeability
**increased entry of complement & other cells to tissue
**increased fluid drainage to lymph nodes
Systemic:
fever
mobilization of metabolites
shock

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IL-1beta has what effects?

Local:
activates vascular endothelium
activates lymphocytes
local tissue destruction
increases access to effector cells
Systemic:
fever
IL-6 production

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What are the affects of CXCL8?

Local:
chemotactic factor
recruits neutrophils & basophils to site of infection

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IL-12 has what affects?

activates NK cells

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What are the principle cytokines that mediate the systemic effects of inflammation?

IL-1
IL-6
TNFalpha

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What is IL-6 predominantly involved in?

acute phase response in liver

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Which 2 cytokines are involved in the induction of fever?

IL-1

TNF alpha

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What does the liver produce?

acute phase proteins
like C-reactive protein & mannose-binding lectin
**leads to activation of complement opsonization

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A 68-year-old woman presents to the ED with a high fever (38.2° C), malaise, and myalgia of four days duration. You suspect an infectious process and order blood cultures and blood chemistries. She has profoundly elevated C-reactive protein indicating systemic inflammation. Which of the following is the predominant cytokine produced during an inflammatory response that induces the liver to produce acute phase reactants like C-reactive protein?
TNF-a
IL-6
TGF-b
IL-12
IFN-g

IL-6

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A 25-year-old man presents with a three day history of cough and fever. He has chest pain and difficulty breathing. A chest films shows right lower lobe consolidation and a blood culture reveals the presence of Streptococcus pneumoniae. In this bacteremic patient, which of the following is an acute phase protein produced in the liver that functions as an opsonin to promote the phagocytosis and killing of this microorganism?
Ferritin
Plasminogen
C-reactive protein
A-1 anti-trypsin
Transferrin

C-reactive protein

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A team of investigators has designed a new drug that lowers fever by blocking the formation of this key arachidonic acid metabolite responsible for resetting of the hypothalamic set point. 
LTB4
PGE2
Prostacyclin
Thromboxane A2
PGD2
5-HPETE

PGE2

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A 5-year boy with no history of immunization presents with an exanthematous skin rash. You notice the presence of Koplik spots in the buccal mucosa and make the diagnosis of measles. He has a fever of 38.5° C and is very uncomfortable, so you recommend acetaminophen to lower his fever. Which of the following enzymes is inhibited by acetaminophen, aspirin, and other non-steroidal anti-inflammatory drugs?
Lipooxygenase
Nitric oxide synthetase
Lysosomal peroxidase
Cyclooxygenase
Phospholipase A2

Cyclooxygenase

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What is the acute phase response ?

and highly coordinated systemic reaction to disturbances in homeostasis caused by infection, tissue injury, trauma or surgery, neoplastic growth, or immunological disorders
orchestrated by IL-1, IL-6, TNF alpha released by macrophages etc

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What’s the deal with acute phase proteins?

produced by the liver

prompted by IL-6

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What is the function of C-reactive protein?

opsonin on microbes

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What is the function of mannan-binding lectin?

mannan-binding lectin pathway of complement activation

What is the function of fibrinogen, prothrombin, factor 8, vwf?

coagulation factors | trapping invading microbes in blood clots

What is the function of ferritin?

binding iron | inhibiting microbe iron uptake

What is the function of alpha 1 -antitrypsin?

serpin | downregulates inflammation

What are the functions of positive acute phase proteins?

1) opsonization and trapping of microorganisms; 2) activating complement; 3) coagulation and fibrinolysis; 4) scavenging free hemoglobin and iron; and 5) neutralizing enzymes

What's the deal with negative acute phase proteins? What are some examples?

decrease in number during inflammation. | . Examples include albumin, transferrin, transthyretin, retinol-binding protein, antithrombin, transcortin

Which family does CRP belong to? What does it do?

family: pentraxin family binds phosphocholine in cell membrane of pathogens, like gram neg bacteria promotes opsonization by binding C1q-->Classical Pathway of Complement Activation. C3b generated.

What is the measurement of CRP levels used to indicate?

systemic inflammation

When do you see phosphocholine on the surface of a cellular pathogen?

when the cell is damaged, it shows its phosphocholine

How does inflammation-associated coagulation begin?

with cytokines, TLR agonists, and other stimuli that induce tissue factor expression on the surface of monocytes & vascular endothelial cells

WHat happens to PAI-1 during inflammation associated coagulation?

plasminogen activator inhibitor increases in conc'n | this prevents the formation of plasmin--which decreases fibrinolysis

Hepatic synthesis changes during times of inflammation associated coagulation. What happens to it?

synthesis of protein c & antithrombin III decreases

What is the end result of the alterations that are made during times of inflammation associated coagulation?

more thrombin less fibrinolysis more fibrin formation more thrombosis

Local infection causes the release of what?

inflammatory mediators: cytokines, chemokines, kinins, prostaglandins CXCL8: neutrophils recruited from bone marrow IL-6: more acute phase proteins

The circulating cytokines of infection have an affect on brain centers. What effect?

``` thru cerebral endothelium vagal nerve affected local cytokine (TNF alpha) & prostaglandin synthesis is increased sickness behavior (depression) & fever prompted ```

There is a counterattack in the presence of the acute phase response. Some molecules that are anti-inflammatory go a little crazy. Explain this.

IL-1 receptor antagonists soluble TNFalpha receptors neutralize neuroendocrine hormones downregulate immune response protease inhibitors antioxidants (neutralize damage from neutrophil release)

What are some important neuroendocrine hormones that down regulate the immune response?

cortisol ACTH epinephrine alpha-MSH

How does the immune system interact with the nervous system?

via the inflammatory reflex inflammatory mediators activate sensory neurons traveling to brainstem via vagus AP generated from brainstem downward to organs synapses with T lymphocytes T lymphocytes release ACH ACH binds macrophage receptors & tells them to chill out & stop secreting pro inflammatory stuff.

Which structure control body temperature?

hypothalamus

What are the important signals received by the pre optic anterior hypothalamus & posterior hypothalamus?

2 signals: 1. peripheral nerves transmit warm/cold receptors in skin 2. info about the temp of the blood bathing that region

How are these signals integrated?

integrated by the thermoregulatory center of the hypothalamus maintain normal temp--hypothalamic set point

What is the mean oral temp?

36.8 +/- 0.4

What is considered a fever in the morning?

>37.2 (>98.9)

What is considered a fever in the afternoon?

>37.7 (>99.9)

What is a fever?

resetting of the hypothalamic set point to a higher level

What happens once the hypothalamic set point is raised?

neurons in the vasomotor center are activated vasoconstriction! **first in the hands & feet **note there is shivering

Most fevers caused by infection raises the body temp by what?

1-2 dC

What is a pyrogen?

used to describe a substance that causes a fever

What are exogenous pyrogens?

derived from outside the patient usu microbial products, toxins, or whole microorganisms Ex: endotoxin from gram neg. bacteria

What are some enterotoxins that are pyrogenic from gram positive organisms?

from staph aureus group A & B strep toxins **called super antigens

What are endogenous pyrogens?

now called pyrogenic cytokines cytokines that cause fever! Ex: IL-1, IL-6, TNFalpha, interferons

T/F You only see fever with a microbial infection of some kind.

False. Can ask be inflammatory process, trauma, tissue necrosis, antigen-antibody complexes Cerebral hemorrhage.

Pyrogenic cytokines mediate the induction of 2 enzymes in the endothelium of blood vessels in the pre optic hypothalamic area to form PGE2 (arachidonic acid metabolite). Which 2 enzymes?

COX-2 | mPGES-1 (microsomal PGE synthase-1)

What does PGE2 from the brain side of the hypothalamic endothelium trigger?

PGE2 receptor on glial cells (EP-3) | this stimulation releases cAMP

What does cAMP do?

activates neuronal endings from the thermoregulatory center | change the hypothalamic set point

T/F Distinct receptors for PAMPs & DAMPs are located on the hypothalamic endothelium.

True. | When they are bound PGE2 production! Upregulation of hypothalamic set point.

What happens if you reduce the level of PGE2 in the thermoregulatory center?

lower the elevated hypothalamic set point

Which enzyme produces PGE2 & is targeted by antipyretic drugs?

cyclooxygenase

T/F PGE2 plays a role in normal thermoregulation. Thus, taking chronic high dose amounts of NSAIDs will lower normal core body temp.

False. So, PGE2 doesn't play a role in normal thermoregulation.

What's the deal with glucocorticoids?

they are also antipyretics reduce PGE2 synthesis by inhibiting phospholipase A2-->used to release arachidonic acid from the cell membrane also block the transcription of mRNA from pyrogenic cytokines

When can hyperthermia be beneficial?

benefits individuals infected with anthrax, pneumococcal pneumonia, leprosy, and various fungal, rickettsial, and viral diseases neurosyphilis (artificial) **helps because it kills the pathogens & antibody production increases

A rectal temp of >41.5 (>106.7) is called what? When do you see this?

hyperpyrexia seen in severe infections usu seen in CNS hemorrhages

When a person's temp is over 43 dC...what can happen?

heat stroke! | possible death