Inhibition of neutrophil degranulation attenuates the development of radiation-induced pulmonary fibrosis

Authors list

Stefanie Ruhland Konstantina Nikolatou Vicky Bridgeman Tatiana Rizou Jayanta Bordoloi Erik Sahai Emma Nolan Alberto Elosegui Artola Ilaria Malanchi

Scroll for detail on labs, facilities & authors

Abstract

Despite advances in radiation delivery techniques that enhance tumour targeting and minimise collateral exposure, healthy tissues remain susceptible to radiation-induced fibrosis, a chronic and progressive condition that can severely compromise patient quality of life. Therapeutic options to prevent or treat radiation-induced fibrosis remain limited. Recent work has shown that neutrophils infiltrating healthy lung tissue after irradiation adopt an activated phenotype capable of perturbing cellular responses of both epithelial and mesenchymal cells. Although neutrophils are known contributors to the early inflammatory response after tissue injury, their direct role in driving the development of radiation-induced fibrosis, as well as their targetability for therapeutic intervention, remains unclear. We used targeted, image-guided lung irradiation to deliver a dose sufficient to induce fibrosis in mice within four months and demonstrated that neutrophils are essential for the efficient development of clinically evident fibrosis. Post-irradiated lung tissue educated neutrophils, enabling them to promote alterations in the extracellular matrix as early as two weeks after radiation exposure. We further showed that this “educated” phenotype persisted in the tissue long-term and depended on neutrophil degranulation. Pharmacological inhibition of degranulation with Nexinhib20 redirected these cells toward a pro-angiogenic and anti-fibrotic phenotype. Interestingly, this was also associated with a transcriptional shift in the mesenchymal cell population away from a pro-fibrotic program. We identified an early therapeutic window of one month, where Nexinhib20 treatment resulted in a marked reduction of radiation-induced fibrosis three months later. Importantly, Nexinhib20 did not impair the efficacy of cancer radiotherapy. Overall, we present that inhibiting neutrophil degranulation with Nexinhib20 has potential as a therapeutic strategy to prevent fibrotic complications without compromising anti-tumour effectiveness.