Acute Phase response and fever-Hunter Flashcards
The host response to invading microbes begins with recognition of (Blank) by (blank) on macrophages and other innate immune cells.
PAMPs (pathogen associated molecular patterns)
PRRs (pattern recogntion receptors)
Microbes also cause tissue damage which elicits (blank) patterns
damage-associated molecular patterns
Once you have PAMPs and DAMPs what happens next?
a variety of secreted inflammatory mediators are produced that orchestrate the initial response to infection or tissue damage.
Mediators like (blank) change the properties of vascular endothelium, prompting an increase in vascular permeability, vasodilation, upregulation of adhesion molecules and clotting.
TNF-alpha
Most responses to pathogens remain (blank)
local
some responses are systemic
Some systemic inflammatory responses to pathogens can be positive and protective such as (blank). Other systemic responses can be negative and harmful such as (blank)
acute phase response and fever
sepsis and septic shock
Where do you find this PAMP:
f-met-leu-phe receptor
Bacteria
Where do you find this PAMP:
mannose receptor
bacteria, fungi, viruses
Where do you find this PAMP
scavenger receptors
acetylated lipoproteins on bacteria
Where do you find this PAMP
dectin-1 glucan receptor
fungi
Where do you find this PAMP
LPS binding protein and CD14
bacteria
Pathogens cause (blank) to release various mediators of inflammation.
macrophages
Activation of the kinin system produces (blank)
bradykinin (pain)
Cytokines produced by macrophages cause (blank) of local small blood vessels
dilation
Leukocytes move to periphery of blood vessel as a result of increased expression of (blank)
adhesion molecules
Once leukocytes move to periphery of blood vessel and adhere what do they do next?
leukocytes extravasate at site of infection and blood clotting occurs in the microvessels
Summarize what happens if you get trauma resulting in a bleed
blood vessel dilation and increased vascular permeability
- upregulation and expression of adhesion molecules
- local coagulation in microvessels
(blank) cytokines released by macrophages in response to microbial produts have both local and systemic effects
Proinflammatory
On sensing microbial products, macrophages secrete a variety of pro-inflammatory cytokines. What are they?
IL-6 TNF alpha IL-1B CXCL8 IL-12
What does TNF alpha do locally?
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
What does IL-Ib do locally?
- activates vascular endothelium
- activates lymphocytes
- local tissue destruction
- increases access of effector cells
What does CXCL8 do locally?
chemotactic factor that recruits neutrophils and basophils to site of infection
What does IL-12 do locally?
activates NK cells
What are the systemic effects of IL-6?
fever
induces acute-phase protein production by hepatocytes
What are the systemic effects of TNF-alpha?
fever, mobilization of metaboites, shock
What are the systemic effects of IL-1b?
fever, production of IL-6
What mediates the acute phase response and fever?
cytokines! (IL-6, TNF-alpha, IL1b)
(blank) (blank) and (blank) are the principle cytokines that mediate the systemic effects of inflammation
IL-1, IL-6, TNF-alpha
(blank) is predominantly involved in the acute phase response in the liver
IL-6
(blank) and (blank) are involved in the induction of fever
IL-1, TNF-alpha
What does IL-1, IL-6, and TNF-alpha do to the liver?
acute phase proteins (c-reactive protein, mannose-binding lectin)
-> activation of complement opsonization
What does IL1, IL6, TNF alpha do to the bone marrow and endothelium?
neutrophil mobilization-> phagocytosis
What does IL1, IL6 and TNF alpha do to the hypothalamus?
increases body temp and results in decreased viral and bacterial replication
What does IL1, IL6 and TNF alpha do to the fat, muscle?
protein and energy mobilization to generate increased body temp-> resulting in decreased viral and bacterial replication
(blank) is predominantly involved in the acute phase response in the liver
IL-6
(blank) and (blank) are involved in the induction of fever
IL-1, TNF alpha
What is the acute phase response?
a systemic reaction to disturbances in homeostasis caused by infection, tissue injury, trauma or surgery, neoplastic growth, or immunological disorders
The APR (acute phase response) is orchestrate by the proinflammatory cytoknes (blank, blank, blank) and other mediators produced by macrophages and other cells
IL-1, IL-6, TNF alpha
APR involves changes in plasma levles of acute phase proteins, many produces in the (blank) in response to IL-6
liver
In the acute phase response, what proteins are increased?
Which are decreased?
Positive acute phase proteins -> increased
negative acute phase proteins-> decreased
The “positive” APP are regarded as have general functions in….?
- opsonization and trapping of microorganisms
- activating complement
- coagulation and fibrinolysis
- scavenging free hemoglobin and iron
- neutralizing enzymes
Negative APP decrease in (blank)
inflammation
What are some negative APPs?
albumin, transferrin, transthyretin, retinol-binding protein, antithrombin, transcortin
What does C-reactive protein do?
opsonin on microbes
What does mannan-binding lectin do?
mannan-binding lectin pathway of complement activation
What does fibrinogen, prothrombin, factor 8, von willebrand factor do?
coagulation factors, trapping invading microbes in blood clots
What does ferritin do?
binding iron, inhibiting microbe iron uptake
What does alpha-1-antitrypsin do?
serpin, downregulates inflammation
What family does C-reactive protein (CRP) belong to?
pentraxin family
What does CRP bind to in the cell membranes of microorganisms (including lipopolysacchardies of gram-neg bacteria)
phosphocholine
How does CRP promote opsonization?
by binding C1q, triggering the classical pathway of complement activation and generating C3b
CRP is normal present at (blank) levels in the plasma but can (blank) 50,000 fold during the inflammation-induced acute phase response
low
increase
Measurement of CRP is used clinically as a good diagnostic marker of (blank)
systemic inflammation
Inflammation associated coagulation begins when cytokines, TLR agonists or other stimuli induce (Blank) expression on the surfaces of monocytes and vascular endothelial cells
Tissue factor
How do you get the procoagulant effects of the acute phase response?
- increased plasminogen activator inhibitor (PAI-1)
- hepatic synthe of protein C and AT-III decreases
What does plasinogen activator inhibitor do?
inhibits plasmin formation thus inhibits fibrinolysis :)
What is the end result of the procoagulant effects of the acute phase?
increased thrombin activity and decreased fibrinolysis, which promotes fibrin formation and thrombosis
In the acute phase response, (blank) molecules are also produced
anti-inflammatory
The acute phase response increases the blood concentrations of numerous molecules that have (blnk) actions
anti-inflammatory actions
Blood levels of (blank) can inhibit the binding of IL-1 to its receptors
IL-1 receptor antagonist
High levels of soluble (blank) neutralize TNF-alpha that enters the circulation
TNF-alpha receptors
(blank) hormones downregulate the immune response
Neuroendocrine hormones (cortisol, ACTH, epi, alpha MSH)
What are protease inhibitors or antioxidants?
acute phase proteins that neutralize potentially harmful molecules released from neutrophils and other inflammatory cells
What are the ways that the acute phase respone can cause anti-inflammatory effects?
- IL-1 antagonists
- high levels of soluble TNF alpha receptors
- neuroendocrine hormones
- protease inhibitors or antioxidants
The acute phase response engages the (Blank) reflex
inflammatory
The nervous system interacts with the immune system through the (blank)
inflammatory reflex
Inflammatory mediators produced by infection or injury activate sensory neurons traveling to the brainstem in the (Blank)
vagus nerve
When you get an injury and sensory neurons of the vagus send a signal the brain about this, what happens?
action potentials are generated from brainstem to the spleen and other organs
The action potentials produced by the brainstem will synapse with (blank) to activate these cells to release the neurotransmitter (blank)
T lymphocytes
acetylocholine
(blank) binds to receptors on macrophages and stimulates an intracellular signaling pathway that blocks secretion of (blank)
Acetycholine
inflammatory mediators like TNF-alpha
Body temp is a vital sign that is controlled by the (blank)
hypothalamus
Neurons in both the preoptic anterior hypothalamus and posterior hypothalamus received 2 kinds of signals, what are they?
- one from peripheral nerves that transmit info from warm/cold receptors in the skin
- one from the temp of blood bathing the region
The 2 signals sent to the hypothalamus are integrated by the (blank) of the hypothalamus to maintain normal temp (hypothalamic set point)
thermoregulatory center
What is the mean oral temp and when do you have the lowest temp? highest?
36.8 C (98.2 F)
6 AM
4-6 PM
Fever is defined as a temp in the morning greater than (Blank) or a temp in the afternoon greater than (blank)
- 2 (98,9)
37. 7 (99.9)
Fever is an elevation of normal body temp caused by resetting of the (blank)
hypothalamic set point
Once the hypothalamic set point is raised neurons in the (blank) are activated and (blank) commences
vasomotor center
vasoconstriction
A febrile individual first notices vasoconstriction in the (blank) and (Blank).
hands and feet
Why do you feel cold when you have a fever? When do you get shivering
you get vasoconstriction in hands and feet and blood is shunted from periphery to internal organs.
At this time
For most fevers caused by infections, body temp only increases (blank) degrees celcius.
1-2
The term (blank) is used to describe any substance that causes fever
pyrogen
(blank) are derived from outside the patient; most are microbial products, microbial toxins, or whole microorganisms
Exogenous pyrogens
The classic example of an exogenous pyrogen is the (blank) produced by all gram-negative bacteria.
LPS (endotoxin)
Pyrogenic products of gram- positive organisms include the enterotoxin of (Blank) and the group A and B streptococcal toxin also called (blank)
Staph aureus
superantigens
Some cytokines also cause fever; formerly referred to as endogenous pyrogens, they are now called (blank)
pyrogenic cytokines
What are the pyrogenic cytokines?
IL1, IL6, TNF apha, ciliary neutropic factor (CNTF), nd interferons-a/b
A wide spectrum of bacterial, fungal, viral and parasitic products induce the synthesis and release of (blank)
pyrogenic cytokines
(blank) can be a manifestation of disease in the absence of microbial infection (e.g inflammatory processes, trauma, tissue necrosis, and antigen-antibody complexes); these processes also trigger the hypothalamus to raise the set point to febrile levels
fever
What is a FUO?
fever of unknown origin
(blank) and (blank) can reset the hypothalamic thermal set point
Pyrogenic cytokines and microbial products
Pyrogenic cytokines mediate the coordinate induction of (blank) and microsomal (blank) in the endothelium of blood vessels in the preoptic hypothalamic area to form the arachdonic acid metabolite PGE2
COX-2
PGE synthase-1 (mPGES-1)
What does PGE2 do?
triggers EP-3 receptors on glial cells and this stimulation results in the rapid release of cyclic AMP
What does cyclic AMP do?
changes the hypothalamic set point via activation of neurons in thermoregulatory center
What type of distinct receptors are located on the hypothalamic endothelium?
PAMPs and DAMPs
Binding of PAMPs and DAMPs also results in (blank) production and upregulation of the (Blank)
PGE2
hypothalamic set point
So give me a quick breakdown how you get a fever
Endotoxin, inflammation. pyrogenic stimuli-> monocytes, macrophages, kupffer cells release cytokines-> preoptic area of hypothalamus->prostaglandins released-> raise temp set point-> fever
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.
PGE2
Reducing the level of (blank) in the thermoregulatory center lowers the elevated hypothalamic set point
PGE2
The synthesis of PGE2 depends on the consitutively expressed enzyme (blank), and the antipyretic drugs inhibit brain (blank)
cyclooxygenase
cyclooxygenase
What are good antipyretics?
acetaminophen, aspirin NSAIDS, COX-2 inhibitors
Chronic high-dose therapy with antipyretics such as aspirin or any NSAID (does/does not) reduce normal core body temp.
Does not, so does not affect normal thermoregulation
Glucocorticoids are (Blank) and work by reducing PGE2 synthesis by inhibiting the activity of (blank) which is needed to release arachidonic acid from the cell membrane.
antipyretics
phospholipase A2
Glucocorticois block the transcription of the (blank) for the pyrogenic cytokines
mRNA
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?
Cyclooxygenase (COX)
What is a fever awesome?
kills pathogens! Also can help with anthrax, pneumococcal pneumonia, leprosy, and various fungal, rickettsial and viral diseases.
Before the advent of antibiotics, fevers were artificialy induced for the treatment (blank) and proved to be beneficial
neurosyphilis
(blank) production is increased when body temp is elevated
antibdy
When does a fever become a bad thing? What do you call this?
with a rectal temp greater than 41.5 C (greater than 106.7 F)
-hyperpyrexia
When does hyperpyrexia usually occur?
with CNS hemorrhages (can also occur w. sever infections)
When the temp is over (blank), heat stroke develops and death is common
43 degrees C
