Benoit Petit

Antifibrotic, Antioxidant, and Immunomodulatory Effects of Mesenchymal Stem Cells in HOCl-Induced Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare intractable disease with unmet medical need and fibrosis‐related mortality. Absence of efficient treatments has prompted the development of novel therapeutic strategies, among which mesenchymal stem cells/stromal cells (MSCs) or progenitor stromal cells appear to be one of the most attractive options. The purpose of this study was to use the murine model of hypochlorite‐induced SSc to investigate the systemic effects of MSCs on the main features of the diffuse form of the disease: skin and lung fibrosis, autoimmunity, and oxidative status.

Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100 Gy/s

This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate. Spatial memory is preserved after WBI with mean dose rates above 100Gy/s, whereas 10Gy WBI at a conventional radiotherapy dose rate (0.1Gy/s) totally impairs spatial memory.

Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis

BACKGROUND Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. METHODS The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. RESULTS In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. CONCLUSION Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.

The advantage of Flash radiotherapy confirmed in mini-pig and cat-cancer patients

Purpose: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Experimental Design: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. Results: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. Conclusions: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients. See related commentary by Harrington, p. 3

X-rays can trigger the FLASH effect: Ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice

This study is the first proof of concept that the FLASH effect can be triggered by X-rays. Our results show that a 10 Gy whole-brain irradiation delivered at ultra-high dose-rate with synchrotron generated X-rays does not induce memory deficit; it reduces hippocampal cell-division impairment and induces less reactive astrogliosis.

SP-0014: Radiation-induced lung fibrosis is associated with M2 interstitial and hybrid alveolar macrophages

Radiation-induced fibrosis is a delayed complication of radiotherapy often associated with chronic inflammatory process and macrophage infiltration. Nowadays, macrophages are suggested to be important cellular contributors to fibrogenic process, but their implication in the context of RIF is not well known. To investigate the role of macrophages in RIF we have used a classical experimental model of lung fibrosis developed in C57Bl/6 mice after 16Gy thorax-IR. We then profiled both alveolar macrophages (AM) and interstitial macrophages (IM) during the various steps of the fibrogenic process. We confirmed the fact that total lung irradiation at 16Gy (IR) induces an interstitial fibrosis associated with delayed recruitment of pulmonary macrophages. We found a transient depletion of AM associated with cytokine secretion during the acute post-IR phase (15 days), followed by an active repopulation and an enhanced number of AM during the late post-IR phase (20 weeks). Interestingly, AM were mostly recruited from the bone marrow and exhibit a hybrid polarization (M1/M2) associated with up-regulation of Th1 and Th2 cytokines. The number of M2-polarized IM significantly increased during the late time points after irradiation and a down-regulation of Th1 cytokine was measured in tissue lysate. These results suggest a differential contribution of hybrid AM vsM2-IM to fibrogenesis. Interestingly, in contrast to activated hybrid AM, activated M2-IM were able to induce fibroblast activation in vitro mediated by an enhanced TGF-β1 expression suggesting a profibrotic role of M2-IM. Specific depletion of hybrid AM using intranasal administration of clodrosome increased radiation-induced fibrosis score and enhanced M2-IM infiltration suggesting a protective role of hybrid AM. These present study shows a dual and opposite contribution of alevolar versus intertitial macrophages in radiationinduced fibrosis and identify M2-IM as a potential therapeutic target to treat radiation-induced fibrosis.