Local hormones Flashcards
What are the signs of inflammation?
- Calor (heat - increased blood flow)
- Rubor (redness - increased blood flow)
- Dolor (pain - sensitisation of sensory nerves)
- Tumor (swelling - increased post-capillary venule/capillary bed permeability)
- Functio laesa (loss of function - pain/injury)
What are the 5 Rs?
- Recognition of the injurious agent
- Recruitment of leukocytes
- Removal of the agent
- Regulation of response
- Resolution
What is the time scale of acute inflammation?
- Mins, hrs to about 3-5 days
- Mediator release whole time
- Microvascular changes - first 24hrs
- Cell accumulation and activation - 12 hrs-4th day
- Systemic effects - 12hrs-4th day
- Repair/healing - 3rd-5th day
What vascular changes are there?
- Mediators disrupt the endothelium and allow it to become more leaky
- The immune cells such as neutrophils and eosinophils, can then get to the infected areas and deal with the pathogens
- This reduces blood volume and therefore blood pressure
What are the benefits of systemic effects?
- Entry of antibodies
- Fibrin formation
- Stimulation of immune response
What are the harmful effects of immune response?
- Destruction of normal tissues
- Swelling
- Inappropriate inflammatory response
Give 6 examples of local hormones
- Gastrin
- CCK
- Glucagon
- VIP
- Substance P
- Motilin
- NA
- DA
- 5-HT
Give a brief overview of basic chemical signalling
- Reception - binding of signal with a cellular protein
- Transduction - binding triggers a series of cellular changes
- Response - transduced signal elicits context-driven specific cellular responses
- Receptors are either membrane bound or nuclear receptors
What is Histamine synthesised from?
Histidine by histidine decarboxylase
What is Histamine metabolised by?
Imidazole-N-methyltransferase (INMT) and diamine oxidase
Where is Histamine synthesised and stored?
- Mast cells
- Basophils
- Neurones
- Enterochromaffin-like cells (ECL)
What causes the release of Histamine?
- IgE mediated release (allergic reaction)
- Production of complement agents C3a and C5a -> act on receptors on mast cells
- Insect stings
- Trauma
- Stimulation of b2 adrenoceptors
What are the actions of mast cells in normal conditions?
- TNFa release -> neutrophil recruitment to kill pathogens
- TGFb and FGF release -> go to site of injury and start wound healing and fibrosis
- Histamine, PGD2 and proteases will be released -> act on nerve cells and SMCs -> neuroimmune interactions, peristalsis, bronchoconstriction and pain
- IL-5,9,13 will cause the recruitment of other immune cells (eosinophils, b cells, Treg)
- Histamine, LTC4 and others will act on the blood-vessel endothelium, causing changes in blood flow, vascular permeability and coagulation -> recruitment of immune cells
What are the different histamine receptors?
- H1 = Gq (PLC) - smooth muscle, endothelium, CNS
- H2 = Gs (increased cAMP) - parietal cells to increase acid secretion, heart
- H3 = Gi (decreased cAMP) - neuronal presynapstic terminals
- H4 = Gi (decreased cAMP) - basophils, bone marrow, gut
How are mast cells activated by IgE?
- Allergen enters
- Mast cell priming - IL-4 from basophils and Th2 acts on mast cells
- Th2 and basophils release IL-4 and 13 to act on B cells -> release of specific IgE
- IgE binds to Fc receptors on mast cells and cross-link
- Now when allergen enters and binds to antibodies on mast cell, it will release its granules
What specific effects does the H1 receptor have?
- Dilates arterioles (decrease TPR)
- Increased permability of post-capillary venules (decreased BP)
- Contraction of smooth muscle (bronchoconstriction)
- Pain, itching and sneezing from sensory nerves
What specific effects does the H2 receptor have?
- Increased HR
- Increased gastric acid secretion
What are two main clinical roles of histamine?
- ACUTE INFLAMMATION (H1)
- STIMULATING GASTRIC ACID SECRETION (H2)
What are antidromic impulses?
- Conduction along the nerve fibre in the opposite direction to normal
- May be produced by electrical stimulation
- Release neuropeptides which cause vasodilation distant from the site of irratation (flare)
What causes the triple response?
Flare = vasoactive transmitters dilate arterioles, also cause degranulation of mast cells -> H1 receptors
Flush then wheal = Dilation of vessels and increased permeability by H1
Exudate vs transudate
- E = a mass of cells and fluid that has seeped out of blood vessels or an organ, especially in inflammation.
- T = ↑ permeability to fluid, but not proteins
What increases/ decreases gastric acid secretion?
- Vagal innervation
- Gastrin and Ach act on ECL cells -> histamine release -> H2 receptors on parietal cells -> increased acid production
- Ach also directly acts on parietal cells to increase production
- PGE2 dampens down the parietal cells acid production and increases the mucus production to protect the gut
3 examples of 1st generation H1 antagonists
Mepyramine
Diphenhydramine
Promethazine
Give an example of a 2nd/3rd generation H1 antagonist
Terfenadine
What is a risk of Terfenadine?
- potential cardiac arrhythmia actions in high conc
- increased with grapefruit juice consumption (inhibits CYP3A4)
What are the effects of H1 antagonists?
- Reduce minor inflammatory reactions
- 1st gen are sedative
- Some (e.g. promethazine) are anti-emetic
- 1st gen also have muscarinic effects such as blurred-vision and constipation
Give 2 examples of H2 antagonists
- Cimetidine
- Ranitidine
What are the effects of H2 antagonists?
- Reduce gastric acid secretion (treatment for gastric and duodenal ulcers and Zollinger-Ellison syndrome)
- Increases INMT activity so more breakdown of histamine
- Mental confusion, dizziness, tiredness and diarrhoea
- Cimitidine decreases CYP so potential for adverse reactions
How is bradykinin synthesised?
PLASMA
- Factor XIIa is activated (allowing its autoactivation)
- It activates prekallikrein to kallikrein
- Kallikrein is a protease that can act on HMWK (high MW kininogen) to produce bradykinin
TISSUE
- Prokallikrein –> tissue kallikrein HMWK –> Lysylbradikinin –> Bradykinin
What is bradykinin activated and metabolised by?
- Kininases activate it
- Metabolised by ACE, aminopeptidase and carboxy peptidase
What are the pharmacological effects of bradykinin?
- Vasoactive peptide
- increases vascular permeability
- Vasodilation
- Pain
- Contraction of gut and bronchus
- Stimulation of Arachidonic acid metabolism
- Chemotactic to leukocytes
- Dry cough (ACE inhibitors inhibit bradykinin breakdown)
How is 5-HT synthesised/ metabolised?
- L-tryptophan + Tryptophan hydroxylase -> -> 5-HT
Metabolised by MAO
Where is 5-HT distributed?
- Platelets release 5-HT (and TXA2) -> platelet aggregation
- mucosal cells in GIT - mediates gut movement and diarrhoea
- Brain
- Some tumours secrete excess 5-HT
What are the inflammatory actions of 5-HT?
- Promotes inflammation by increasing number of mast cells at site of injury
- Mast cell adhesion and migration
- Enhances inflammatory reactions of skin, lungs and gut
- Synergises with TXA2 to cause platelet aggregation
