Advances in asthma and COPD Flashcards
Asthma and COPD pathology
COPD is mostly caused by cigarette smoke. it is from a alpha-1-antitrypsin deficiency. it is not readily reversible. steroid resistant
Asthma is mainly extrinsic (allergic-type hypersensitivity) or intrinsic (non-allergic sensitivity to irritants, e.g., smoke). airway inflammation and bronchoconstriction that is reversible. sees airway remodelling due to histamine release.
Some asthma is difficult-to-treat (DTT). it is uncontrolled with prescriptions and severe.
Asthma is heterogeneous. there are multiple different phenotypes and endotypes (molecular mechanisms) through which it arises. Phenotypes include eosinophilic (allergic and/or nonallergic), neutrophilic, paucigranulocytic (absence of granulocytic inflammation), and mixed eosinophilic and neutrophilic.
The end-types can be T2 high or T2 low.
T2 high sees upregulation of T2 immune pathway (includes IL4 and IL13) and eosinophilic airway inflammation.
T2 low lacks signature biomarkers. it includes neutrophilic and paucigranulocytic phenotypes
mAbs for asthma
Benralizumab binds tot he IL5Ra to prevent IL5-mediated activation of eosinophils and basophils. the IL5Ra is a subunit that IL5 binds to and induces dimerisation with IL5RBc component. IL5 is produced by Th2 lymphocytes in response to antigen presenting cells. IL5 stimulates eosinophil differentiation, survival, proliferation and degranulation. IL5 contributes to recruiting these cells to the airways. used in eosinophilic DDT. Benralizumab also binds to the FcyRIIIa receptor on NK cells, leading to the apoptosis of the eosinophils. mepolizumab and reslizumab are also anti-IL5.
Tezepelumab binds to thyme stromal lymphopoietin (TSLP), an epithelial-derived cytokine. it is produced in the airway in response to allergens. it is seen to be over expressed in asthmatics. a major mediator of eosinophilic inflammation. TSLP binding to the TSLP receptor leads to heterodimer formation with IL7R to stimulate differentiation of T-cells into Th2 cells, promoting airway remodelling.
These mAb treatments only see modest responses, with exacerbation rates in studies being reduced by only 50%. These medicines target downstream mediators of the type 2 inflammatory cascade. It is the combination of chemicals released initiated by “alarmins” (such as TSLP, IL33 and IL25) that leads to the inflammation.
Omalizumab is anti-IgE
dupilumab is anti-IL4/13. phase 3 for COPD
Bitter taste receptor agonists
TAS2R is receptors found in mouth and the airways. detects harmful substances
in asthma, activation triggers a protective response, causing mucociliary clearance and SM relaxation.
Possible target, but not effective due to current agonists poor potency
Rho kinase inhibitors
Y27632 is a rho kinase inhibitor
Rho kinase is activated by RhoA and is involved in SM contraction and hyper-responsiveness of SM. also role in airway remodelling. It is also found in eosinophils, recruiting them.
Increased Rho Kinase activity is seen in asthma.
Rho kinase inhibits myosin phosphatase. Myosin phosphatase dephosphorylates myosin light chain. As such Rho kinase prevents this. this promotes contraction at low [Ca2+].
Y27632 sees rapid bronchodilatation after inhalation
Calcilytics for asthma
target calcium-sensing receptor (CaSR), a GPCR that mediates IC responses to EC [Ca2+].
It couples to Gq, Gi, and G12/13 (RhoA signalling pathway).
NAMs (calcilytics) reduce their sensitivity to calcium.
CaSR can be over expressed in asthma, leading to hyperresponsivness.
NPS2143, a calcilytic, was seen to reduce calcium in the airway SM for asthmatics, but had no effect in control patients, suggesting a selective effect in the target population
Leukotrienes and prostaglandins as a target
COX creates PGs and lipoxygenase creates LTs. both out of arachidonic acid
Zileuton (clinical use) and setileuton (phase 2) are lipoxygenase inhibitors. improve FEV1 and reduce immune recruitment. hepatotoxic however.
PGD2 mediates its effects through the DP1 and DP2 receptor. the DP2R is found of Th2, mast, basophils and eosinophils.
Setipiprant (phase 2) and fevipiprant are selective DP2R antagonists that inhibit Th2 and eosinophils activatoin
PDE as target
PDEs catalyse breakdown of cAMP and cGMP.
PDE4 found to play crucial role in regulating SM in airways. it degrades cAMP, leading to SM contraction. PDE4 is found to be more expressed in asthmatics and in COPD
Same mechanism as B2-AR increase SM relaxation - increase in cAMP stimulates opening of potassium channels and closing of calcium channels - decrease.
Roflumilast is a PDE4 inhibitor. its use however, was not found to affect SM tone, but rather it reduces the release of inflammatory mediators due to the presence of PDE4 on mast cells. Aprelimast is another PDE4 inhibitor that alongside roflumilast was shown to reduce eosinophil recruitment through reducing Th2 cell cytokine production.
Enoximone is a PDE3 inhibitor that causes bronchodilator in asthmatics, however PDE3 inhibition incerases cardiac contraction - thus limited use.
Ensifentrine is a dual PDE3/4 inhibitor that reduces airway inflammation and causes bronchodilator. improves lung function in clinical trials, and inhaled administration reduces cardiac exposure.
