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Identification of a Pre-Fibrotic Inflammatory and Apoptotic Phase Following Extremity Radiation
Alex G. Lambi
*1, Brendan Hilliard
2, Frank L. Chen
2, Lewis Bright-Rowe
2, Ryan E. Tomlinson
3, Mary F. Barbe
21University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 2Lewis Katz School of Medicine at Temple University, Philadelphia, PA; 3Thomas Jefferson University, Philadelphia, PA
BACKGROUND: Radiation-induced fibrosis develops months to years after exposure, suggesting an early inflammatory phase that may be amenable to intervention. We sought to identify early systemic and tissue changes following extremity irradiation.
METHODS: Studies were conducted on 20 young adult female, Sprague-Dawley rats (IACUC-approved). We constructed a beam restriction and shielding device to limit irradiation to the elbow-digits, connected through a manifold for isoflurane anesthesia. Rats underwent forelimb irradiation (5, 10, or 20 Gy), with contralateral limbs serving as controls. Blood and tissue were analyzed at baseline, 1 day, and 12 days post-irradiation. Serum inflammatory markers and oxidative stress (TNF-alpha, MDA) were assessed. Muscle tissue was analyzed for apoptotic signaling (Beclin-1, caspase-3) and collagen production.
RESULTS: Radiation induced early systemic inflammatory and oxidative responses (Fig. 1), with increased TNF-alpha and MDA at the early timepoint (1 day) but not the latter time point (12 days). Peripheral blood demonstrated dynamic immune shifts, including early lymphocyte increases followed by monocytic predominance. Muscle tissue exhibited increased apoptotic signaling at 12 days. In contrast, collagen production was not increased.
CONCLUSION: These findings demonstrate a pre-fibrotic phase characterized by inflammation and apoptosis in the absence of collagen deposition. This early biologic window may represent an opportunity for targeted interventions following radiation therapy to prevent progression to irreversible fibrosis.
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