ESTRO 2024 - Abstract Book

S5243

Radiobiology - Normal tissue radiobiology

ESTRO 2024

640

Digital Poster

Club cell depletion worsen tissue damage in response to small volume irradiation on the mouse lung

Sarmini BAVANANTHAN 1 , Morgane DOS SANTOS 2 , Fabien MILLIAT 1 , Agnès FRANCOIS 1

1 Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE/SERAMED/LRMED, Fontenay-aux-roses, France. 2 Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE/SERAMED/LRACC, Fontenay-aux roses, France

Purpose/Objective:

Stereotactic body radiation therapy (SBRT) is currently used for the treatment of early stage broncho pulmonary tumors for patients with high surgery risk. It involves the irradiation of small tumor volumes using converging mini beams. Volume reduction and precise targeting allow to used high doses per fraction (1). Despite good tumor control obtained with severe hypofractionation, some patients may develop radiation pneumonitis and lung fibrosis. Recently, the laboratory set up a stereotactic mouse lung irradiation model with a SARRP (Small Animal Radiation Research Platform). Exposing rodent small lung volumes accurately approximates clinical conditions when applying new radiotherapy protocols to early-stage bronchopulmonary cancers. Our previous studies have shown that irradiation of very small volumes of the mouse lung generates inflammatory and fibrotic lesions, with a significant loss of a particular cell type of the bronchiolic epithelium, the club cells (2). Club cells secrete uteroglobin (UGB or CCSP for Club Cell Secretory Protein), a protein involved in epithelial protection. They participate in the detoxification of inhaled harmful substances, thanks to their high cytochrome P450 activity. They play an overall role in protecting the epithelium via their immunomodulatory, antioxidant and regenerative capacities (3). Dysregulation of CCSP protein production has been observed in various human pathologies such as acute respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease. Numerous research projects are currently underway to determine the therapeutic opportunities offered using CCSP in a wide range of acute and chronic lung diseases (4). However, little is known about the role of club cells in the response of lung tissue to ionizing radiation. The aim of this project is to study the response of the bronchoalveolar epithelium, particularly after high doses of irradiation on small volumes of the mouse lung, and in particular the role of club cells in the development of radiation-induced lung damage. In C57Bl6/J mice, transient club cell depletion is induced by intraperitoneal injection of naphthalene, NA, (or corn oil, CO, its vehicle), an aromatic hydrocarbon specifically toxic to club cells. It is classically used as a model for club cell depletion in the literature (5). Irradiation is performed with a SARRP, using a 3x3mm2 collimated beam and a single dose of 80 Gy delivered in arc on the left lung, generating focal acute inflammation and lung fibrosis. Radiation exposure is performed either three days after naphthalene injection, at club cell nadir, or 14 days after naphthalene injection, when club cells had returned. Lung tissue is studied at 1 month (inflammation) and 6 months (fibrosis) post-exposure, using micro-computed tomography and anatomopathological and immunohistological analyses. Here we suggest hypotheses only with results from the 1-month time point, analyses of the 6-month time point are ongoing. Material/Methods:

Results:

Irradiation generated severe tissue inflammation and complete loss of lung architecture in the exposed volume as observed on HES tissue sections 1-month post-exposure. Damaged area was characterized by radiation induced loss of club cells and reduced bronchiolic epithelial cell numbers. NA-treated mice showed more diffuse