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

2. 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

3. Clinical phenotypes of asthma
Haldar P et al, AJRCCM 2008

4. 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

5. 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

6. 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

7. 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

8. 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