Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Asthma is a common disorder of the airways characterized by airway inflammation and by decline in lung function and airway remodeling in a subset of asthmatics. Airway remodeling is characterized by structural changes which include airway smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis due to thickening of the reticular basement membrane, mucus metaplasia of the epithelium, and angiogenesis. Epidemiologic studies suggest that both genetic and environmental factors may contribute to decline in lung function and airway remodeling in a subset of asthmatics. Environmental factors include respiratory viral infection-triggered asthma exacerbations, and tobacco smoke. There is also evidence that several asthma candidate genes may contribute to decline in lung function, including ADAM33, PLAUR, VEGF, IL13, CHI3L1, TSLP, GSDMB, TGFB1, POSTN, ESR1 and ARG2. In addition, mediators or cytokines, including cysteinyl leukotrienes, matrix metallopeptidase-9, interleukin-33 and eosinophil expression of transforming growth factor-β, may contribute to airway remodeling in asthma. Although increased airway smooth muscle is associated with reduced lung function (i.e. forced expiratory volume in 1 second) in asthma, there have been few long-term studies to determine how individual pathologic features of airway remodeling contribute to decline in lung function in asthma. Clinical studies with inhibitors of individual gene products, cytokines or mediators are needed in asthmatic patients to identify their individual role in decline in lung function and/or airway remodeling.

Protection Against Respiratory Syncytial Virus Infection Induced Airway Hyperresponsiveness by DNA Encoding RSV-G Protein Immunization / 소아알레르기및호흡기학회지

PURPOSE: Respiratory syncytial virus is the primary cause of pneumonia and bronchiloitis in young children and infants. RSV infection is also known to be very important to asthma patient, because previous RSV infection increases the frequency of the asthma development and RSV infection may cause airway hyperresponsiveness. Natural RSV infection does not provide complete immunity and reinfection occurs throughout life. Several strategies have recently been used in RSV vaccine development, including the generation of formalin inactivated RSV(FI-RSV), peptides, recombinant vaccine viruses (rVV), and DNA based vaccines. Previous studies in mice primed with RSV G protein enhanced lung pathology resulted from a Th2 host immune response against the viral G protein. We studied for the evaluation of protective immunity, effect on airway hyperesponsiveness, and influence on lung pathology after pND G immunization. METHODS: BALB/c mice were injected with pND G(50g in 1 g/l PBS), pND G-HA (50 g), pND(50 g) FI-RSV(10 6PFU) i.d.at 0, 2, 4 weeks. Four weeks later, mice were challenged with RSV(10 6PFU). Mice were sacrificed on postchallenge day 4 and their lungs were removed for RT-PCR and viral titration. The other mice were sacrificed on postchallenge day 6 for bronchoalveolar lavage, serum and histologic examination. Airway responsiveness was assessed by using a single chamber whole body plethysmography on post challenge day 5. RESULTS: 1) Vaccination with pND-G reduced the Mch(methacholine) induced airway hyperresponsiveness after RSV infection(P0.05). CONCLUSION: In this study, immunization with pND encoding G protein induced decrease in airway hyperresponsiveness, and protection against RSV infection of the lower respiratory tract infection and also induced virus neutralizing antibody and decrease in lymphocytic inflammation. pND G immunization elicited balanced pulmonary Th1/Th2 cytokine response without atypical pulmonary inflammatory responses.