Nerve Growth Factor (NGF): ein pro-fibrotischer Faktor im Modell der chronisch allergischen Atemwegsentzündung
Die Gewebsfibrosierung, als ein Charakteristikum vieler chronisch entzündlicher Erkrankungen, wird mit der Beeinträchtigung der Organfunktion assoziiert. Sie wird als unvollständiger Reparaturversuch des Gewebes auf einen chronischen Entzündungsreiz verstanden. Beim allergischen Asthma manifestiert...
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Excessive extra cellular matrix deposition is a disease limiting process in various chronic inflammatory diseases and is associated with loss of organ function. In bronchial asthma exaggerated matrix deposition leads to subepithelial fibrosis in the airways and contributes to lung function decline in the progression of the disease. This fibrotic response is thought to result from repetitive injury-repair cycles upon tissue damage and is considered as imperfect wound healing. Growth factors, which are secreted by damaged epithelial cells and inflammatory cells upon allergen provocation, orchestrate the subsequent repair process at wound sites. In chronic inflammatory conditions the augmented expression of these factors is found to drive this pathological process. During allergic airway inflammation Nerve Growth Factor (NGF) levels are elevated. The identification of the airway epithelium as a major cellular source for NGF and the documented wound healing properties of this molecule in airway epithelial cells and lung fibroblasts, led to the hypothesis that NGF contributes to deregulated repair-processes in the chronic allergic inflamed lung. To investigate this, mouse models of acute and chronic allergic airway inflammation were utilized, where structural changes were seen to be accompanied by augmented NGF levels. Functional blocking of NGF in experimental chronic asthma markedly prevented subepithelial fibrosis. Conversely, transgenic over-expression of NGF in murine airways (NGF-Tg) was seen to alter airway wall morphology and lung physiology. Peribronchial collagen deposition in NGF-Tg mice developed in the absence of an inflammatory response and unaltered transforming growth factor (TGF) β1 levels. Studies, aiming the delineation of the NGF receptor and signalling pathway important for collagen production, were conducted. In vivo and in vitro data clearly demonstrated the importance of the NGF receptor tropomyosin related kinase (Trk) A and not p75NTR in collagen expression. Furthermore, NGF/TrkA signalling was seen to involve p38 MAPK independent of the TGFβ1/mothers against decapentaplegic homolog (SMAD) pathway. These data demonstrate for the first time the pro-fibrotic activity of NGF in chronic allergic airway inflammation and provide evidence for a novel pathway for collagen deposition, which relies on NGF and TrkA signalling.