The toxicity of silica nanoparticles (SiNPs) to lung is known. We previously demonstrated that exposure to SiNPs promoted pulmonary impairments, but the precise pathogenesis remains elucidated. Ferroptosis has now been identified as a unique form of oxidative cell death, but whether it participated in SiNPs-induced lung injury remains unclear. In this work, we established a rat model with sub-chronic inhalation exposure of SiNPs via intratracheal instillation, and conducted histopathological examination, iron detection, and ferroptosis-related lipid peroxidation and protein assays. Moreover, we evaluated the effect of SiNPs on epithelial ferroptosis, possible mechanisms using in vitro-cultured human bronchial epithelial cells (16HBE), and also assessed the ensuing impact on fibroblast activation for fibrogenesis. Consequently, fibrotic lesions occurred in the rat lungs, concomitantly by enhanced lipid peroxidation, iron overload, and ferroptosis. Consistently, the in vitro data showed SiNPs triggered oxidative stress and caused the accumulation of lipid peroxides, resulting in ferroptosis. Importantly, the mechanistic investigation revealed miR-21-5p as a key player in the epithelial ferroptotic process induced by SiNPs via targeting GCLM for GSH depletion. Of note, ferrostatin-1 could greatly suppress ferroptosis and alleviate epithelial injury and ensuing fibroblast activation by SiNPs. In conclusion, our findings first revealed SiNPs triggered epithelial ferroptosis through miR-21-5p/GCLM signaling and thereby promoted fibroblast activation for fibrotic lesions, and highlighted the therapeutic potential of inhibiting ferroptosis against lung impairments upon SiNPs exposure.

Silicon dioxide nanoparticles (SiNPs) are one of the major forms of silicon dioxide and are composed of the most-abundant compounds on earth. Based on their excellent properties, SiNPs are widely used in food production, synthetic processes, medical diagnostics, drug delivery, and other fields. The mass production and wide application of SiNPs increases the risk of human exposure to SiNPs. In the workplace and environment, SiNPs mainly enter the human body through the respiratory tract and reach the lungs; therefore, the lungs are the most important and most toxicologically affected target organ of SiNPs. An increasing number of studies have shown that SiNP exposure can cause severe lung toxicity. However, studies on the toxicity of SiNPs in ex vivo and in vivo settings are still in the exploratory phase. The molecular mechanisms underlying the lung toxicity of SiNPs are varied and not yet fully understood. As a result, this review summarizes the possible mechanisms of SiNP-induced lung toxicity, such as oxidative stress, endoplasmic reticulum stress, mitochondrial damage, and cell death. Moreover, this study provides a summary of the progression of diseases caused by SiNPs, thereby establishing a theoretical basis for future studies on the mechanisms of SiNP-induced lung toxicity.

Micro/nanoplastics (MNP) are ubiquitous in the environment and multiple living organisms. The toxicity of some common types of MNP, e.g., polyethersulfone (PES) MNP, remains poorly understood. Multi-omics approaches were used in this study to determine the effects of foodborne and airborne PES MNP on liver and lung, respectively. Foodborne MNP were capable of inducing gut microbial dysbiosis, gut and serum metabolic disruption, and liver transcriptomic dysregulation, and affecting serum antioxidant activity and liver function, resulting in liver injury. As for the airborne MNP, they were found to induce nasal and lung microbial dysbiosis, serum and lung metabolic disruption, and liver transcriptome disturbance, and cause disrupted serum antioxidant activity and lung injury. Foodborne and airborne PES NP were found to respectively induce greater liver and lung toxicity than MP, which could be associated with the differences between NP and MP exposures. The relevant results suggest that foodborne PES MNP could disrupt the \"gut microbiota-gut-liver\" axis and induce hepatic injury, while airborne PES MNP could affect the \"airborne microbiota-lung\" axis and cause lung injury. The findings could benefit the diagnoses of liver and lung injury respectively induced by foodborne and airborne PES MNP, as well as the proper use of PES in human living environment.

Lead-based perovskite nanoparticles (Pb-PNPs) have found extensive applications across diverse fields. However, because of poor stability and relatively strong water solubility, the potential toxicity of Pb-PNPs released into the environment during their manufacture, usage, and disposal has attracted significant attention. Inhalation is a primary route through which human exposure to Pb-PNPs occurs. Herein, the toxic effects and underlying molecular mechanisms of Pb-PNPs in the respiratory system are investigated. The in vitro cytotoxicity of CsPbBr3 nanoparticles in BEAS-2B cells is studied using multiple bioassays and electron microscopy. CsPbBr3 nanoparticles of different concentrations induce excessive oxidative stress and cell apoptosis. Furthermore, CsPbBr3 nanoparticles specifically recruit the TGF-β1, which subsequently induces epithelial-mesenchymal transition. In addition, the biodistribution and lung toxicity of representative CsPbBr3 nanoparticles in ICR mice are investigated following intranasal administration. These findings indicate that CsPbBr3 nanoparticles significantly induce pulmonary inflammation and epithelial-mesenchymal transition and can even lead to pulmonary fibrosis in mouse models. Above findings expose the adverse effects and molecular mechanisms of Pb-PNPs in the lung, which broadens the safety data of Pb-PNPs.

Fine particulate matter (PM2.5) contributes to adverse health effects through the promotion of inflammatory cytokine release. Rosavidin (Ro), a phenylpropanoid compound having multiple biological activities, is extracted from Rhodiola crenulata, a medicine and food homology plant. However, the protective role and mechanism of Ro in PM2.5-induced lung toxicity have not been previously studied. This study aimed to investigate the potential protective effect and mechanism of Ro in PM2.5-induced lung toxicity. A lung toxicity rat model was established through trachea drip of PM2.5 suspension after the different dose pretreatment of Ro (50 mg/kg and 100 mg/kg) to evaluate the effect of Ro on PM2.5 caused lung toxicity. The results showed that Ro attenuated the pathological changes, edema, and inflammation response in rats. The PI3K/AKT signaling pathway may be associated with the protective effect of Ro against pulmonary toxicity. Subsequently, we verified the role of PI3K/AKT in the PM2.5 exposure lung tissue. Moreover, expression levels of p-PI3K and p-AKT were lower, and those of NLRP3, ASC, cleaved caspase-1, cleaved IL-1β, and GSDMD-N were higher in PM2.5 group compared to those in control group. Whereas pre-administration of Ro reversed the expression trends of these proteins in lung tissue. Notably, those protective effects of Ro were not observed after pretreatment with a combination of Ro with nigericin or LY294002. These results indicate that Ro mitigates PM2.5-caused lung toxicity by inhibiting NLRP3 inflammasome-mediated pyroptosis through activation of the PI3K/AKT signaling pathway.

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK TKIs) have shown remarkable clinical activity in patients with non-small-cell lung cancer (NSCLC). However, pneumonitis is a serious side effect of ALK TKIs in NSCLC patients. In this meta-analysis, we aimed to determine the incidence of ALK-TKI-associated pneumonitis.
We searched electronic databases to identify relevant studies published until August 2022. The incidence of pneumonitis was calculated using a fixed-effects model when no substantial heterogeneity was observed. Otherwise, a random-effects model was used. Subgroup analyses of different treatment groups were performed. Statistical analyses were conducted using STATA 17.0.
Twenty-six clinical trials involving 4752 patients were eligible for analysis. All-grade pneumonitis incidence was 2.92% (95% confidence interval [CI]: 1.79%-4.27%), high-grade (Grade 3-4) pneumonitis incidence was 1.42% (95% CI: 0.84%-2.12%) and Grade 5 pneumonitis incidence was 0.09% (95% CI: 0.00%-0.28%). The subgroup analysis showed that brigatinib was associated with the highest incidence of both all-grade and high-grade pneumonitis (7.09% and 3.06%, respectively). ALK TKI treatment after chemotherapy was associated with a higher incidence of all-grade and high-grade pneumonitis than first-line ALK TKI treatment (7.73% vs. 2.26% and 3.64% vs. 1.26%, respectively). Cohorts from Japanese trials had a higher incidence of all-grade and high-grade pneumonitis.
Our study provides precise data on the incidence of pneumonitis in patients receiving treatment with ALK TKIs. Overall, ALK TKIs have tolerable pulmonary toxicity. Early pneumonitis identification and treatment are required to prevent further deterioration in patients receiving treatment with brigatinib and in those who received prior chemotherapy, particularly in the Japanese population.

Exposure to fine particulate matter (PM2.5), an environmental pollutant, significantly contributes to the incidence of and risk of mortality associated with respiratory diseases. Sipeimine (Sip) is a steroidal alkaloid in fritillaries that exerts antioxidative and anti-inflammatory effects. However, protective effect of Sip for lung toxicity and its mechanism to date remains poorly understood. In the present study, we investigated the lung-protective effect of Sip via establishing the lung toxicity model of rats with orotracheal instillation of PM2.5 (7.5 mg/kg) suspension. Sprague-Dawley rats were intraperitoneally administered with Sip (15 mg/kg or 30 mg/kg) or vehicle daily for 3 days before instillation of PM2.5 suspension to establish the model of lung toxicity. The results found that Sip significantly improved pathological damage of lung tissue, mitigated inflammatory response, and inhibited lung tissue pyroptosis. We also found that PM2.5 activated the NLRP3 inflammasome as evidenced by the upregulation levels of NLRP3, cleaved-caspase-1, and ASC proteins. Importantly, PM2.5 could trigger pyroptosis by increased levels of pyroptosis-related proteins, including IL-1β, cleaved IL-1β, and GSDMD-N, membrane pore formation, and mitochondrial swelling. As expected, all these deleterious alterations were reversed by Sip pretreatment. These effects of Sip were blocked by the NLRP3 activator nigericin. Moreover, network pharmacology analysis showed that Sip may function via the PI3K/AKT signaling pathway and animal experiment validate the results, which revealed that Sip inhibited NLRP3 inflammasome-mediated pyroptosis by suppressing the phosphorylation of PI3K and AKT. Our findings demonstrated that Sip inhibited NLRP3-mediated cell pyroptosis through activation of the PI3K/AKT pathway in PM2.5-induced lung toxicity, which has a promising application value and development prospect against lung injury in the future.

Pollution from fine particulate matter (PM2.5) has become a major threat to public health and has been related to lung toxicity. One of the key regulators of the Hippo signaling system, Yes-associated protein 1 (YAP1), is speculated to play a role in ferroptosis development. Here, we focused on investigating the function of YAP1 in pyroptosis and ferroptosis, aiming to explore its therapeutic potential in PM2.5-induced lung toxicity. PM2.5-induced lung toxicity was induced in Wild-type WT and conditional YAP1-knockout mice, and lung epithelial cells were stimulatd by PM2.5 in vitro. We used western blot, transmission electron microscopy, and fluorescence microscopy to investigate pyroptosis- and ferroptosis-related characteristics. We found that PM2.5 leads to lung toxicity using mechanisms involving pyroptosis and ferroptosis. YAP1 knockdown impeded pyroptosis, ferroptosis, and PM2.5-induced lung damage, as shown by increased histopathology, higher levels of proinflammatory cytokines, GSDMD protein, lipid peroxidation, and iron accumulation, as well as increased NLRP3 inflammasome activation and decreased SLC7A11 expression. YAP1 silencing consistently promoted NLRP3 inflammasome activation and reduced SLC7A11 levels, aggravating PM2.5-induced cellular damage. In contrast, YAP1-overexpressing cells inhibited NLRP3 inflammasome activation and increased SLC7A11 levels, preventing pyroptosis and ferroptosis. Overall, our data suggest that YAP1 ameliorates PM2.5-induced lung injury by inhibiting NLRP3-mediated pyroptosis and SL7A11-dependent ferroptosis.

OBJECTIVE: To study the regulatory relationship between ozone-induced mitophagy and pyroptosis in lung epithelial cells.
RESULTS: First, type I primary alveolar epithelial cells and male Wistar rats were treated with ozone at different dosages. The ATP content and mitochondrial membrane potential significantly decreased in type I primary alveolar epithelial cells. The mitophagy-related markers and PINK1/Parkin pathway-related proteins, and the co-localization of LC3, Parkin, and mitochondria in type I alveolar epithelial cells indicated that ozone exposure triggered mitophagy. On the other hand, the reactive oxygen species (ROS) inhibitor NAC could significantly alleviate mitophagy in epithelial cells. After treatment with the mitophagy inhibitor MDIVI-1, the levels of the NLRP3 inflammasome, cleaved caspase-1, and N-gasdermin D (N-GSDMD) significantly decreased in the cells. Altogether, these results indicated that mitophagy can be triggered by ozone exposure, and subsequently induces cell death mediated by the NLRP3 inflammasome. Finally, the overexpression and knockdown of NLRP3 confirmed this conclusion.
CONCLUSIONS: Ozone exposure induced oxidative damage, leading to mitochondrial structural and functional damage. Ozone-induced ROS triggered mitophagy through the activation of the PINK1/Parkin signaling pathway, then pyroptosis through activation of the NLRP3 inflammasome.

Exposure to particulate matter (PM)2.5 in air pollution is a serious health issue worldwide. At present, effective prevention measures and modalities of treatment for PM2.5-caused lung toxicity are lacking. This study elucidated the protective effect of astragaloside IV (Ast), a natural product from Astragalus membranaceous Bunge, against PM2.5-caused lung toxicity and its possible molecular mechanisms. The mice model of lung toxicity was performed by intratracheal instillation of PM2.5 dust suspension. The investigation was performed with Ast or in combination with nigericin, which is a NOD-like receptor protein 3 (NLRP3) activator. The results revealed that PM2.5 lead significant lung inflammation and promoted the pyroptosis pattern of cell death by upregulating pro-inflammatory cytokines and causing oxidative stress related to the NLRP3 inflammasome-mediated pyroptosis pathway. Ast protected against PM2.5 resulted lung toxicity via suppressing NLRP3 inflammasome-mediated pyroptosis via NLRP3/caspase-1 axis inhibition, thereby protecting the lung against PM2.5-induced lung inflammation and oxidative damage, eventually resulting in prolonged survival in mice. Nigericin partially reversed the protective effects of Ast. The present research provides new insights into the therapeutic potential of Ast, demonstrating that it might be a possible candidate for the prevention of PM2.5-caused respiratory diseases. Targeting the NLRP3 inflammasome might be a novel therapeutic tactic for PM2.5-caused respiratory diseases.