Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity.
The medical options available to prevent or treat radiation-induced injury are scarce and developing effective countermeasures is still an open research field. In addition, more than half of cancer patients are treated with radiation therapy, which displays a high antitumor efficacy but can cause, albeit rarely, disabling long-term toxicities including radiation fibrosis. Progress has been made in the definition of molecular pathways associated with normal tissue toxicity that suggest potentially effective therapeutic targets. Targeting the Rho/ROCK pathway seems a promising anti-fibrotic approach, at least in the gut; the current study was performed to assess whether this target was relevant to the prevention and/or treatment of injury to the main thoracic organs, namely heart and lungs. First, we showed activation of two important fibrogenic pathways (Smad and Rho/ROCK) in response to radiation-exposure to adult cardiomyocytes; we extended these observations in vivo to the heart and lungs of mice, 15 and 30 weeks post-irradiation. We correlated this fibrogenic molecular imprint with alteration of heart physiology and long-term remodelling of pulmonary and cardiac histological structures. Lastly, cardiac and pulmonary radiation injury and bleomycin-induced pulmonary fibrosis were successfully modulated using Rho/ROCK inhibitors (statins and Y-27632) and this was associated with a normalization of fibrogenic markers. In conclusion, the present paper shows for the first time, activation of Rho/ROCK and Smad pathways in pulmonary and cardiac radiation-induced delayed injury. Our findings thereby reveal a safe and efficient therapeutic opportunity for the abrogation of late thoracic radiation injury, potentially usable either before or after radiation exposure; this approach is especially attractive in (1) the radiation oncology setting, as it does not interfere with prior anti-cancer treatment and in (2) radioprotection, as applicable to the treatment of established radiation injury, for example in the case of radiation accidents or acts of terrorism.
Monceau
Virginie
V
UPRES EA 27-10 Radiosensibilité des tumeurs et tissus sains, Institut de Radioprotection et de Sûreté Nucléaire/Institut Gustave Roussy, Villejuif, France.
Pasinetti
Nadia
N
Schupp
Charlotte
C
Pouzoulet
Fred
F
Opolon
Paule
P
Vozenin
Marie-Catherine
MC
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology / Q000528:radiation effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D017035:Pravastatin / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011832:Radiation Injuries / Q000378:metabolism / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000378:metabolism / Q000517:prevention & control; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013909:Thorax / Q000528:radiation effects*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000577:Amides; C526318:CCN2 protein, mouse; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D001761:Bleomycin; C108830:Y 27632; D055513:Connective Tissue Growth Factor; D019821:Simvastatin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020743:rhoB GTP-Binding Protein; D017035:Pravastatin