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• W2914943600 abstract "Idiopathic pulmonary fibrosis (IPF) is a devastating and lethal disease, with a median survival of 2-3 years after diagnosis. It is chronic, progressive and occurs predominantly in middle-age and older adults. Multiple working hypotheses speak of possible triggers of IPF development, e.g. multiple microinjuries of the alveolar epithelium, aberrant fibroblast activation, and immune deregulation. Currently, there are two drugs approved for the treatment of mild-to-moderate IPF worldwide, neither Pirfenidone or Nintedanib provide a definitive cure for disease, but slow in disease progression. Thus, animal models of pulmonary fibrosis are a critical tool for disease understanding, drug development and pre-clinical intervention. In chapter 2.1, the first study included in this thesis (Fernandez et al., 2016a), we comprehensively analyzed IPF-relevant peripheral biomarkers, histological compromise along with physiological parameters, to determine disease onset, progression and resolution in preclinical models of fibrosis. We observed and validated that the bleomycin-induced pulmonary fibrosis model reached its peak of fibrosis 14 days after treatment and from there on, resolution started. Furthermore, we created a semi-automatized histologic scoring system to quantify the degree of fibrosis, and correlated histology score with lung function decline during the initiation, peak and resolution phase of the model. Interestingly, we observed that at day 28 and 56 although histological compromise was still present, lung function was close to normal. Furthermore, we determine that plasma levels of ICAM-1 strongly correlate with the extent of fibrosis. We complemented and extended our characterization of the model further. In a following study, we performed multi-compartmental deep proteomics in lung tissue and bronchoalveolar lavage (Schiller, Fernandez et al., 2015), with emphasis on characterizing the matrisome, from the initiation to the resolution of bleomycin-induced fibrosis, in where we could determine the initial signatures of injury, as well as the ones that drive lung repair.In chapter 2.2, we highlighted the second study of this thesis (Sun et al., 2015), that goes along with a complementary publication of our authorship. We use the ability of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to simultaneously record the distribution of hundreds of molecules, in a highly multiplexed and unbiased manner. After oral administration of pirfenidone, we could detect, visualize, and quantify the pharmacokinetics and in-situ distribution of pirfenidone in lung, liver and kidney from unchallenged mice. Furthermore, we performed analysis in fibrotic mice and IPF patients, untreated and under pirfenidone therapy (Sun*, Fernandez* et al. 2018). As expected, we detected mouse and human specific and shared responses; specific alterations of metabolite pathways in fibrosis, and most importantly, metabolic recalibration following pirfenidone treatment. Taking together, bleomycin-induced pulmonary fibrosis is an extremely valuable tool for preclinical drugs evaluation, as well as for target validation and modulation of Idiopathic Pulmonary Fibrosis." @default.
• W2914943600 created "2019-02-21" @default.
• W2914943600 creator A5000312215 @default.
• W2914943600 date "2018-11-27" @default.
• W2914943600 modified "2023-09-23" @default.
• W2914943600 title "Biomarker discovery and drug testing in Idiopathic Pulmonary Fibrosis" @default.
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