http://repub.eur.nl/res/aut/13006/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/16994/ 2009-10-01T00:00:00Z Altered bronchial vascular reactivity and remodelling including angiogenesis are documented features of asthma and other chronic inflammatory airway diseases. Expansion of the bronchial vasculature under these conditions involves both functional (vasodilation, hyperperfusion, increased microvascular permeability, oedema formation, and inflammatory cell recruitment) and structural changes (tissue and vascular remodelling) in the airways. These changes in airway vascular reactivity and vascularisation have significant pathophysiological consequences, which are manifest in the clinical symptoms of airway disease. Airway vascular reactivity is regulated by a wide variety of neurotransmitters and inflammatory mediators. Similarly, multiple growth factors are implicated in airway angiogenesis, with vascular endothelial growth factor amongst the most important. Increasing attention is focused on the complex interplay between angiogenic growth factors, airway smooth muscle and the various collagen-derived fragments that exhibit anti-angiogenic properties. The balance of these dynamic influences in airway neovascularisation processes and their therapeutic implications is just beginning to be elucidated. In this review article, we provide an account of recent developments in the areas of vascular reactivity and airway angiogenesis in chronic airway diseases. http://repub.eur.nl/res/pub/9390/ 2000-01-01T00:00:00Z Airway smooth muscle (ASM) is considered to be an end-target cell for the effects of mediators released during airway wall inflammation. Several reports suggest that activated ASM may be capable of generating various proinflammatory cytokines. We investigated the effects of tumor necrosis factor (TNF)-alpha, a potent proinflammatory cytokine, on cultured human ASM cells by examining the expression and release of the cytokine interleukin (IL)-6, cell proliferation, and the expression pattern of c-fos and c-jun, two nuclear proto-oncogenes constituting the activator protein-1 transcription factor. Growth-arrested cell monolayers were stimulated with human recombinant TNF-alpha in a concentration- and time-dependent manner. TNF-alpha stimulated the expression of IL-6 messenger RNA (mRNA), which was detected after 15 min, reaching a maximum at 1 h. IL-6 protein was readily detected in ASM cell-conditioned medium after 2 h of TNF-alpha stimulation. Protein levels increased in a time- and concentration-dependent manner. Release of IL-6 elicited by TNF-alpha was significantly inhibited by dexamethasone, cycloheximide, and nordihydroguaiaretic acid (NDGA). TNF-alpha did not alter DNA biosynthesis up to 48 h or cell numbers up to 120 h. Northern blot analysis of proto-oncogene expression revealed that c-fos and c-jun mRNA levels were elevated after 30 min of TNF-alpha incubation with maximum levels at 1 h and 45 min, respectively. Expression of c-fos mRNA was downregulated by NDGA. Four hours of TNF-alpha treatment resulted in translocation of c-jun immunofluorescence from the cytoplasm to the nucleus in human ASM cells. Our results suggest that despite the lack of a mitogenic response to TNF-alpha, upregulation of primary response genes in human ASM cells may account for the induction of proinflammatory cytokines, such as IL-6, in human airways.