Drugs affecting airway and lung remodelling Flashcards
What is the function of glucocorticoids in asthma?
- decrease inflammatory cell numer and activation to decrease probability and severity of an episode of asthma
- reduce activity, recruitment, and survival of eosinophils and T cells
- reduced activation of mast cell cytokine production
- reduced macrophage cytokine production
- reduction in proliferation, cytokine and collagen production by smooth muscle and fibroblasts
- over time, leads to an improvement in FEV1
- not a bronchodilatory effect
What is the mechanism of action of glucocorticoids?
- intercellularly; diffuse across memrbrane to engage GC receptor
transactivation:
- receptor dimerizes (activates own transcription factor)
- translocates to the nucleus, and engages a specific sequence on the promoter region (GC response element)
- b2-aR expression –> increased; beneficial to b2 agonists (SABAs, LABAs), maintains bronchodilator effectiveness
- annexin-1 –> turns off inflammation
- serpin A3 –> inhibits serin proteases, influencing inflammation and remodeling
transrepression:
- monomers of receptor bind to other transcription factors eg Jun Fos (activated protein 1), NFkB
- eg binds to AP-1, inhibits its pro-inflammatory function
- represses transcription of:
- cytokines and their receptors
- inducible enzymes for inflammatory mediators (PLA2, iNOS, COX-2)
- adhesion molecules (ICAM-1, E-selectin)
- this diminishes the amount of GR that can dimerize (reduces transactivation)
When are GCS indicated in asthma?
- asthma requiring b2 agonist rescue therapy more than 3x/week (mild persistent asthma)
What are the inhaled GCS used to treat asthma?
older:
- beclomethasone diproprionate
most commin (in combination with b2 agonists (LABA), or as monotherapy):
- budesonide
- fluticasone proprionate
newer (lower systemic effects due to rapid metabolism):
- mometasone
- ciclosenide
How are GCS dosed in asthma?
- start at an effective dose, then step down if full control is achieved
What are the indications for oral GCS tx in asthma?
eg prednisolone
- **several days **when asthma has not been controlled by maintenance therapy (acute exacerbations)
-
chronically for severe asthma (corticosteroid-dependent)
- resistance; asthmatics don’t achieve full airway function even when compliant on best possible meds
- affects ~5% of asthmatics
What are the adverse effects of GCS?
inhaled:
- usually well-tolerated
- dysphonia (change in voice), oral candidiasis (thrush), decreased serum cortisol levels
oral:
- dose and indication-limiting side effects
- osteoporosis, diabetes, muscle wasting, hypertension, grwoth suppression (used cautiously in children)
- suppression of adrenal/pituitary/hypothalamic axis
- trophic hormones suppressed by the exogenous steroids
- causes adrenal atrophy
- need to wean off meds to avoid adrenal crisis and withdrawal
What is the progressive indication of therapeutics and combinations in asthma?
- most patients will be on a GCS inhaler/rapid reliever
- SABAs eg salbutamol, now also formoterol (LABA)
- some pt will have a LABA added if asthma is not controlled by relievers
- dosage is then increased if still not controlled
- beyond this, oral GCS therapy (prednisolone) may be required
What are the pathological differences in airways between asthma and COPD?
asthma:
- remodel to have more muscle, eosinophilic inflammation
COPD:
- normal amount of muscle, lots of fibrosis
- thickened by fibrosis rather than muscle
- loss of alveolar attachments makes airways more readily collapsible than airways in asthma
What are the two cell types that drive thea inflammation of COPD in response to cigarrette smoke?
alveolar macrophages and respiratory eptihelial cells
What are the cellular mechanisms of cigarette smoke in COPD?
- induces release of chemokines (CXC, CC)
- recruit Th1 and CD8 NK cells and neutrophils
- neutrophils release proteases that degrade elastin
- respiratory epithelial cells apoptose
- proteases and other cytokines activate epithelium to promote mucous release
- growth factors promote fibroblast activity, increasing collagen, and myofibroblast activity that induces the scarring of small airways in COPD
What are the effects of oxidative stress in COPD?
- reduce secretion of protease inhibitors and alpha-1 antitrypsin
- increase in degradation of elastin and apoptosis of respiratory epithelium
- recruits neutrophils through NFkB which +IL-8 (powerful chemoattractant of neu) and +TNF expression
- mucous hypersecretion
- oxidative products of AA (isoprostanes) that affect smooth muscle
- corticosteroid resistance
- cellular ageing
- also get nitric stress increasing nitric oxide and inflammation (macro recruitment)
What is the causative difference of airflow limitation in asthma vs COPD?
- asthma is due to bronchoconstriction of the airway smooth muscle in response to allergens, it is reversible
- mast cell recrutiment, CD4 (Th2) cell recruitment, eosinophil inflammation
- COPD is due to the fibrotic narrowing of the small airways and decreased parenchymal tethering that promotes alveolar collapse, it is irreversible
- alveolar macrophages triggering CD8 (Th1) cells, neutrophils (elastase)
What is the result of decreased alveolar tethering due to fibrosis in COPD (and loss of elasticity in emphysema)?
- air trapping at low lung volumes
- unloading of airway smooth muscle leads to collapse of the airways, trapping gas inside
- ie there is not enough tension to keep them open on exhalation
- limits exercise tolerance
What is the role of neutrophils in COPD?
- release elastase that breaks down ECM
- induces epithelial cell apoptosis
- promote mucous secretion
