Dataset Information

Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction.

ABSTRACT:

Background

Wide applications of nanoparticles (NPs) have raised increasing concerns about safety to humans. Oxidative stress and inflammation are extensively investigated as mechanisms for NPs-induced toxicity. Autophagy and lysosomal dysfunction are emerging molecular mechanisms. Inhalation is one of the main pathways of exposing humans to NPs, which has been reported to induce severe pulmonary inflammation. However, the underlying mechanisms and, more specifically, the interplays of above-mentioned mechanisms in NPs-induced pulmonary inflammation are still largely obscure. Considered that NPs exposure in modern society is often unavoidable, it is highly desirable to develop effective strategies that could help to prevent nanomaterials-induced pulmonary inflammation.

Results

Pulmonary inflammation induced by intratracheal instillation of silica nanoparticles (SiNPs) in C57BL/6 mice was prevented by PJ34, a poly (ADP-ribose) polymerase (PARP) inhibitor. In human lung bronchial epithelial (BEAS-2B) cells, exposure to SiNPs reduced cell viability, and induced ROS generation, impairment in lysosome function and autophagic flux. Inhibition of ROS generation, PARP and TRPM2 channel suppressed SiNPs-induced lysosome impairment and autophagy dysfunction and consequent inflammatory responses. Consistently, SiNPs-induced pulmonary inflammation was prevented in TRPM2 deficient mice.

Conclusion

The ROS/PARP/TRPM2 signaling is critical in SiNPs-induced pulmonary inflammation, providing novel mechanistic insights into NPs-induced lung injury. Our study identifies TRPM2 channel as a new target for the development of preventive and therapeutic strategies to mitigate nanomaterials-induced lung inflammation.

SUBMITTER: Wang M

PROVIDER: S-EPMC7281956 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction.

Wang Mingxiang M Li Jin J Dong Shunni S Cai Xiaobo X Simaiti Aili A Yang Xin X Zhu Xinqiang X Luo Jianhong J Jiang Lin-Hua LH Du Binyang B Yu Peilin P Yang Wei W

Particle and fibre toxicology 20200608 1

<h4>Background</h4>Wide applications of nanoparticles (NPs) have raised increasing concerns about safety to humans. Oxidative stress and inflammation are extensively investigated as mechanisms for NPs-induced toxicity. Autophagy and lysosomal dysfunction are emerging molecular mechanisms. Inhalation is one of the main pathways of exposing humans to NPs, which has been reported to induce severe pulmonary inflammation. However, the underlying mechanisms and, more specifically, the interplays of ab ...[more]

PMID: 32513195

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Project description:Background Hypertension and vascular toxicity are major unwanted side effects of antiangiogenic drugs, such as vascular endothelial growth factor inhibitors (VEGFis), which are effective anticancer drugs but have unwanted side effects, including vascular toxicity and hypertension. Poly (ADP-ribose) polymerase (PARP) inhibitors, used to treat ovarian and other cancers, have also been associated with elevated blood pressure. However, when patients with cancer receive both olaparib, a PARP inhibitor, and VEGFi, the risk of blood pressure elevation is reduced. Underlying molecular mechanisms are unclear, but PARP-regulated transient receptor potential cation channel, subfamily M, member 2 (TRPM2), a redox-sensitive calcium channel, may be important. We investigated whether PARP/TRPM2 plays a role in VEGFi-induced vascular dysfunction and whether PARP inhibition ameliorates the vasculopathy associated with VEGF inhibition. Methods and Results Human vascular smooth muscle cells (VSMCs), human aortic endothelial cells, and wild-type mouse mesenteric arteries were studied. Cells/arteries were exposed to axitinib (VEGFi) alone and in combination with olaparib. Reactive oxygen species production, Ca2+ influx, protein/gene analysis, PARP activity, and TRPM2 signaling were assessed in VSMCs, and nitric oxide levels were determined in endothelial cells. Vascular function was assessed by myography. Axitinib increased PARP activity in VSMCs in a reactive oxygen species-dependent manner. Endothelial dysfunction and hypercontractile responses were ameliorated by olaparib and a TRPM2 blocker (8-Br-cADPR). VSMC reactive oxygen species production, Ca2+ influx, and phosphorylation of myosin light chain 20 and endothelial nitric oxide synthase (Thr495) were augmented by axitinib and attenuated by olaparib and TRPM2 inhibition. Proinflammatory markers were upregulated in axitinib-stimulated VSMCs, which was reduced by reactive oxygen species scavengers and PARP-TRPM2 inhibition. Human aortic endothelial cells exposed to combined olaparib and axitinib showed nitric oxide levels similar to VEGF-stimulated cells. Conclusions Axitinib-mediated vascular dysfunction involves PARP and TRPM2, which, when inhibited, ameliorate the injurious effects of VEGFi. Our findings define a potential mechanism whereby PARP inhibitor may attenuate vascular toxicity in VEGFi-treated patients with cancer.

Dataset Information

Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction.

Background

Results

Conclusion

Publications

Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction.

Similar Datasets

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