氣喘: 風雲再起 Asthma: an old disease, a new challenge of future 王圳華 醫師 Chun-Hua Wang, MD

Schematic representation of a) pro-asthmatic epithelium with a close relationship between altered epithelial cell transcription factors, goblet cell metaplasia and T-helper cell (Th) type 2 inflammation. b) The altered epithelium also interacts with the underlying mesenchyme in a chronic wound response to contribute towards airway wall remodelling and ongoing inflammation

Clinical phenotypes of asthma Haldar P et al, AJRCCM 2008

Adult Asthma Low dose or high dose GINA Guideline Well controlled Not Well controlled Compliance Step down The most ideal treatment of asthma is to adequately control their clinical manifestations and then step down the use of medications towards the self-management stage with minimal medications. Many patients fail to do so. The compliance is always the major problem for inadequate control of asthma. If we can improve compliance, we believe a large proportion of asthma patients may achieve well control and step down their asthma therapy. Thus, to ensure whether patients are adherent to therapy is the first step to improve asthma control. Identify triggering factors NO Succeed Fail Yes Severe Asthma Self Management With minimal medications Avoid / Treat

Not Well Controll Asthma Compliance monitor Bad compliance Good compliance History Therapeutic trial GERD Rhinitis Sinusitis Emotional Occupational Drug induced Exercise Menstruation No identified causes Induced Sputum Blood Breath condensate FeNO Bronchial biopsy Severe Asthma Eosinophilic Neutrophilic Allergic (IgE) Airway remodeling

Severe Asthma Inflammation Structural Changes (steroid insensitive) Structural Changes High airway hyper-responsiveness High collapsibility of airways Lung hyperinflation Genomics Environmental Factors Host Factors Epigenetics

Anti-IgE antibodies (Omalizumab) Airway remodeling Allergen, virus, or oxidant stress induced injury Anti-IgE antibodies (Omalizumab) Acute inflammation Chronic stimulation Epithelial shedding Submucosal inflammation Higher level of IL-13, TGF-b1 CCL19 CXCL12 Recruit fibrocytes to submucosa, ASM Recruit bone-marrow-derived fibrocytes Thus, the subepithelial fibrosis in chronic asthma may be a consequence of repeated allergen, virus or oxidative stress induced injury which may cause epithelial shedding and submucosa inflammation leading to release of some unknown factors to recruit bone marrow-derived fibrocytes to airway submucosa. Under the stimulation of EGF, TGF-b or connective tissue growth factors, the fibrocytes may then proliferate and differentiate into myobroblasts and secrete extracellular matrix proteins. CCR7 EGFR CXCR4 EGF, TGF-b CTGF Fibroblast proliferation Myofibroblast Fibroblast ? Myofibroblast Tissue repairing Airway remodeling ASM

Treatment-resistant severe asthma Airway remodeling Eosinophils Neutrophil Allergy Enviromental PDE4 inhibitors ? Anti-IgE Ab Anti-IL5 antibodies ? Anti-elastase Thermoplasty Fibrocytes Oxidative stress Mast cells Progressive remodeling Poorly control