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Asthma & COPD


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