ML Watson Lec 1 & 2 Flashcards
What is the role of sensory neurones in inflammation?
- Mediate nociception (perception of noxious things e.g pain)
- Release neuropeptides (substance P and CGRP)
What do neuropeptides generally do?
- Contribute to redness and swelling by acting on blood vessels and pain receptors
What does CGRP stand for?
What is its role?
- Calcitonin-gene related peptide
- It is a potent vasodilator that induces erythema (reddening)
What does substance P act on?
What effect does this have?
- NK1 receptor on endothelial cells
- Stim further histamine release from mast cells
- Induces oedema formation (wheal) at injection site, local reddening and flare due to sensory nerve mediated axon reflex
- Induce cytokine release
Talk through the 4 steps of neuropeptide induced inflammation in the skin…
1) Injury is followed by mast cell activation and histamine and PG release
2) PG causes vasodilation and Histamine activates sensory neurones via H1 receptors to stimulate orthodromic stimulation to spinal cord and antidromic stimulation to surrounding skin which leads to neuropeptide release (Sub P and CGRP)
3) Sub P acts via NK1 receptors on endothelial cells of postcapillery venues or by causing increased histamine from mast cells to mediate plasma extravasation at trauma site
4) Substance P increases blood flow but CGRP acts via CGRP receptors and is a potent, long lasting microvascular dilator - this mediates the FLARE at site of injury
How does SP affect microvascular permeability?
- SP affects microvascular permeability via two main mechanisms:
- via endothelial NK1 receptors to increase plasma leakage
- via mast cells, which SP activates to release oedema inducing mast cell amines (histamine)
1) In RA what mediates bone erosion?
2) SPECIFICALLY…
3) What secretes these?
- Proteinases
- MMPs (Matrix metallo proteinases)
- Tissue cells such as synovial fibroblasts and chondrocytes
1) What activates tissue cells that secrete these bone eroding proteinases?
2) What drives this?
1) Infiltrating leukocytes
2) Driven by inflammatory mediators and cytokines, derived from macrophages (TNF-a, IL-1b)
What helps to maintain cytokine production?
- T and B lymphocytes
What is angiogenesis?
- Physiological process through which new blood vessels form from pre-existing vessels
What cell types infiltrate a rheumatoid joint?
- Lymphocytes
- Macrophages
- Interdigitating cell
- Plasma cell
Why does inflammation occur in a rheumatoid joint?
- More blood vessels are formed (angiogenesis)
- Vessels are leaking due to SP
- Cells infiltrate
Where do macrophages arise from?
What are they a major source of?
- Blood monocytes
- Cytokines e.g IL-1, TNF, chemokines TNF (lead to inflam)
What are lymphocytes defined by?
- List some lymphocytes
- Surface antigens, the cytokines they make and function
- T cells (CD3+):
- T helper cells (CD4+)
e. g Th1, Th2 - Cytotoxic T cells (CD8+)
- Natural killer (NK, NKT)
- Th17
- Regulatory T cells (T reg)
- B cells
- Mature to become antibody secreting ‘plasma cells’
What do T cells do?
What can an imbalance or inappropriate activation of T cell subsets lead to?
- Control specific immune system
- Secrete different cytokines associated with diff immune responses
- Th cells activate B cells leading to production of antibodies
- DISEASE
Where does ATP that targets vasculature and leukocytes come from?
- Cell stores (from nerves and inflammatory cells)
What do cytokines target?
- Leukocytes (WBC’s) and tissue cells
Do chemical mediators of inflammation have a LOW or HIGH specificity?
- LOW (not antibodies)
How can inflammation be beneficial? (2)
Increased supply of cells and chemical mediators to site of inflammation:
1) Redness: inc blood flow
2) Swelling: inc vascular perm
Allows removal of damaged tissue, infectious agents
Tells body to rest
1) Pain
2) Loss of function
Acute and chronic inflammation mechanisms overlap
- List the aspects of acute and chronic inflammation..
Acute:
Redness, swelling, chemical mediators, neutrophil recruitment
Chronic: Cytokines, macrophage and lymphocyte recruitment
List the different mediators that respond to local injury:
1) Pre formed mediators - Histamine
2) Production of mediators from membrane lipids - eicosanoids (PGE2, PGI2) leukotrienes (LTB4), PAF
3) Release of peptides from stimulated neurones - SP, CGRP
4) Mediator production following proteinase activation - bradykinin, complement fragments (C3a, C5a)
5) Hours later production following protein synthesis - iNOS, COX-2, cytokines
What effects does Histamine have on local blood vessels?
- Vasodilation
- Increases vascular perm
- (but bronchoconstriction)
Which eicosanoids are vasodilators?
What are the others responsible for?
PGE2, PGI2, LTB4, LTC4
- PGE2, PGI2 = vasodilators
- LTB4, LTC4 = increase vascular permeability
Name some agents that increase plasma leakage via an action directly on the endothelium…
- Histamine, bradykinin
Name some neutrophil activators that increase plasma leakage via a neutrophil dependent mechanism…
- LTB4 (eicosanoid), fMLP, C5a, IL-8
Talk throughs the steps of histamine synthesis and degradation
1) L-histidine to histamine by histidine decarboxylase
2) Histamine to imidazolyl acetic acid (inactive) by histaminase
Which drug inhibits the conversion of L-histidine to Histamine?
- How?
- Tritotoqualine (inhibits histidine decarboxylase)
Where does histamine storage occur and what is it stored as?
- In mast cells (skins, lungs, gut and nasal mucosa)
- Complexed with HMW heparin
histamine basic HMWH acidic
How does mast cell degranulation occur?
- Antigens interact with IGE bound to Fc receptors on surface of mast cells
- Induced degranulation
- Mast cells release Histamine and other compounds
Name 3 stimuli for histamine release:
- Type 1 immediate hypersensitivity via IgE (allergy)
- Chemicals: insect bites
- Mechanical injury to skin
What is the triple response associated with histamine or allergen?
1) Arterial vasodilation (LOCAL reddening)
Depends on soluble, chemical mediator
2) Oedema formation (WHEAL)
Depends on soluble, chemical mediator
3) Axon reflex (FLARE) and release of neuropeptides
Depends on nerve supply
What does the H1 receptor do?
- Gq coupled - PLC linked to Ca2+ elevation
- Endothelial cell contraction increase vascular perm - OEDEMA
- Endothelial cell release of NO - VASODILATION
- Neuropeptide release - VASODILATION
- Airway and gut smooth muscle contraction
What role does the H2 receptor play?
- Gs coupled - Adenylyl cyclase - cAMP
- Vascular smooth muscle cell relaxation
- Histamine causes simulation of gastric acid secretion from parietal cells
List an H2 receptor antagonist…
- Whats a disadvantage of these?
- Cimetidine
- Ranitidine
- CYP450 inhibitors (interactions)
List an H1 receptor antagonist…
- Antihistamines
- Chlorpheniramine
- Loratadine, Astemizole
Useful in skin rashes and nasal congestion
What are eicosanoids derived from?
- What is this a component of?
- From a C20 unsaturated fatty acid (Arachidonic acid) (from phosphatidylcholine)
- Component of membrane phospholipids
Phospholipids form arachidonate which are converted to products by either lipoxygenases or COX.
What are these products?
Lipoxygenases - leukotrienes (LTB4, LTC4, LTD4)
COX - Prostaglandin H2 (PGH2)
Prostaglandins can be converted to _____ by prostacyclin synthase or by thromboxane syntheses to _____ or to other prostaglandins
1) Prostacyclin
2) Thromboxanes
What are the physiological functions of PGs?
1) Initiation of labour (PGF2a and PGE2)
2) Inhibition of gastric acid secretion, increased gastric mucus production (PGE2)
3) Vascular (PGI2 from endothelium)
- inhibition of platelet aggregation
- vasodilator
4) Vascular (TXA2 from platelets)
- Causes platelet aggregation
- Vasoconstrictor
PGE2 and PGI2 increase permeability TRUE or FALSE?
- FALSE
- They increase blood flow but have limited effects on permeability
Which of the following increase permeability via neutrophil-dependent mechanisms?
- Histamine, LTB4, fMLP, Bradykinin, IL-8
- LTB4, fMLP, IL-8
- Histamine and Bradykinin increase permeability by direct effects on the endothelium
Histamine is a vasoconstrictor TRUE or FALSE
- Histamine is a vasodilator
