Lecture 4 Flashcards
Corticosteroids
Suppress the IR by mimicking the action of endogenous glucocorticoids
the term corticosteroids includes both endogenous glucocorticoids and artificial steroids (e.g. prednisolone)
Neg feedback in HPA axis
Short feedback loop from ACTH (from pituitary) to the hypothalamus
Long feedback loop from glucocorticoids acting on both the pituitary and the hypothalamus
Ani-inflammatory actions of corticosteroids `
- reduced activity of leukocytes
- reduced activity of monocytes
- reduced clonal expansion of T/B cells
- reduced pro-inflammatory cytokine production
- reduced eicosanoid production
- increased release of anti-inflammatory factors
Corticosteroid mechanism of action
- Bind glucocorticoid receptor (GRα) present as homomers in the cytoplasm bound to hsp90
- binding of ligand to receptor induces dissociation from Hsp90 and dimerization of GRα receptors
- translocation to nucleus to either transactivate or transrepress a wide range of genes (up to 1% of the total genome)
What are the 4 ways in which ligand bound GRα can regulate gene expression
1) GRα binds a positive glucocorticoid response element (GRE) within a promoter region for a gene with low transcriptional activity and activates transcriptional machinery (TM)
2) The TM is constitutively driven by transcription factors (TF) and GRα binds to negative GREs causing TF displacement and repression
3) The TM is driven at a high level by fos/jun TFs binding to their AP-1 regulatory site - the effect of which is reduced by GRα binding
4) prior GRα binding prevents the TFs p65 and p50 binding to the NF-KB site, therefore reducing TM activity
Non-genomic actions of corticosteroids
- Hydrocortisone inhibits neutrophil degranulation (this is not prevented by either GRα antagonists nor by inhibitors of translation)
- Inhibits degranulation of mast cells (membrane impermeable and membrane permeable corticosteroids have identical effects i.e. binding to intracellular GRα not required)
- i.v betamethasone significantly reduced pollen induced nasal irritation. (occurred within 10 mins - too fast for genomic effect)
Side effects of corticosteroids
- opportunistic infection
- thinning of skin and impaired wound healing
- oral thrush (candidiasis)
- osteoporosis (inc osteoclast/dec osteoblast)
- hyperglycaemia
- muscle wasting
- stomach ulceration
- avascular necrosis of femoral head
- reduced sleep and psychosis
How are the side effects of steroid treatment limited?
- co-prescribe
- low doses for minimal amount of time
- give locally
Cushing’s syndrome
Can occur from long term steroid use
symptoms include: pot bellied appearance, hair loss (primarily body, not face and legs), polydipsia and polyuria
Why should patients not suddenly withdraw from length steroid therapy (>1-2 weeks) ?
Acute adrenal insufficiency as the patient fails to resynthesise enough steroids
Withdrawal should be tapered to enable full HPA recovery and is often patient specific
Name 2 different corticosteroids with very different potencies and duration of action
- Hydrocortisone (cortisol used therapeutically). Short acting (<24hrs)
- Dexamethasone - given via iv for treating swelling and inflammation in metastatic cancer
When are corticosteroids prescribed?
- Asthma (inhalation)
- Eczema (1% hydrocortisone topical cream)
- Autoimmune conditions
- To reduce brain tumour/high altitude cerebral oedema
- Addison’s disease where adrenal glands produce insufficient glucocorticoids
Cellular response to asthma
Mainly Th2
Dendritic cell presentation of allergen and presentation to CD4+ T cell leading to Th0 and Th2
Th2 releases:
- IL-5 (eosinophil priming)
- IL-4 and IL-13 (IgE production by B cells and plasma cells and induces FcεR1 expression in mast cells and eosinophils
high circulating IgE levels also increase mast cell FcεR1 expression
FcεR1 crosslinking
Allergen induced FcεR1 crosslinking on mast cells leads to degranulation and histamine and CysLT release (bronchoconstriction and vasodilatation)
Mast cells also release cytokines that recruit macrophages and eosinophils for delayed/late phase
In late phase the epithelium is damaged by release of granule proteins such as eosinophil cationic protein and eosinophil major basic protein which leads to airway hypersensitivity
more nociceptive C fibres accessible to irritant stimuli
Which patients are recommended prophylactic asthma therapy
Those who suffer asthmatic symptoms or use a bronchodilator >2x per week or wakes up once a week with asthmatic symptoms
