Molecular Biology of Bronchial and Vascular Remodelling
: The work embodied in this thesis mainly focuses on the molecular mechanisms underlying bronchial angiogenesis and repetitive injury/repair of airway epithelium that eventually contribute to the airway remodelling, a hallmark in the pathogenesis of chronic lung diseases, such as asthma and COPD. A number of mediators could regulate airway epithelial repair and angiogenesis that directly add to the airway narrowing and hyperresponsiveness by exudation and transudation of pro-inflammatory mediators, cytokines and growth factors. Our results suggest a critical role for the insulin-like growth factor-I/receptor-I (IGF-I/IGFR-I) and fibroblast growth factors/receptor-1 (FGF/FGFR-1) systems in bronchial epithelial repair and airway remodelling. Results included in the second half of the thesis clearly support the notion of ongoing complex mechanisms leading to angiogenesis/vascularisation. We demonstrated an enhanced bronchial expression of VEGF and its receptors ! (Flt 1 and KDR/Flk 1), which may contribute to angiogenesis in COPD. Using human airway smooth muscle (ASM) cells in culture, we showed that apart from their critical role in controlling airway function, ASM cells expressed and released biologically active VEGF in response to pro-inflammatory cytokines (IL 1ï¢ and TNF ï¡), vasoactive mediators (ANG II and ET-1) and nitric oxide donors. Finally, simulating the in vivo state of hypercontractility seen in chronic airway diseases, we established an in vitro model of cyclical stretch. We found an enhanced production of direct and indirect angiogenic molecules via ERK1/2 signalling pathway, clearly advocating for an important role of ASM cells in ongoing angiogenic processes during chronic airway diseases. It is anticipated that our findings may be useful in the development of selective therapeutic strategies to achieve regulated bronchial angiogenesis and diminished tissue remodelling in patients with chronic airway diseases, ! like COPD and asthma.
|Keywords||angiogenesis, asthma, bronchial remodelling, chronic obstructive pulmonary diseases, epithelial repair, fibroblast growth factor, growth factor, human, insulin-like growth factor, vascular endothelial growth factor, vascular remodelling|
|Promotor||Saxena, P.R. (Pramod Ranjan) , Sharma, H.S. (Hari)|
|Sponsor||Astellas Pharma Europe R&D (Leiderdorp, The Netherlands), , Astma Fonds (Leusden, The Netherlands) , Pfizer bv (Capelle aan den IJssel, The Netherlands)|
Alagappan, V.K.T.. (2006, May 31). Molecular Biology of Bronchial and Vascular Remodelling. Retrieved from http://hdl.handle.net/1765/7766