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Asthma & COPD
Asthma
| Question | Answer |
|---|---|
| Characteristics of Asthma and COPD | Chronic inflammation condition, airflow limitation, tissue remodelling |
| Causes | allergic disease/ tobacco smoke and irritants |
| Outcomes | Reversible airflow obstruction/ incompletely reversible airflow limitation, resulting in progressive decline of lung function |
| Classical pathlogies | asthmatic airways show CD4+ lymphocytes, eosinophil and macrophage immune response/ CD8+ T cell, neutrophils and macrophage |
| However, in severe/ sudden onset fatal asthma | neutrophilic (IL-17A) |
| in acute exacerbation of COPD (frequently triggered by viral infection) | eosinophilic |
| Inflammatory response in asthma | Predominance of Th2 cytokines: IL-4, IL-5, IL-13 and chemokines: RANTES, eotaxins, monocyte chemoattractant-1 |
| Inflammatory response in COPD | Th1-dominated responses: IFNgmma, IL-8 (neutrophil chemoat.) leukotriene B4, IL-1 and TNFa (which induce asthma via IL-4, IL-5 and IL-13) |
| Pathological changes in the airways are similar | Inflammatory characteristics of asthma and COPD are interchangeable during exacerbation and infection, due to the association with the similar cytokine profiles and levels |
| Asthma pathology | Notion: imbalance Th1/Th2 allergic inflammatory response which polarises Th2 cell pathway |
| Asthma - initiation | professional APCs present fragment of antigen on MHCII molecule to naive T cells, directing them in favour of Th2 cell phenotype |
| Asthma - T cell co-stimulation | T cell upregulates expression of genes including IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF, which involved in a) isotype switching of B cell, b) recruitment of mast cell and c) maturation of e-phil and b-phil. |
| More recently | CD25+ FOXP3+ T cell is suggested to control Th2 through IL-10 and TGFbeta |
| Central mediator of allergic response (atopic form asthma) - IgE | Upon exposure to allergen, along with Th cytokines, B cells produce and release IgE. IgE binds to FceR1 on mast cell, e- and b-phils, thereby sensitizing these cells to antigen resposne |
| Upon subsequent antigen exposure | cross-linking of adjacent IgE-FceR1 complexes trigger the a) deregulation of cytoplasmic vesicles containing histamine and b) the de novo formation of eicosanoids and reactive oxygen species, resulting SM contraction, mucous secretion and vasodilation. |
| Then move on the the later allergic response (6-72 hrs later) | The release of cytokines/ chemokines that recruit macrophages, e- and b-phils that comprise the late allergic response |
| Eosinophil | prominent in allergic airway disease, linked asthma severity |
| Eosinophil activities | 1)release of pre-stored granular proteins e.g. e- cationic proteins and e-peroxidase, which are cytotoxic 2)synthesis and release of oxygen radicals and lipid mediators as well as numerous cytokines 3)role in airway remodelling: fibrogenic cytokines |
| IL-5 is the most important cytokines associated with eosinophil | produced by Th2, mast cell and eosinophil, regulate most aspects of eosinophil behaviour |
| Airway remodelling - resulting in airway hyper-responsiveness and mucous secretion | 1)collagen 2)fibronectin deposition 3)thinkness of subepithelial basement membrane 4)goblet cell hyperplasia 5)increased ASM mass and size 6)angiogenesis 7)fibrosis |
| Airway remodelling - pathology | imbalance of matrix metalloproteinases and their inhibitors, also increase in ASM content, along with change in the phenotype of fibroblasts cause permanent reduction of airway caliber, which is steroid insensitive |
| Airway remodelling - associated cytokines | TGF-beta, PDGF, IL-6, IL-11, IL-13, IL-17 and IL-25 |
| Immunomodulation - IL-10 actions | 1)on eosinophil survival by prevent the release of chemoattractants 2)downregulation of IL-4, which induces isotype switching of B cell, 3)inhibit IFNgamma and IL-2,4)interfere with function of mono and Macro, 5) MHC expression on APCs |
| Chemokines | class CC, target T cells, monocytes and eosinophils. Eotaxin and RANTES, acting in synergy with IL-5, chemoattractant in allergic inflammation, induce A4 and B1 integrin expression on eosinphil- firm adhesion to epitheilium and tranmigration |
| Therapies - 1 | Inhaled corticosteroids e.g. beclomethasone binds GR in the cytosol, leading to the dissociation of hsp complex and translocation, transsupression and transactivation |
| Transsupression action | interacts with co-activators with HAT activity, which activate pro-in transcription factors wuch as NFkB and AP1 |
| Transactivation action | IL-10 and IkB-alpha |
| Ineffective in virus-induced exacerbation and COPD | IL-2 and IL-4 induce p38 MAP kinase which phosphoylates GR/ HDAC2 is reduced |
| Therapies - 2 | B-adrenoceptor agonists (short/long-acting) e.g. salbutamol/salmeterol, rapid relif of asthma symptoms |
| actions | Gs-adenylate cyclase-cAMP-PKA PKA mediates SM relaxation through P myosin light-chain kinase and by opening of KCa ch. |
| Therapies - 3 | Immunotherapy, increase the production of IgA and IgG, Treg cell (TGFbeta adn IL-10), reduction in the recruitment of Macro B and E-phil |
| Therapies - 4 | IgE, direct neutralization by IgG antibodies e.g. Omalizumab |
| Therapies - 5 | inhibitors of mast cells (e.g. sodium cromoglicate), inhibit Cl- flux in mast cell and epithelial cell to increase the threshold of actication; KCa ch. can also be targeted since it mediates mast cell chemotaxis/ activation |
| Therapies - 6 | Cytokines-based-5 sites of actions:signal transdution, transcription, translation process, soluble and receptor e.g. increase IL-10 and IL12(Th1 differentiation), dicrease IL-4, IL-5, IL-9, IL-13 and IFNs e.g.suplatast tosilate inhibits Th2 cell+cytokine |
| COPD initiation | Inhaled cigarette smoke and other irritants activates epithelial cells and Macrophage to release chemotactic factors |
| COPD chemokines | CCL2 on CCR2 monocytes, CXCL1 and CXCL8 on CCR2 neutrophils and monocytes, CXCL9, CXCL10, CXCL11 on CCR3 Th1 and Tc1 cells |
| COPD - pathology | protases-antiprotase imbalance, such as matrix metalloproteinase which cause elastin degradation and emphysema |
| COPD - Epithelial cells and Macrophages | release TGFbeta, which stimulates fibroblast proliferation, resulting in fibrosis in small airways |
| Therapy | B2 agonist theophylline (PDE inhibitor, increasing cAMP) Muscarinic receptor antagonist |
| other approaches for both | B cell inhbition, NKkB pathway inhibition, chemokine receptors, Th17 |
Created by:
JonLai
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