Inhalable Textile Microplastic Fibers Impair Airway Epithelial Differentiation.

Rationale: Microplastics are a pressing global concern, and inhalation of microplastic fibers has been associated with interstitial and bronchial inflammation in flock workers. However, how microplastic fibers affect the lungs is unknown. Objectives: Our aim was to assess the effects of 12 × 31 µm nylon 6,6 (nylon) and 15 × 52 µm polyethylene terephthalate (polyester) textile microplastic fibers on lung epithelial growth and differentiation. Methods: We used human and murine alveolar and airway-type organoids as well as air-liquid interface cultures derived from primary lung epithelial progenitor cells and incubated these with either nylon or polyester fibers or nylon leachate. In addition, mice received one dose of nylon fibers or nylon leachate, and, 7 days later, organoid-forming capacity of isolated epithelial cells was investigated. Measurements and Main Results: We observed that nylon microfibers, more than polyester, inhibited developing airway organoids and not established ones. This effect was mediated by components leaching from nylon. Epithelial cells isolated from mice exposed to nylon fibers or leachate also formed fewer airway organoids, suggesting long-lasting effects of nylon components on epithelial cells. Part of these effects was recapitulated in human air-liquid interface cultures. Transcriptomic analysis revealed upregulation of Hoxa5 after exposure to nylon fibers. Inhibiting Hoxa5 during nylon exposure restored airway organoid formation, confirming Hoxa5's pivotal role in the effects of nylon. Conclusions: These results suggest that components leaching from nylon 6,6 may especially harm developing airways and/or airways undergoing repair, and we strongly encourage characterization in more detail of both the hazard of and the exposure to microplastic fibers.

Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy.

BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.

Distinct latitudinal patterns and drivers of topsoil nitrogen and phosphorus across urban forests in eastern China.

Nitrogen (N) and phosphorus (P) are the two most important macronutrients supporting forest growth. Unprecedented urbanization has created growing areas of urban forests that provide key ecosystem services for city dwellers. However, the large-scale patterns of soil N and P content remain poorly understood in urban forests. Based on a systematic soil survey in urban forests from nine large cities across eastern China, we examined the spatial patterns and key drivers of topsoil (0-20 cm) total N content, total P content, and N:P ratio. Topsoil total N content was found to change significantly with latitude in the form of an inverted parabolic curve, while total P content showed an opposite latitudinal pattern. Variance partition analysis indicated that regional-scale patterns of topsoil total N and P contents were dominated by climatic drivers and partially regulated by time and pedogenic drivers. Conditional regression analyses showed a significant increase in topsoil total N content with lower mean annual temperature (MAT) and higher mean annual precipitation (MAP), while topsoil total P content decreased significantly with higher MAP. Topsoil total N content also increased significantly with the age of urban park and varied with pre-urban soil type, while no such effects were found for topsoil total P content. Moreover, topsoil N:P ratio showed a latitudinal pattern similar to that of topsoil total N content and also increased significantly with lower MAT and higher MAP. Our findings demonstrate distinct latitudinal trends of topsoil N and P contents and highlight a dominant role of climatic drivers in shaping the large-scale patterns of topsoil nutrients in urban forests.

Metabolomic insights into pulmonary fibrosis: a mendelian randomization study.

BACKGROUND: This study leverages a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between 1,400 metabolites and pulmonary fibrosis, using genetic variation as instrumental variables. By adhering to stringent criteria for instrumental variable selection, the research aims to uncover metabolic pathways that may influence the risk and progression of pulmonary fibrosis, providing insights into potential therapeutic targets. METHODS: Utilizing data from the OpenGWAS project, which includes a significant European cohort, and metabolite GWAS data from the Canadian Longitudinal Aging Study (CLSA), the study employs advanced statistical methods. These include inverse variance weighting (IVW), weighted median estimations, and comprehensive sensitivity analyses conducted using the R software environment to ensure the robustness of the causal inferences. RESULTS: The study identified 62 metabolites with significant causal relationships with pulmonary fibrosis, highlighting both risk-enhancing and protective metabolic factors. This extensive list of metabolites presents a broad spectrum of potential therapeutic targets and biomarkers for early detection, underscoring the metabolic complexity underlying pulmonary fibrosis. CONCLUSIONS: The findings from this MR study significantly advance our understanding of the metabolic underpinnings of pulmonary fibrosis, suggesting that alterations in specific metabolites could influence the risk and progression of the disease. These insights pave the way for the development of novel diagnostic and therapeutic strategies, emphasizing the potential of metabolic modulation in managing pulmonary fibrosis.

Genetic association of telomere length, obesity and tobacoo smoking with idiopathic pulmonary fibrosis risk.

BACKGROUND: Due to the inadequacy of published evidence, association of telomere length (TL), obesity and tobacco smoking with idiopathic pulmonary fibrosis (IPF) remains unclear. The aim of the study was to explore whether these exposures genetically affected the risk of the disease. METHODS: Genetic variants from genome-wide association studies for TL, body mass index (BMI), body fat percentage (BFP) and tobacco smoking (including maternal smoking) were used as instrumental variables. Inverse-variance weighted were mainly adopted to determine the genetic association of these exposures with IPF. All analyses were conducted by R-software (version 3.6.1). RESULTS: Firstly, longer TL was associated with the decreased risk of IPF (OR = 0.475 per SD increase in TL, 95%CI = 0.336 ~ 0.670, P<0.001). Secondly, higher levels of BMI and BFP were related to the increased risk of the disease (OR = 1.425 per SD increase in BMI level, 95%CI = 1.114 ~ 1.823, P = 0.005; OR = 1.702 per SD increase in BFP level, 95%CI = 1.202 ~ 2.409, P = 0.003). Thirdly, maternal smoking was implicated in the increased risk of the disease (OR = 13.183 per SD increase in the prevalence of maternal smoking, 95%CI = 1.820 ~ 95.484, P = 0.011). CONCLUSION: TL should be a genetic risk factor for IPF. Obesity and exposure to tobacco smoking as a fetus might also contribute to the development of this fibrotic diseases. These findings should be verified by future studies.

VX-11e protects articular cartilage and subchondral bone in osteoarthritis by inhibiting the RIP1/RIP3/MLKL and MAPK signaling pathways.

Necroptosis of chondrocytes contributes to the progression of osteoarthritis (OA). Recent studies have shown that VX-11e, an ERK inhibitor, exhibited a contrasting expression pattern to RIP3, the key protein of necroptosis. However, its effect on OA remains to be determined. Therefore, we investigated whether VX-11e affected the loss of articular cartilage and subchondral bone during OA. In in vivo experiments, a mouse OA model induced by medial meniscus instability (destabilization of the medial meniscus [DMM]) was used. In in vitro experiments, interleukin-1ß (IL-1ß) was used to simulate the inflammatory microenvironment of chondrocytes, and RANKL was used to induce osteoclast differentiation. Histological analysis, cell viability experiments, high-density cell culture experiments, immunofluorescence assay, western blot assay, quantitative PCR, and molecular docking experiments were conducted to determine the protective effect of VX-11e on articular cartilage during OA. We also performed histological analysis, tartrate-resistant acid phosphatase (TRAP) staining, F-actin ring formation test, quantitative PCR, and western blot assay to study the effect of VX-11e on subchondral bone during OA progression. We found that after the medial meniscus was severed, the articular cartilage of the mice showed pathological changes, accompanied with the loss of subchondral bone. However, an intraperitoneal injection of VX-11e protected the cartilage and subchondral bone of the mouse knee joint. The results of in vitro experiments showed that VX-11e promoted the anabolism of the extracellular matrix of chondrocytes by inhibiting the expression and phosphorylation of RIP3 and MLKL. VX-11e also inhibited RANKL-induced osteoclast differentiation by inhibiting the ERK/RSK signaling pathway, but not the NF-κB pathway. Overall, VX-11e inhibited the loss of articular cartilage and subchondral bone during OA by regulating the RIP1/RIP3/MLKL and MAPK signaling pathways.

Effect of goal-directed fluid therapy on renal function in critically ill patients: a systematic review and meta-analysis.

OBJECTIVE: To evaluate whether goal-directed fluid therapy (GDFT) reduces the risk of renal injury in critical illness. METHODS: MEDLINE via PubMed, EMBASE, CENTRAL and CBM was searched from inception to 13 March 2022, for studies comparing the effect of GDFT with usual care on renal function in critically ill patients. GDFT was defined as a protocolized intervention based on hemodynamic and/or oxygen delivery parameters. A fixed or random effects model was applied to calculate the pooled odds ratio (OR) based on heterogeneity through the included studies. RESULTS: A total of 28 studies with 9,019 patients were included. The pooled data showed that compared with usual care, GDFT reduced the incidence of acute kidney injury (AKI) in critical illness (OR 0.62, 95% confidence interval (CI) 0.47 to 0.80, p< 0.001). Sensitivity analysis with only low risk of bias studies showed the same result. Subgroup analyses found that GDFT was associated with a lower AKI incidence in both postoperative and medical patients. The reduction was significant in GDFT aimed at dynamic indicators. However, no significant difference was found between groups in RRT support (OR 0.88, 95% CI 0.74 to 1.05, p= 0.17). GDFT tended to increase fluid administration within the first 6 h, decrease fluid administration after 24 h, and was associated with more vasopressor requirements. CONCLUSIONS: This meta-analysis suggests that GDFT aimed at dynamic indicators may be an effective way to prevent AKI in critical illness. This may indicate a benefit from early adequate fluid resuscitation and the combined effect of vasopressors.

Yangonin treats inflammatory osteoporosis by inhibiting the secretion of inflammatory factors and RANKL expression.

OBJECTIVES: As the main cause of osteoporosis, abnormal activity of osteoclasts could disrupt the balance between bone resorption and formation. Moreover, up-regulation of nuclear factor-kappa ligand (RANKL) expression by chronic inflammation-mediated inflammatory factors might contribute to the differentiation of osteoclast precursor cells. Therefore, an anti-inflammatory agent named yangonin was presented for inhibiting osteoclast and relieving inflammatory osteoporosis through down-regulating inflammatory factors. METHODS: We established a model of macrophage inflammation and then verified the anti-inflammatory effect of yangonin. The inhibitory effect of yangonin on osteoclasts was detected by tartrate-resistant acid phosphatase (TRAP) staining, Western blotting and quantitative real-time PCR (qRT-PCR). Finally, micro-CT, TRAP and hematoxylin-eosin (HE) staining were used to show the effect of yangonin on inflammatory osteoporosis in vivo. RESULTS: Our results suggested that yangonin was able to reduce the secretion of inflammatory factors, down-regulate osteoclast-related genes such as TRAP, RANKL, cathepsin K (CTSK) and nuclear factor-activated T-cell 1 (NFATc1). Furthermore, it was demonstrated that yangonin could suppress the function of inflammatory cytokines in osteoclast differentiation and reporting, wherein NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways were involved. In an in vivo study, we implied that yangonin has a relieving effect on inflammatory osteoporosis. CONCLUSION: Our research shows that yangonin down-regulates inflammatory factors and inhibits the bone-breaking effect of inflammation through NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways to achieve the purpose of treating inflammatory osteoporosis.

LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE.

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.