| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS | REGISTER |
|
|
|
|
|||||||||||||
|
|
|||||||||||||||
INTESTINAL MOTILITY |
1 UPRES EA 27-10 "Radiosensibilité des tumeurs et tissus sains", Institut Gustave Roussy/Institut de Radioprotection et de Sûreté Nucléaire, Villejuif, France, and "Laboratoire d’étude des pathologies radio-induites", SRBE/DRPH. Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France
2 "Laboratoire d’étude des pathologies radio-induites", SRBE/DRPH. Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France
3 Surgery Department, Institut Gustave Roussy, Villejuif, France
4 UPRES EA 27-10 "Radiosensibilité des tumeurs et tissus sains", Institut Gustave Roussy/Institut de Radioprotection et de Sûreté Nucléaire, Villejuif, France, and Radiation Oncology Department, Institut Gustave Roussy, Villejuif, France
5 UPRES EA 27-10 "Radiosensibilité des tumeurs et tissus sains", Institut Gustave Roussy/Institut de Radioprotection et de Sûreté Nucléaire, Villejuif, France
Correspondence to:
Correspondence to:
Dr M-C Vozenin-Brotons
Laboratoire UPRES EA 27-10, "Radiosensibilité des tumeurs et tissus sains", PR1, 39, Rue Camille Desmoulins, 94805 Villejuif Cedex, France; vozenin{at}igr.fr
ABSTRACT
Background: Late radiation enteritis in humans is associated with accumulation of extracellular matrix and increased connective tissue growth factor (CTGF) expression that may involve intestinal muscular layers.
Aims: We investigated the molecular pathways involved in maintenance of radiation induced fibrosis by gene profiling and postulated that alteration of the Rho pathway could be associated with radiation induced fibrogenic signals and CTGF sustained expression.
Patients and methods: Ileal biopsies from individuals with and without radiation enteritis were analysed by cDNA array, and primary cultures of intestinal smooth muscle cells were established. Then, the effect of pharmacological inhibition of p160 Rho kinase, using Y-27632, was studied by real time reverse transcription-polymerase chain reaction, western blot, and electrophoretic mobility shift assay.
Results: Molecular profile analysis of late radiation enteritis showed alterations in expression of genes coding for the Rho proteins. To investigate further the involvement of the Rho pathway in intestinal radiation induced fibrosis, primary intestinal smooth muscle cells were isolated from radiation enteritis. They retained their fibrogenic differentiation in vitro, exhibited a typical cytoskeletal network, a high constitutive CTGF level, increased collagen secretory capacity, and altered expression of genes coding for the Rho family. Rho kinase blockade induced a simultaneous decrease in the number of actin stress fibres, 
smooth muscle actin, and heat shock protein 27 levels. It also decreased CTGF levels, probably through nuclear factor 
B inhibition, and caused decreased expression of the type I collagen gene.
Conclusion: This study is the first showing involvement of the Rho/Rho kinase pathway in radiation fibrosis and intestinal smooth muscle cell fibrogenic differentiation. It suggests that specific inhibition of Rho kinase may be a promising approach for the development of antifibrotic therapies.
Abbreviations: CTGF, connective tissue growth factor; /
-sm actin, / smooth muscle actin; HSP, heat shock protein; ROCK, Rho kinase; N/RE SMC, normal/radiation enteritis smooth muscle cells; COL1A1, type I collagen alpha 1; MLCK, myosin light chain kinase; RT-PCR, reverse transcription-polymerase chain reaction; EMSA, electrophoretic mobility shift assay; PAGE, polyacrylamide gel electrophoresis; NFB, nuclear factor B; TNF-, tumour necrosis factor ; TGF-ß1, transforming growth factor ß1
Keywords: connective tissue growth factor; intestinal smooth muscle cells; Rho pathway; fibrosis; radiotherapy
This article has been cited by other articles:
|
|
 |
|
  V. Haydont, B. L. Riser, J. Aigueperse, and M.-C. Vozenin-Brotons Specific signals involved in the long-term maintenance of radiation-induced fibrogenic differentiation: a role for CCN2 and low concentration of TGF-{beta}1 Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1332 - C1341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bourgier, M.-C. Vozenin-Brotons, and R. Arriagada Enhanced Local Control by Radiation Boost in Breast Cancer: Back Side of the Coin? J. Clin. Oncol., December 20, 2007; 25(36): 5841 - 5843. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Haydont, C. Bourgier, M. Pocard, A. Lusinchi, J. Aigueperse, D. Mathe, J. Bourhis, and M.-C. Vozenin-Brotons Pravastatin Inhibits the Rho/CCN2/Extracellular Matrix Cascade in Human Fibrosis Explants and Improves Radiation-Induced Intestinal Fibrosis in Rats Clin. Cancer Res., September 15, 2007; 13(18): 5331 - 5340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V Haydont, C Bourgier, and M-C Vozenin-Brotons Rho/ROCK pathway as a molecular target for modulation of intestinal radiation-induced toxicity Br. J. Radiol., September 1, 2007; 80(Special_Issue_1): S32 - S40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Chaqour, R. Yang, and Q. Sha Mechanical Stretch Modulates the Promoter Activity of the Profibrotic Factor CCN2 through Increased Actin Polymerization and NF-{kappa}B Activation J. Biol. Chem., July 21, 2006; 281(29): 20608 - 20622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Thorlacius, J. E. Slotta, M. W. Laschke, Y. Wang, M. D. Menger, B. Jeppsson, and H. Thorlacius Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury J. Leukoc. Biol., May 1, 2006; 79(5): 923 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nubel, J. Damrot, W. P. Roos, B. Kaina, and G. Fritz Lovastatin Protects Human Endothelial Cells from Killing by Ionizing Radiation without Impairing Induction and Repair of DNA Double-Strand Breaks Clin. Cancer Res., February 1, 2006; 12(3): 933 - 939. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS | REGISTER |
