Efferocytosis and enhanced FPR2 expression following apoptotic cell instillation attenuate radiation-induced lung inflammation and fibrosis

Kim, Sang Yeon; Kim, JinMo; Lee, Son Ro; Kim, Hyun‐Jin; Lee, Jae Hee; Choi, Ho Lim; Lee, Yoonjin; Lee, Yun‐Sil; Cho, Jaeho

doi:10.1016/j.bbrc.2022.02.075

Cited by 6 publications

(4 citation statements)

References 26 publications

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“…FPR2 is expressed in the surface of numerous cell types like neutrophils, monocytes, macrophages, T-cells, enterocytes, airway epithelium, fibroblasts and intestinal epithelial cells (28, 29). Studies have shown that activation of FPR2 receptors offers protection in animal models of lung injury (30,31). The interaction of LxA4 with FPR2 to provide protection was recently shown in a mice model of endotoxin induced acute lung injury (32).…”

Section: Discussionmentioning

confidence: 99%

Lipoxin A₄/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury

Kollareth,

Leroy,

et al. 2024

Preprint

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BACKGROUND: Post-lung transplantation (LTx) injury can involve sterile inflammation due to ischemia-reperfusion injury (IRI). We investigated the cell-specific role of ferroptosis (excessive iron-mediated cell death) in mediating lung IRI and determined if specialized pro-resolving mediators such as Lipoxin A4 (LxA4) can protect against ferroptosis in lung IRI. METHODS: Single-cell RNA sequencing of lung tissue from post-LTx patients was analyzed. Lung IRI was evaluated in C57BL/6 (WT), formyl peptide receptor 2 knockout (Fpr2-/-) and nuclear factor erythroid 2-related factor 2 knockout (Nrf2-/-) mice using a hilar-ligation model with or without LxA4 administration. Furthermore, the protective efficacy of LxA4 was evaluated employing a murine orthotopic LTx model and in vitro studies using alveolar type II epithelial (ATII) cells. RESULTS: Differential expression of ferroptosis-related genes was observed in post-LTx patient samples compared to healthy controls. A significant increase in the levels of oxidized lipids and reduction in the levels of intact lipids were observed in mice subjected to IRI compared to shams. Furthermore, pharmacological inhibition of ferroptosis with liproxstatin-1 mitigated lung IRI and lung dysfunction. Importantly, LxA4 treatment attenuated pulmonary dysfunction, ferroptosis and inflammation in WT mice subjected to lung IRI, but not in Fpr2-/- or Nrf2-/- mice, after IRI. In the murine LTx model, LxA4 treatment increased PaO2 levels and attenuated lung IRI. Mechanistically, LxA4-mediated protection involves increase in NRF2 activation and glutathione concentration as well as decrease in MDA levels in ATII cells. CONCLUSIONS: LxA4/FPR2 signaling on ATII cells mitigates ferroptosis via NRF2 activation and protects against lung IRI.

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Section: Discussionmentioning

confidence: 99%

Lipoxin A₄/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury

Kollareth,

Leroy,

et al. 2024

Preprint

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“…11,20,21 Inflammatory reaction and oxidative stress always play important roles in the development of the disease. 43 When the body is stimulated by a range of pathogenic factors, such as dust and viruses, inflammatory reactions are triggered and various inflammatory cells start to infiltrate the lung tissue. 44 These inflammatory cells can trigger the production of cytokines including TGF-β1, IL-6 and IL-18, 45 all of which promote fiber proliferation.…”

Section: Discussionmentioning

confidence: 99%

Antifibrotic effect of AD-1 on lipopolysaccharide-mediated fibroblast injury in L929 cells and bleomycin-induced pulmonary fibrosis in mice

Chen

et al. 2022

Food Funct.

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“…The dose response with respect to induction of fibrosis was previously determined to be 6 weeks after ionizing radiation (IR) [15][16][17]. Mice were weighed once a week during the 6 weeks of NXC736 administration.…”

Section: Treatment With Nxc76 Changed Gross Morphological Findings An...mentioning

confidence: 99%

“…Additionally, previously we developed a mouse model that simulated clinical stereotactic body radiotherapy and validated the induction of RILF [15]. Thus, using this model, in this study we investigated the effects of NXC736 on the regulation of EMT and pulmonary fibrosis by inhibiting the signaling pathways of NLRP3 and IL-1β in RILF, with the goal of assessing its potential as a pulmonary fibrosis inhibitory drug.…”

Section: Introductionmentioning

confidence: 99%

NXC736 Attenuates Radiation-Induced Lung Fibrosis via Regulating NLRP3/IL-1β Signaling Pathway

Kim,

Park,

Cui

et al. 2023

IJMS

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Radiation-induced lung fibrosis (RILF) is a common complication of radiotherapy in lung cancer. However, to date no effective treatment has been developed for this condition. NXC736 is a novel small-molecule compound that inhibits NLRP3, but its effect on RILF is unknown. NLRP3 activation is an important trigger for the development of RILF. Thus, we aimed to evaluate the therapeutic effect of NXC736 on lung fibrosis inhibition using a RILF animal model and to elucidate its molecular signaling pathway. The left lungs of mice were irradiated with a single dose of 75 Gy. We observed that NXC736 treatment inhibited collagen deposition and inflammatory cell infiltration in irradiated mouse lung tissues. The damaged lung volume, evaluated by magnetic resonance imaging, was lower in NXC736-treated mice than in irradiated mice. NXC736-treated mice exhibited significant changes in lung function parameters. NXC736 inhibited inflammasome activation by interfering with the NLRP3-ASC-cleaved caspase-1 interaction, thereby reducing the expression of IL-1β and blocking the fibrotic pathway. In addition, NXC736 treatment reduced the expression of epithelial–mesenchymal transition markers such as α-SMA, vimentin, and twist by blocking the Smad 2,3,4 signaling pathway. These data suggested that NXC736 is a potent therapeutic agent against RILF.

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Efferocytosis and enhanced FPR2 expression following apoptotic cell instillation attenuate radiation-induced lung inflammation and fibrosis

Cited by 6 publications

References 26 publications

Lipoxin A₄/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury

Lipoxin A₄/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury

Antifibrotic effect of AD-1 on lipopolysaccharide-mediated fibroblast injury in L929 cells and bleomycin-induced pulmonary fibrosis in mice

NXC736 Attenuates Radiation-Induced Lung Fibrosis via Regulating NLRP3/IL-1β Signaling Pathway

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Efferocytosis and enhanced FPR2 expression following apoptotic cell instillation attenuate radiation-induced lung inflammation and fibrosis

Cited by 6 publications

References 26 publications

Lipoxin A4/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury

Lipoxin A4/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury

Antifibrotic effect of AD-1 on lipopolysaccharide-mediated fibroblast injury in L929 cells and bleomycin-induced pulmonary fibrosis in mice

NXC736 Attenuates Radiation-Induced Lung Fibrosis via Regulating NLRP3/IL-1β Signaling Pathway

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Lipoxin A₄/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury

Lipoxin A₄/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury