Ch 17 - Chemical Mediators

what dod the observation that factors present in blood could cause a physiological response in lab setting do in the field of pahramacology

catalyzed the growth of the pharmaceutical industry and the quest for biologically active molecules and compounds

factors in the early 1900s were what and how did this change as technology developed

• only the simplest substances that were identifies (5-HT, histamine, etc.)

• complicated structures were revealed (protaglandins, endothelin)

modern day state of factor identification

though the structure of many meidators have been identified, there are several with yet to be determined role and functions (NO)

hormones

released from a single endocrine gland and circulate in the bloof to affect other target tissues or cells

local hormone

a chemical messenger that conveys information from one cell to another (but can also be carried by blood)

relationshop between hormone and local hormone function

some hormones can act as local hormones, and some local hormones can act systemically

hormones that can act as local hormones example

hydrocortisone

local hormones that can act systemically examples

cytokines, histamine

what type of fatcor are mediators

local hormones are the mediators between a stimulus and a physiological response

mediator describes

local hormone

classes of local hormones

• small molecules

• peptides and proteins

a mediator must have the following characteristics (similar to Koch’s postulates)

1. must be produced and released by local cells and initiate a timely biological response at target tissues

2. administration of the mediator reproduces the same biological response

3. inhibiting the synthesis, release, or action of mediator attenuates or changes the biological response

histamine what class of mediator

small molecule

histamine was originally identified in ___ as _____

the allergic response the primary mediator of anaphylaxis

histamine chemical properties/class, what it’s derived from, and what enzyme is used to derive it

histamine is a basic amine derived from histidine by histidine decarboxylase

where is most histamine in the body generated

in granules in mast cells, basophils, and eosinophils (WBCs)

histamine distribution in body

present in most tissues but at high []s in tissues exposed to the outside world (lungs, skin, GI tract)

biological effects of mediators of immediate response (other side is my notes okay dont be mad)

• biological effects of mediators of immediate response

  • eosiniphils and mast cells

  • have cross linking of Ab from ligand that triggers release from cell

• release

  • histamines

  • lipid mediators

  • cytokines

  • other enzymes (not focus in this class)

• mediators have diff effects on diff target tissues

• lipid mediators and histamine have multiple physiological effects

  • vasodialation, vascular leaking, bronchoconst, intestinal hypermobility, inflammation

  • think of allergic reaction

  • runny eyes and nose related to these mediators, local reaction to certain allergens/irritants

• some people

  • affect breathing

  • narrows airways, obstructive

histamine release stpes

• exposure to an allergen activates the immune system, triggering histamine release

• antigen → antigen presenting cell → T-cell activation → B-cell activation → IgE release → mast cell activation → histamine release

how is histamine removed from the body

mainly degraded, occurs mainly through metabolic inactivation by histaminase

what is another wy histamine can be released (non-specific response)

• blunt trauma type of way

  • localized tissue damage can cause histamine release and trigger inflammation

what immunoglobin is associated with allergies and why

• IgE is the one associated with allergies

  • reason is Fc region binds to receptors (Fc epsilon receptors) that are specific to histamine carrying cells

  • binding activates mast cells and causes histamine release

illustrating mast cell activation and histamine release

.

notes again sorry gang

• no need to remember all this

• know the top and bottom not the middle

  • a little redundant but shows the internal cellular responses responsible for the release of mediators

• binding, crosslinking of receptors, cascade, production of PGD2 (release of lipid mediators), production of cytokines and release of granule contents

• cytokines are made in response to the trigger while granule contents are already there but get released

  • cytokines and lipid mediators are delayed, enzymatic framework is alr there tho, just need to make it

  • granule contents are more immediate

• picture represents a mast cell

histamine receptors are all what type

GPCR

how many histamine receptor homologs and how named

H1 - H4

what do histamine receptors fo

transduce signals though adenylyl cyclase and cAMP in peripheral tissues

actions of each histamine receptor homolog

• H1 and H2 generally have stimulatory actions

• H3 and H4 have inhibitory actions (however, tissue specific responses for H4 are not well characterized)

main antihistamine drug class and what are they used for

H1 antagonists, principal antihistamines used in the treatment or prevention on inflammation

physiological responses to histamine - H1

• SM: contracts in response to H1 activation in bronchi, bronchioles, small intestine, and uterus

• cardiovascular system: increases vasodilation, makes post capillary venules more permeable

physiological responses to histamine - H2

• heart: increases CO (SV and heart rate)

• GI tract: stimulates gastric secretions, especially gastric acid

histamine antagonists (both comp and non-comp are available) are all considered antagonists, but fall into what categories

• sedative

• non sedative

what is the diff between sedative and non-sedative histamine antagonists

sedative have CNS effects

what do histamine antagonists do

decrease mediated contraction of the smooth muscle of the bronchi, the intestine, and the uterus

apllication of histamine antagonists

not very good as bronchodilators but have clinical applications in anaphylaxis

Fexofenadine - class of drug, clinical uses

• H1 blocker (antagonist)

• clinical uses: hay fever, rhinities, skin rashes (hives), insect bites

Cimetidine - drug class, clinical uses

• H2 blocker

• clinical uses: peptic ulcers, reflux oesophagitis → through inhibition of gastric secretion

eicosanoid

general term for mediators that are generated from fatty acid precursors as required (ie. not stored for later use)

a precursor for several mediators

arachidonic acid

arachidonic acid is a precursor for

• prostanoids

• leukotrienes

• lipoxins, and resolvins

prostanoids include

prostaglandin and thromboxanes

eicosanoids are synthesized from

arachidonic acid

synthesis pathway for prostaglandins

arachidonate is metabolized by cyclo-oxygenases (COX-1 or COX-2) to prostanoids

synthesis pathway for leukotrienes

5-lipoxygenase converts arachidonate to leukotrienes

eicosonoid synthesis

.

chemical feature of arachidonate that allows for it to be made into so many diff things

• have unsaturated carbons (double bonds) which gives opportunity to add smth else

• number of mediators

• some double bonds can be changed to allow for addition of subsequent moeities to the molecule

“PG” indicates

prostaglandins

PGE_2 is (what it stands for/class of mediator)

a prostanoid, prostaglandin E2

what is PGE2 (functional meaning not what it stands for)

prominent in inflammatory responses and is a mediator of fever and pain

where is PGE2 made

generated by local tissues and blood vessels

what does PGE2 activate

three of the PG receptors

1. EP_1 receptors

2. EP_2 receptors

3. EP_3 receptors

what does activation of EP1 receptors do

contraction of bronchial and GI tract SM

what does activation of EP2 receptors do

relaxation fo bronchial, vascular, and GI tract SM

what does activation of EP3 receptors do

inhibition of gastric acid secretion, increased gastric mucus secretion, contraction of pregnant uterus and GI SM, inhibition of lipolysis and of autonomic NT release

phospholipid inflammatory mediators (notes)

• number of pathways and look at what happens when you start to interfere w the pathways

• the precursor can be made into a bunch of things

• bottom is all the PGs and leukotrienes

• made by enzyme pathways

  • cyclo-oxygenase

  • can block at diff parts

• NSAIDs - inhibit enzyme

• other drugs we can use

  • leukotriene RECEPTOR antagonists - inhibiting reception

  • she mentioned another but I didnt catch it lowkey I think you need tk all

NSAIDs - stands for what and examples

• non-steroidal anti-inflammatory drugs

• aspirin, ibuprofen

what do NSAIDs do

inactivate COX enzymes to combat the inflammatory response, arachidonic acid is not metabolized to prostanoids, have side effects

misoprostol

PGE agonist (activates EP2/EP3 receptors)

clinical uses of misoprostol

the pregnant uterus is highly sensitive to misoprostol and will contract in response to threshold levels

• early pregnancy - terminates pregnancy

• late pregnancy - induces labor (ripens cervix)

• post delivery - uterus clamping (stops bleeding)

additional uses

• prevents gastirc acid secretion (used in combination with NSAIDs) to prevent NSAID-induced ulcers

LT

leukotrienes

LTs made by what and from what primarily

• by WBCs

• made from arachidonic acid by 5-lipoxygenase

LT synthesis cascade (from LTA_4)

LTA4 can be further converted to LTB4, LTC4, LTD4, LTE4, and LTF4

what are LTC4-F

cystinyl containing LTs

what does LTB4 do

is an important mediator of chemotaxis and activator of WBCs

CysLT

cysteinyl-containing LTs

CysLT cause

contraction of bronchial muscles and peripheral vasodilation

Montelukast

CysLT receptor agonist used to treat asthma

chemotaxis

chemical mediated movement - WBC drawn to an area where these are present

lipoxin

• other small molecule mediator

• acts on polymorphonuclear leukocytes to oppose the inflammatory response

• also act as a high affinity antagonist to CysLT1 (therefor lipoxin analogues are being studied as antiasthmatics)

PAF

• platelet activatig factor

• other small molecule mediator

• produced by platelets in response to thrombin and by activated immune cells

key mediator between inflammatory response and thrombosis and its additional function

PAF, also intiates the inflammatory response in allergic reactions

small molcecule mediators

• histamine

• eicosonoids (prostanoids, LTs, lipoxins and resolvins)

peptide and protein mediators length (# residues)

generally vary from three to about 200 aa residues in length (50 aa cut off for peptide to protein)

similarities between peptides and proteins

both udergo post-transcriptional modifications that often affect their biological activity

differences between peptides and proteins

proteins must adopt tertiary or quaternary structures that make them rigid (sterically hindered and functional groups are stabilized) wherease peptides are flexible

peptides and proteins are classificed into 4 categories (broadly) based on

biological activity

peptide and protein mediator classes

• NTs and neuroendocrine mediators

• hormones from non-neuronal sources

• growth factors

• immune system mediators

peptide synthesis steps

• genes code for peptide structure (generally as a precursor molecule that has the desired peptide embedded)

• preprohormone is translated, signal peptide is removed and preprohormone is converted to prohormone

• prohormone contains complete hormone sequence plus other peptide sequences

• prohormone is transferred to golgi apparatus where it is processed

• prohormone is packaged into secretory vesicles

POMC (stands for)

pro-opiomelanocortin

POMC (definition)

a precursor peptide that is cleaved into hormones and peptide mediators

what does POMC give rise to

ACTH, MSH, and \beta-endorphin

ACTH

adrenocorticotrophic hormone

MSH

melanocyte-stimulating hormones

POMC gives rise to many molecules, what is their function

all have specific functions, but also work together in inflammatory response

processes that permit extensive diversity within peptide/protein families

geen splicing and post translational processing of prohormone

how does gene splicign contribute to peptide/protein diversity

a single gene can code for multiple proteins through differential expression of exons and introns, usually through experimental cues that govern differing trasncriptional start sites

how do post-translational modifications contribute to peptide/protein mediator diversity

include peptides that cleave prohormones at different sites giving rise to similar but distinct peptides - usually tissue specific phenomenon

proteolytic cleavage of kininogens gives rise to

bradykinin and lysyl-bradykinin (kallidin)

bradykinin

• a vasodilator and increases vascular permeability, also causes sustained contraction in SM

• strong pain producing agent that is potentiated by prostaglandins

types of BK receptors

two main types

• constitutively expressed B2

• inflammatory response induced B1

icatibant

• bradykinin antagonist

• peptide analogue of bradykinin

• seelctive competitive antagonist for B2 receptors

• used to treat acute attacks of hereditary angioedema

B1 and B2 antagonists are known and may be developed for treating

inflammatory disorders

neuropeptides

often co-released during normal physiological responces with non-peptide neurotransmitters

most important neuropeptide

substance P

neurogenic inflammation

arises from the local release of neuropeptides from afferent neurons that affect mast cells (release histamine)

aprepitant

neurokinin NK1 receptor antagonist used to treat emesis

signalling molecules of the inflmmatory response

cytokines

cytokines

protein or polypeptide mediators synthesized and released by cells of the immune system during inflammation (via autocrine or paracrine mechanisms)

cytokines bind to what to do what

bind to specific kinase linked receptors with high affinity and intiate a signal transduction cascade to phosphorylate and activate downstream proteins

receptor expression for cytokines

not usually expressed unless in an inflammatory response