دورية أكاديمية
أعرض في EDS

Insights into Disease Progression of Translational Preclinical Rat Model of Interstitial Pulmonary Fibrosis through Endpoint Analysis.

التفاصيل البيبلوغرافية
العنوان: Insights into Disease Progression of Translational Preclinical Rat Model of Interstitial Pulmonary Fibrosis through Endpoint Analysis.
المؤلفون: Kadam AH; Proteogenomics Research Institute for Systems Medicine (PRISM), 505 Coast Blvd. South, La Jolla, CA 92037, USA., Schnitzer JE; Proteogenomics Research Institute for Systems Medicine (PRISM), 505 Coast Blvd. South, La Jolla, CA 92037, USA.
المصدر: Cells [Cells] 2024 Mar 15; Vol. 13 (6). Date of Electronic Publication: 2024 Mar 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI
مواضيع طبية MeSH: Procollagen* , Idiopathic Pulmonary Fibrosis*/pathology, Rats ; Humans ; Animals ; Fibrosis ; Collagen/metabolism ; Bleomycin ; Disease Progression
مستخلص: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung distortions and dysfunction. Animal models of human IPF can provide great insight into the mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches. In this study, we describe the effect of bleomycin concentration on disease progression in the classical rat bleomycin model. In a dose-response study (1.5, 2, 2.5 U/kg i.t), we characterized lung fibrosis at day 14 after bleomycin challenge using endpoints including clinical signs, inflammatory cell infiltration, collagen content, and bronchoalveolar lavage fluid-soluble profibrotic mediators. Furthermore, we investigated fibrotic disease progression after 2 U/kg i.t. bleomycin administration at days 3, 7, and 14 by quantifying the expression of clinically relevant signaling molecules and pathways, epithelial mesenchymal transition (EMT) biomarkers, ECM components, and histopathology of the lung. A single bleomycin challenge resulted in a progressive fibrotic response in rat lung tissue over 14 days based on lung collagen content, histopathological changes, and modified Ashcroft score. The early fibrogenesis phase (days 3 to 7) is associated with an increase in profibrotic mediators including TGFβ1, IL6, TNFα, IL1β, CINC1, WISP1, VEGF, and TIMP1. In the mid and late fibrotic stages, the TGFβ/Smad and PDGF/AKT signaling pathways are involved, and clinically relevant proteins targeting galectin-3, LPA1, transglutaminase-2, and lysyl oxidase 2 are upregulated on days 7 and 14. Between days 7 and 14, the expressions of vimentin and α-SMA proteins increase, which is a sign of EMT activation. We confirmed ECM formation by increased expressions of procollagen-1Aα, procollagen-3Aα, fibronectin, and CTGF in the lung on days 7 and 14. Our data provide insights on a complex network of several soluble mediators, clinically relevant signaling pathways, and target proteins that contribute to drive the progressive fibrotic phenotype from the early to late phase (active) in the rat bleomycin model. The framework of endpoints of our study highlights the translational value for pharmacological interventions and mechanistic studies using this model.
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معلومات مُعتمدة: P01 HL119165 United States HL NHLBI NIH HHS; R01 HL169760 United States HL NHLBI NIH HHS; R01HL169760 United States NH NIH HHS; P01HL119165 United States NH NIH HHS
فهرسة مساهمة: Keywords: clinically relevant protein targets; disease progression; mechanistic studies; pharmacological interventions; rat bleomycin model; soluble profibrotic mediators
المشرفين على المادة: 0 (Procollagen)
9007-34-5 (Collagen)
11056-06-7 (Bleomycin)
تواريخ الأحداث: Date Created: 20240327 Date Completed: 20240328 Latest Revision: 20240330
رمز التحديث: 20240330
مُعرف محوري في PubMed: PMC10969066
DOI: 10.3390/cells13060515
PMID: 38534359
قاعدة البيانات: MEDLINE
الوصف
تدمد:2073-4409
DOI:10.3390/cells13060515