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Title: Altered gene expression in rat mesenteric tissue following in vivo exposure to a phosphodiesterase 4 inhibitor

Abstract

Vascular injury is a relatively common finding during the pre-clinical toxicity testing of drugs. The mechanisms of the injury are poorly understood and in turn, sensitive and specific biomarkers for pre-clinical and clinical monitoring do not exist. The present study was undertaken to investigate the molecular mechanisms of drug-induced vascular injury in mesenteric tissue of rats treated with the selective phosphodiesterase 4 (PDE4) inhibitor CI-1044. In a time-course study, male Sprague Dawley rats were given daily doses of 40 or 80 mg/kg for 1, 2 or 3 successive days and were euthanized the following day. Gene expression profiles in mesenteric tissue were determined using Affymetrix RG{sub U}34A microarrays and fibrinogen and cytokine measurements were performed in blood samples. Hierarchical clustering analysis produced a clear pattern separation of the animals with inflammation, animal with inflammation and necrosis and animals without any lesion. Genes associated with inflammation, procoagulation, extracellular matrix remodeling were up-regulated. An altered expression of genes involved in vascular tone regulation, lipid and glucose metabolism was also observed. Selected genes expression changes were confirmed by TaqMan real-time RT-PCR. The inflammatory process was also detected in the bloodstream at the protein level since fibrinogen, IL6 and IL1{beta} concentrations were increased inmore » treated animals. Overall, the present study reveals several molecular changes supporting the hypothesis by which PDE4 inhibitor-induced vascular lesions in rats are triggered by an inflammatory mechanism and/or a vascular tone dysregulation.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [2];  [3];  [2]
  1. Pfizer Global R and D, Drug Safety, Amboise (France). E-mail: nicolas.dagues@pfizer.com
  2. Pfizer Global R and D, Drug Safety, Amboise (France)
  3. Universite Francois-Rabelais de Tours, CNRS UMR 6542, Tours (France)
Publication Date:
OSTI Identifier:
20976838
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 218; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2006.10.018; PII: S0041-008X(06)00393-0; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL MARKERS; BLOOD; DRUGS; FIBRINOGEN; GENES; GLUCOSE; IN VIVO; INFLAMMATION; INJURIES; LIPIDS; MESENTERY; METABOLISM; NECROSIS; POLYMERASE CHAIN REACTION; RATS; TOXICITY

Citation Formats

Dagues, Nicolas, Pawlowski, Valerie, Guigon, Ghislaine, Ledieu, David, Sobry, Cecile, Hanton, Gilles, Freslon, Jean-Louis, and Chevalier, Stephan. Altered gene expression in rat mesenteric tissue following in vivo exposure to a phosphodiesterase 4 inhibitor. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.10.018.
Dagues, Nicolas, Pawlowski, Valerie, Guigon, Ghislaine, Ledieu, David, Sobry, Cecile, Hanton, Gilles, Freslon, Jean-Louis, & Chevalier, Stephan. Altered gene expression in rat mesenteric tissue following in vivo exposure to a phosphodiesterase 4 inhibitor. United States. doi:10.1016/j.taap.2006.10.018.
Dagues, Nicolas, Pawlowski, Valerie, Guigon, Ghislaine, Ledieu, David, Sobry, Cecile, Hanton, Gilles, Freslon, Jean-Louis, and Chevalier, Stephan. Mon . "Altered gene expression in rat mesenteric tissue following in vivo exposure to a phosphodiesterase 4 inhibitor". United States. doi:10.1016/j.taap.2006.10.018.
@article{osti_20976838,
title = {Altered gene expression in rat mesenteric tissue following in vivo exposure to a phosphodiesterase 4 inhibitor},
author = {Dagues, Nicolas and Pawlowski, Valerie and Guigon, Ghislaine and Ledieu, David and Sobry, Cecile and Hanton, Gilles and Freslon, Jean-Louis and Chevalier, Stephan},
abstractNote = {Vascular injury is a relatively common finding during the pre-clinical toxicity testing of drugs. The mechanisms of the injury are poorly understood and in turn, sensitive and specific biomarkers for pre-clinical and clinical monitoring do not exist. The present study was undertaken to investigate the molecular mechanisms of drug-induced vascular injury in mesenteric tissue of rats treated with the selective phosphodiesterase 4 (PDE4) inhibitor CI-1044. In a time-course study, male Sprague Dawley rats were given daily doses of 40 or 80 mg/kg for 1, 2 or 3 successive days and were euthanized the following day. Gene expression profiles in mesenteric tissue were determined using Affymetrix RG{sub U}34A microarrays and fibrinogen and cytokine measurements were performed in blood samples. Hierarchical clustering analysis produced a clear pattern separation of the animals with inflammation, animal with inflammation and necrosis and animals without any lesion. Genes associated with inflammation, procoagulation, extracellular matrix remodeling were up-regulated. An altered expression of genes involved in vascular tone regulation, lipid and glucose metabolism was also observed. Selected genes expression changes were confirmed by TaqMan real-time RT-PCR. The inflammatory process was also detected in the bloodstream at the protein level since fibrinogen, IL6 and IL1{beta} concentrations were increased in treated animals. Overall, the present study reveals several molecular changes supporting the hypothesis by which PDE4 inhibitor-induced vascular lesions in rats are triggered by an inflammatory mechanism and/or a vascular tone dysregulation.},
doi = {10.1016/j.taap.2006.10.018},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 218,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}