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Mitigating radiation induced skin fibrosis through Rosiglitazone mediated targeting of macrophages
Jorge Flores Garcia, Barbara Granicz, Sabita Pokhrel, Subrahmanya Vallabhapurapu, Michael Sorkin MD*
The Ohio State University College of Medicine
2024-01-15
Presenter: Jorge Flores Garcia
Affidavit:
This work is the original work of The Ohio State University College of Medicine and the Department of Plastic and Reconstructive Surgery, comprised of the authors listed in the abstract. Jorge is a member of this group and has contributed a significant and appropriate portion of the created work.
Director Name: Gregory Pearson, MD
Author Category: Medical Student
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
Background: Radiation therapy is a fundamental modality in the treatment of cancer. However, radiation-induced skin fibrosis (RISF) remains a significant limitation and poses extensive reconstructive challenges in our field. The underlying mechanisms are poorly understood and curative therapy is lacking. Macrophages and fibroblasts are thought to play important roles in fibrosis progression, yet the specific alterations in their phenotype, function, and gene expression require further investigation. In this study, we explore the interaction of macrophages and fibroblasts in the development of RISF. Furthermore, we utilize Rosiglitazone, a drug shown to modulate macrophage function, to mitigate RISF.
Methods: We use an in vitro fibrosis model of co-cultured murine macrophages and fibroblasts. Collagen gel contraction (CGC) assays were used to study the effect of radiation and rosiglitazone treatment. Flow cytometry, bulk RNA-sequencing, and qPCR were performed to characterize the phenotype, function and global gene expression profiles of macrophages and fibroblasts subjected to radiation and rosiglitazone treatment.
Results: Our findings reveal radiation induced skewing of macrophages towards a pro-fibrotic M2 phenotype. Radiated macrophages demonstrated the strongest induction of CGC. In addition, RNA-sequencing uncovered global gene expression changes in inflammatory and pro-fibrotic pathways in radiated macrophages. Therapeutically, rosiglitazone administration attenuated CGC and reprogrammed radiated macrophages to a less fibrotic phenotype, decreasing expression of NOS2 and CCR5.
Conclusion: Our study provides mechanistic insight into the intricate relationship between RISF and macrophage biology. The ability of rosiglitazone to abolish pro-fibrotic function of radiated macrophages suggests a promising avenue for therapeutic intervention in RISF.
