Characterization of Early and Late Damage in a Mouse Model of Pelvic Radiation Disease

Author:

Vitali Roberta1ORCID,Palone Francesca1ORCID,De Stefano Ilaria1,Fiorente Chiara1ORCID,Novelli Flavia1ORCID,Pasquali Emanuela1,Fratini Emiliano1ORCID,Tanori Mirella1ORCID,Leonardi Simona1,Tanno Barbara1ORCID,Colantoni Eleonora1,Soldi Sara2,Galletti Serena2,Grimaldi Maria3,Morganti Alessio Giuseppe4ORCID,Fuccio Lorenzo4,Pazzaglia Simonetta1,Pioli Claudio1ORCID,Mancuso Mariateresa1ORCID,Vesci Loredana3

Affiliation:

1. Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy

2. AAT Advanced Analytical Technologies Srl, Via P. Majavacca 12, 29017 Fiorenzuola d’Arda (PC), Italy

3. Corporate R&D, Alfasigma S.p.A., Via Pontina km 30.400, 00071 Pomezia, Italy

4. Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-Università di Bologna, Via Zamboni 33, 40126 Bologna, Italy

Abstract

Pelvic radiation disease (PRD), a frequent side effect in patients with abdominal/pelvic cancers treated with radiotherapy, remains an unmet medical need. Currently available preclinical models have limited applications for the investigation of PRD pathogenesis and possible therapeutic strategies. In order to select the most effective irradiation protocol for PRD induction in mice, we evaluated the efficacy of three different locally and fractionated X-ray exposures. Using the selected protocol (10 Gy/day × 4 days), we assessed PRD through tissue (number and length of colon crypts) and molecular (expression of genes involved in oxidative stress, cell damage, inflammation, and stem cell markers) analyses at short (3 h or 3 days after X-ray) and long (38 days after X-rays) post-irradiation times. The results show that a primary damage response in term of apoptosis, inflammation, and surrogate markers of oxidative stress was found, thus determining a consequent impairment of cell crypts differentiation and proliferation as well as a local inflammation and a bacterial translocation to mesenteric lymph nodes after several weeks post-irradiation. Changes were also found in microbiota composition, particularly in the relative abundance of dominant phyla, related families, and in alpha diversity indices, as an indication of dysbiotic conditions induced by irradiation. Fecal markers of intestinal inflammation, measured during the experimental timeline, identified lactoferrin, along with elastase, as useful non-invasive tools to monitor disease progression. Thus, our preclinical model may be useful to develop new therapeutic strategies for PRD treatment.

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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