Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of rat mechanically ventilated lungs from strains resistant or susceptible to ventilation-associated lung injury (VALI)

ABSTRACT: We sought to confirm the genetic influence in the development of Ventilation-Associated Lung Injury (VALI) and, in the process, identify potential candidate genes involved in the disease by integrating differential gene expression profiling on rat lungs to a traditional strain survey analysis of the parental rat strains, VALI-sensitive Brown Norway rats versus VALI-resistant Dahl Salt Sensitive rats, comparing control (under room air ventilation) versus under high tidal volume (HTV) ventilation. We used microarrays to detail the global programme of gene expression underlying VALI susceptibility and identified distinct classes of up-regulated and down-regulated genes during this process. Experiment Overall Design: Rat lungs (Right lungs) from both sets of parents under the two conditions (control vs. HTV ventilation) were isolated for RNA extraction and hybridization on Affymetrix microarrays.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Ankit Desai

PROVIDER: E-GEOD-7041 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Use of consomic rats for genomic insights into ventilator-associated lung injury.

Nonas Stephanie A SA Moreno-Vinasco Liliana L Ma Shwu Fan SF Jacobson Jeffrey R JR Desai Ankit A AA Dudek Steven M SM Flores Carlos C Hassoun Paul M PM Sam Lee L Ye Shui Q SQ Moitra Jaideep J Barnard Joe J Grigoryev Dmitry N DN Lussier Yves A YA Garcia Joe G N JG

American journal of physiology. Lung cellular and molecular physiology 20070427 2

Increasing evidence supports the contribution of genetic influences on susceptibility/severity in acute lung injury (ALI), a devastating syndrome requiring mechanical ventilation with subsequent risk for ventilator-associated lung injury (VALI). To identify VALI candidate genes, we determined that Brown Norway (BN) and Dahl salt-sensitive (SS) rat strains were differentially sensitive to VALI (tidal volume of 20 ml/kg, 85 breaths/min, 2 h) defined by bronchoalveolar lavage (BAL) protein and leuk ...[more]

PMID: 17468131

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Project description:Pulmonary hypertension (PH) and cancer pathophysiology share common signal transduction pathways leading to abnormal endothelial and smooth muscle cell interactions and angioproliferative vasculopathy. Sorafenib (Sor) a drug in clinical trials for cancer treatment, is an inhibitor of multiple kinases important in angiogenesis (Raf-1 kinase, VEGFR-2, VEGFR-3, PDGFR-ï¢)ï©. In this study, we assessed the efficacy of Sor as a potential therapy for PH, and hypothesized that Sor prevents the development of both a conventional and an augmented rodent model of PH. We performed studies in Dahl Salt-Sensitive rats (SS) exposed to hypoxia alone and in combination with the VEGFR-2 inhibitor, SU5416, known to induce a well-characterized augmented PH phenotype. Rats were, thus, divided into 5 groups: normoxia/vehicle (Norm), hypoxia/vehicle (H), hypoxia/ SU5416 (H-SU), hypoxia/Sorafenib (H-Sor) and hypoxia/ SU5416/ Sorafenib (H-SU-Sor). Except for the Norm group, all rats were maintained in a hypoxia chamber with a FiO2 of 10%. Rats received a single injection of SU5416 on Day 1 (20 mg/kg) and Sor solution was administered daily by gavage (2.5mg/kg). After 3.5 weeks, all rats were assessed by open chest catheterizations for pulmonary vascular and right ventricular pressures. Lung and heart tissue were harvested for histological and microarray analyses. Our results showed H-SU rats developed severe PH with changes in hemodynamic and histologic parameters when compared to Norm controls while rats exposed to H alone only displayed mildly elevated pressures compared with Norm. There was no significant change in pressures in the H-Sor or H-SU-Sor compared to Norm. Histopathology demonstrated a dramatic prevention of the PH phenotype in the H-SU-Sor rats with no significant remodeling compared with H-SU rats. Expression profiling data from H (n=4) and H-SU (n=3) rat lungs were compared to Norm (n=4) using normalization in R and SAM (Î´>.639,) (minimum fold change >1.4). With false discovery rates (FDR) of 6.5% in hypoxia and 1.6% in H-SU, 1019 and 465 genes, respectively, were differentially-regulated compared to Norm. In addition, 38 genes were differentially expressed between H-SU and H-SU-Sor (n=4, FDR 6.7%) revealing a molecular signature with potentially novel target genes of Sor. Five differentially expressed genes (Tgfï¢3, C1qg, Nexn, Frzb, and Plaur) were examined by real-time RT-PCR and three were further validated by immunohistochemistry confirming the regulation on protein level. Based on the known pathways of hypoxic-induced PH and Sor, we further utilized immunohistochemistry to show the up-regulation of mediators of the MAPK cascade in the H and H-SU models of PH with subsequent, down-regulation by Sor. We therefore present Sor as a novel treatment for the development of severe PH and theorize that the MAPK cascade is a canonical pathway involved both in the development of PH and in the attenuation by Sor. Experiment Overall Design: Rats were divided into 5 groups of which 4 groups were analyzed by microarrays: normoxia/vehicle (n=4), hypoxia/vehicle (n=4), hypoxia/ SU5416 (n=3), and hypoxia/ SU5416/ Sorafenib (n=4). RNA was harvested from lung tissue at 3.5 weeks.Expression profiling data from H and H-SU rat lungs were compared to Norm using normalization in R and SAM (Î´>.639,) (minimum fold change >1.4). With false discovery rates (FDR) of 6.5% in hypoxia and 1.6% in H-SU, 1019 and 465 genes, respectively, were differentially-regulated compared to Norm. In addition, 38 genes were differentially expressed between H-SU and H-SU-Sor (FDR 6.7%) revealing a molecular signature with potentially novel target genes of Sor.

Project description:Pulmonary hypertension (PH) and cancer pathophysiology share common signal transduction pathways leading to abnormal endothelial and smooth muscle cell interactions and angioproliferative vasculopathy. Sorafenib (Sor) a drug in clinical trials for cancer treatment, is an inhibitor of multiple kinases important in angiogenesis (Raf-1 kinase, VEGFR-2, VEGFR-3, PDGFR-ï¢)ï©. In this study, we assessed the efficacy of Sor as a potential therapy for PH, and hypothesized that Sor prevents the development of both a conventional and an augmented rodent model of PH. We performed studies in Dahl Salt-Sensitive rats (SS) exposed to hypoxia alone and in combination with the VEGFR-2 inhibitor, SU5416, known to induce a well-characterized augmented PH phenotype. Rats were, thus, divided into 5 groups: normoxia/vehicle (Norm), hypoxia/vehicle (H), hypoxia/ SU5416 (H-SU), hypoxia/Sorafenib (H-Sor) and hypoxia/ SU5416/ Sorafenib (H-SU-Sor). Except for the Norm group, all rats were maintained in a hypoxia chamber with a FiO2 of 10%. Rats received a single injection of SU5416 on Day 1 (20 mg/kg) and Sor solution was administered daily by gavage (2.5mg/kg). After 3.5 weeks, all rats were assessed by open chest catheterizations for pulmonary vascular and right ventricular pressures. Lung and heart tissue were harvested for histological and microarray analyses. Our results showed H-SU rats developed severe PH with changes in hemodynamic and histologic parameters when compared to Norm controls while rats exposed to H alone only displayed mildly elevated pressures compared with Norm. There was no significant change in pressures in the H-Sor or H-SU-Sor compared to Norm. Histopathology demonstrated a dramatic prevention of the PH phenotype in the H-SU-Sor rats with no significant remodeling compared with H-SU rats. Expression profiling data from H (n=4) and H-SU (n=3) rat lungs were compared to Norm (n=4) using normalization in R and SAM (Î´>.639,) (minimum fold change >1.4). With false discovery rates (FDR) of 6.5% in hypoxia and 1.6% in H-SU, 1019 and 465 genes, respectively, were differentially-regulated compared to Norm. In addition, 38 genes were differentially expressed between H-SU and H-SU-Sor (n=4, FDR 6.7%) revealing a molecular signature with potentially novel target genes of Sor. Five differentially expressed genes (Tgfï¢3, C1qg, Nexn, Frzb, and Plaur) were examined by real-time RT-PCR and three were further validated by immunohistochemistry confirming the regulation on protein level. Based on the known pathways of hypoxic-induced PH and Sor, we further utilized immunohistochemistry to show the up-regulation of mediators of the MAPK cascade in the H and H-SU models of PH with subsequent, down-regulation by Sor. We therefore present Sor as a novel treatment for the development of severe PH and theorize that the MAPK cascade is a canonical pathway involved both in the development of PH and in the attenuation by Sor. This SuperSeries is composed of the following subset Series:; GSE8078: A Multi- Kinase Inhibitor Modulates Pulmonary Hypertension in a Rodent Model 1; GSE8132: A Multi- Kinase Inhibitor Modulates Pulmonary Hypertension in a Rodent Model 2 Experiment Overall Design: Refer to individual Series

Dataset Information

Transcription profiling of rat mechanically ventilated lungs from strains resistant or susceptible to ventilation-associated lung injury (VALI)

Publications

Use of consomic rats for genomic insights into ventilator-associated lung injury.

Similar Datasets

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