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Low-dose administration of bleomycin leads to early alterations in lung mechanics.
Headley, Lauren; Bi, Weizhen; Wilson, Cory; Collum, Scott D; Chavez, Melissa; Darwiche, Tamara; Mertens, Tinne C J; Hernandez, Adriana M; Siddiqui, Saad R; Rosenbaum, Stephanie; Johnston, Richard A; Karmouty-Quintana, Harry.
Afiliação
  • Headley L; Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Bi W; Department of Pharmacology and Therapeutics, King's College London, London, UK.
  • Wilson C; Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Collum SD; Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Chavez M; Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Darwiche T; Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Mertens TCJ; Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Hernandez AM; Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Siddiqui SR; Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Rosenbaum S; Department of Pediatrics, Division of Critical Care Medicine, McGovern Medical School, UTHealth, Houston, TX, USA.
  • Johnston RA; SCIREQ, an Emka technologies company, Montreal, QC, Canada.
  • Karmouty-Quintana H; Department of Pediatrics, Division of Critical Care Medicine, McGovern Medical School, UTHealth, Houston, TX, USA.
Exp Physiol ; 103(12): 1692-1703, 2018 12.
Article em En | MEDLINE | ID: mdl-30260066
ABSTRACT
NEW

FINDINGS:

What is the central question of this study? When do alterations in pulmonary mechanics occur following chronic low-dose administration of bleomycin? What is the main finding and its importance? Remarkably, we report changes in lung mechanics as early as day 7 that corresponded to parameters determined from single-frequency forced oscillation manoeuvres and pressure-volume loops. These changes preceded substantial histological changes or changes in gene expression levels. These findings are significant to refine drug discovery in idiopathic pulmonary fibrosis, where preclinical studies using lung function parameters would enhance the translational potential of drug candidates where lung function readouts are routinely performed in the clinic. ABSTRACT Idiopathic pulmonary fibrosis (IPF) is the most widespread form of interstitial lung disease and, currently, there are only limited treatment options available. In preclinical animal models of lung fibrosis, the effectiveness of experimental therapeutics is often deemed successful via reductions in collagen deposition and expression of profibrotic genes in the lung. However, in clinical studies, improvements in lung function are primarily used to gauge the success of therapeutics directed towards IPF. Therefore, we examined whether changes in respiratory system mechanics in the early stages of an experimental model of lung fibrosis can be used to refine drug discovery approaches for IPF. C57BL/6J mice were administered bleomycin (BLM) or a vehicle control i.p. twice a week for 4 weeks. At 7, 14, 21, 28 and 33 days into the BLM treatment regimen, indices of respiratory system mechanics and pressure-volume relationships were measured. Concomitant with these measurements, histological and gene analyses relevant to lung fibrosis were performed. Alterations in respiratory system mechanics and pressure-volume relationships were observed as early as 7 days after the start of BLM administration. Changes in respiratory system mechanics preceded the appearance of histological and molecular indices of lung fibrosis. Administration of BLM leads to early changes in respiratory system mechanics that coincide with the appearance of representative histological and molecular indices of lung fibrosis. Consequently, these data suggest that dampening the early changes in respiratory system mechanics might be used to assess the effectiveness of experimental therapeutics in preclinical animal models of lung fibrosis.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Bleomicina / Mecânica Respiratória / Pulmão Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Exp Physiol Assunto da revista: FISIOLOGIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Bleomicina / Mecânica Respiratória / Pulmão Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Exp Physiol Assunto da revista: FISIOLOGIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos