Trigger 4 Flashcards
What is Sepsis
Rare but serious complications after infection
Blood poisoning
Body attacks itself
Where is IL-1B produced and what does it lead to?
Made by macropahges and monocytes
leads to fever, inflammation and pain
Where is IFNy produced and what does it lead to?
secreted by lymphocytes
activates macrophages and many other functions
Where is Il-6 produced and what does it lead to?
made by T cells and macrophages
lead to fever and acute phase proteins response
Where is TNF-a produced and what does it lead to?
secreted by monocytes and others
activates macrophages and endothelium
actiavtes NFk-B
causes fever pain and inflammation
What is systematic inflammatory response
serious condition related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of cytokine storm, in which there is abnormal regulation of various cytokines.
Where is renin released from and what does it stimulate
released from the kidneys
stimulates formation of angiotensin
How is renin released (stimulated)
Reduction in arterial pressure –> release renin fomr JG cells
B-1 adrenoceptor responds to systematic nerve stimulation by releasing renin
Mucula densa, sense decrese in Na and Cl in the tubular fluid and stimulate the JG
Describe the RASS system
Renin released from kidney, travel in blood to liver
Activates angiotensinogen to angiotensin I
Travel to lungs
ACE cleaves angitensin I to angotensin II
- Travels to the brain, release on ADH
- Travels to adrenal gland, release aldosterone
both act on the kidney
Effect of aldosterone on the kidney
increase Na+ absorption
increase water reaborption
Effect of ADH on the kindey
Causes aquaporin in the collecting duct
increase water reabsorption
outline the steps of the JAK/STAT pathway
Cytokine binds to receptor and the dimerise
dimerisation attracts cytosolic JAK
JAK phosphorylates receptor on TYR residue
STAT recruited via STAT SH2 domain binding to receptor phophoryrosine groups
STAT phosphorylated by JAK
STAT dimer translocates to the nucleus
STAT dimer binds to DNA and activates gene expression
what are the biological effects of ROS
react with enzyme sites and stimulate pathways
MAP kinase, PI3 kinase and Jak pathway stimulated by cytokines
ROS may induce receptor clustering
activate nuclear receptors - NFk-B, HIF
Biological consequens - prliferation, apoptosis, cell adhesion, inflammation
Descibe the NFk-B signalling pathway
ligand binds to TLR4 - TNFα, IL-1β, ROS, Cocaine, Viral and Bacterial antigens e.g. LPS
Confomational change, PTK binding, Kinase cascade
Cause phosphorylation and actiavtion of IKK (IkB Kinase)
IKK phosphorylates IkB, which is an inhibitor of NFk-B
IkB-P marked for ubinqunation and protesomal degradation
NFk-B translocates to oxidse active cite of Cys
gene transcritpion - prodcution of cytokines
ROS produced, positve feedback
What are PAMPs
Pathogen assocaited molecular patterns
Allow the innate immune system to recognize the pathogen
Specific to each micro-organism
Expressed by dendritic cells, macrophages,
What are PRRs
Recognize PAMPs The PRR are divided in four families: - Toll-like receptors (TLR) - Nucleotide oligomerisation receptors (NLR) - C-type lectin receptors (CLR) - RIG-1 like receptors (RLR)
What are DRRs/Alarmins
released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response.
Initiate a non-infectious inflammatory response.
What genes does the NFk-B pathway code for
iNOS to generate NO
Cytokines
Adhesion molecules
Important in pro and anti-apoptotic gene regulation
What is meningitis
inflammation of the meninges and subarachnoid space. It may result from infections, other disorders, or reactions to drugs.
Normal chemical and visual levls of the CSF
Appearance: Clear Opening pressure: 10-20 cm H 2 O WBC count: 0-5 cells/µL (< 2 polymorphonucleocytes [PMN]); normal cell counts do not rule out meningitis or any other pathology Glucose level: >60% of serum glucose Protein level: < 45 mg/dL
Meningitis - streptocouus pneumonia
Dipoloid shape
positive gram
70% of acutue bacerial meningitis
Vaccine - pneumoncoccal conjugate vaccine
meningitsis - Haemophilus influenza
rods or coccobacilli shape
negative gram
eliminated due to vaccine
Chemical and visual levls of the CSF for bacterial menigitis
Appearance: Clear, cloudy, or purulent
Opening pressure: Elevated (>25 cm H 2 O)
WBC count: >100 cells/µL (>90% PMN); partially treated cases may have as low as 1 WBC/µL
Glucose level: Low (< 40% of serum glucose)
Protein level: Elevated (>50 mg/dL)
Chemical and visual levls of the CSF for viral menigitis
Appearance: Clear
Opening pressure: Normal or elevated
WBC count: 10-1000 cells/µL (lymph but PMN early)
Glucose level: >60% serum glucose (may be low in HSV infection)
Protein level: Elevated (>50 mg/dL)
live vaccines
contain a version of the living microbe that has been weakened in the lab so it can’t cause disease.
inactive vaccine
contains killed disease-causing microbe with chemicals, heat, or radiation
Congulated vaccine
many harmful bacteria possesses an outer coating of polysaccharides, which disguise a bacterium’s antigens so that the immature immune systems of infants and younger children can’t recognize or respond to them.
Subunit vaccine
include only the antigens that best stimulate the immune system.
Toxoid vaccine
used when a bacterial toxin is the main cause of illness.
detoxified bacterial toxin
DNA vaccines
are experimental vaccines similar to recombinant vector vaccines
DNA injceted into cells so cells machinery synthesis antigens which are expressed on cell surface
Describe the pre clinical stages of vaccine production
Often lasts 10-15 years
Exploratory phases (2-4 years) identifying natural or synthetic antigens that might help prevent or treat a disease
Pre-clinical stage (1-2yrs) - use tissue-culture or cell-culture systems and animal testing to assess the safety of vaccine and its immunogenicity, or ability to provoke an immune response.
IND application - A sponsor, submits an application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration. Describes the manufacturing and testing processes, summarizes the laboratory reports, and describes the proposed study. The FDA has 30 days to approve the application
Describe phase I of a clincical trail
Small study 20 - 100volunteers last serval motnhs to a year testing - dose (gradullay increase) - side effects - body reaction - process in body
Describe phase II of a clincical trail
testing safety, efficacy and side effects
several hundred participants
6 months - 3 years
often randomaised and double blinded
Phase IIa - small number to show safety and efficacy
Phase IIb - establish dose and overal efficacy
- establish inital benefit to risk ratio
Describe phase III of a clincical trail
test efficacy and adverse reactions
300 - 3000 volunteers who have the condition
1 - 3 years
randomaised and double blind trail
Phase IIIa - evidence of efficacy, saftey and side effects
Phase IIIb - after drug has been submitted for marketing approval, compare to current treatments and use in additional populations
what is the arachidonic acid pathway
inflamation mediated by unsaturated factty acids
production of prostaglandins
tissue specific pathway
describe the arachidonic acid pathway
Cell damage, platelets, fribroblast
Trigger phosolipase A2, phosphorylated
Cuts phosolipids, produces prescusour - Arachidonate
Cox enzymes cut it and produces precusors - cyclo endoperoxides, e.g PGG2 –> PGH2
make tissue specific
decribe the role of COX enzyme
Cox enzymes cut arachidonate and produces precusors - cyclo endoperoxides
COX1 - expressed at all times
COX2 - only induced in certain inflammation pathways
encisanoids/prostanoids produced in Platelets
precusors male thromboaxin
key molecule in platelet adhersion
encisanoids/prostanoids produced in vascular endothelium
prostacyclan
vasdilation and Gas signalling
produce PGD2 (vasodilator) and PGF2a (vasoconttictor) in smooth muscle
encisanoids/prostanoids produced in Leukocytes
Leukotrines
key molescule in chemotaxin and bronchoconstriction
What do NSAIDS do
Block Cox enzymes
inhibts gastric acid secretion and promotes mucus secretion
