Abstract
Radiation therapy is an important modality in the treatment of lung cancer, but it can lead to radiation pneumonitis, and eventually radiation fibrosis. To date, only few available drugs can effectively manage radiation-induced pulmonary fibrosis. Lipoxins are endogenous molecules exhibit anti-inflammatory and pro-resolving effects. These molecules play a vital role in reducing excessive tissue injury and chronic inflammation; however, their effects on radiation-induced lung injury (RILI) are unknown. In this study, we investigated the effects of lipoxin A4 (LXA4) on RILI using our specialized small-animal model of RILI following focal-ablative lung irradiation (IR). LXA4 significantly inhibited immune-cell recruitment and reduced IR-induced expression of pro-inflammatory cytokines and fibrotic proteins in the lung lesion sites. In addition, micro-CT revealed that LXA4 reduced IR-induced increases in lung consolidation volume. The flexiVentTM assays showed that LXA4 significantly reversed IR-induced lung function damage. Moreover, LXA4 downregulated the activities of NF-κB and the Smad-binding element promoters. The expression of FPR2, an LXA4 receptor, increased during the development of IR-induced pulmonary fibrosis, whereas silencing of endogenous LXA4 using an antagonist (WRW4) or FPR2 siRNA resulted in impaired development of pulmonary fibrosis in response to IR. Collectively, these data suggest that LXA4 could serve as a potent therapeutic agent for alleviating RILI.
Highlights
Radiation therapy is an important modality for treating lung cancer
We investigated whether lipoxin A4 (LXA4) regulates proteins that are important for EMT, whether the crosstalk between LXA4-ALX/FPR2 and transforming growth factor β (TGF-β)/Smad signaling plays a key role in EMT
IR increases inflammatory reactions, thereby causing inflammatory cells to accumulate in the lesion sites of lung tissue, enhancing inflammatory cytokine expression (IL-6, IL-1b, and TGF-β) in lung tissues, and recruiting immune cells in BALF6,28
Summary
Radiation therapy is an important modality for treating lung cancer. Generally, it is necessary to increase the radiation dose to control the tumor by radiation, but higher radiation dose results in higher probability of developing side effects. Radiation pneumonitis develops within hours or days of lung IR and is accompanied by increased capillary permeability, leukocyte infiltration, and release of cytokines, such as transforming growth factor β (TGF-β), interleukin. Subsequent alveolar lung inflammation and Official journal of the Cell Death Differentiation Association. Kim et al Cell Death and Disease (2020)11:653 persistent inflammation may lead to symptomatic phases, including pulmonary fibrosis[9,10]. Alveolar epithelial cells (AECs) are another important source of myofibroblasts and may differentiate into myofibroblasts during idiopathic pulmonary fibrosis and radiation-induced pulmonary fibrosis. This epithelial or endothelial–mesenchymal transition (EMT or EndMT) is generally known to be involved in the development of pulmonary fibrosis[13]. NF-κB signaling—an important regulator of inflammatory responses—and TGF-β/Smad signaling are important regulatory mechanisms of EMT12,13,15
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