Effect of macrophage-to-myofibroblast transition on silicosis.

BACKGROUND: The aim was to explore the effect of macrophage polarization and macrophage-to-myofibroblast transition (MMT) in silicosis. METHODS: Male Wistar rats were divided into a control group and a silicosis group developed using a HOPE MED 8050 dynamic automatic dusting system. Murine macrophage MH-S cells were randomly divided into a control group and an SiO2 group. The pathological changes in lung tissue were observed using hematoxylin and eosin (HE) and Van Gieson (VG) staining. The distribution and location of macrophage marker (F4/80), M1 macrophage marker (iNOS), M2 macrophage marker (CD206), and myofibroblast marker (α-smooth muscle actin [α-SMA]) were detected using immunohistochemical and immunofluorescent staining. The expression changes in iNOS, Arg, α-SMA, vimentin, and type I collagen (Col I) were measured using Western blot. RESULTS: The results of HE and VG staining showed obvious silicon nodule formation and the distribution of thick collagen fibers in the lung tissue of the silicosis group. Macrophage marker F4/80 increased gradually from 8 to 32 weeks after exposure to silica. Immunohistochemical and immunofluorescent staining results revealed that there were more iNOS-positive cells and some CD206-positive cells in the lung tissue of the silicosis group at 8 weeks. More CD206-positive cells were found in the silicon nodules of the lung tissues in the silicosis group at 32 weeks. Western blot analysis showed that the expressions of Inducible nitric oxide synthase and Arg protein in the lung tissues of the silicosis group were upregulated compared with those of the control group. The results of immunofluorescence staining showed the co-expression of F4/80, α-SMA, and Col I, and CD206 and α-SMA were co-expressed in the lung tissue of the silicosis group. The extracted rat alveolar lavage fluid revealed F4/80+α-SMA+, CD206+α-SMA+, and F4/80+α-SMA+Col I+ cells using immunofluorescence staining. Similar results were also found in MH-S cells induced by SiO2. CONCLUSIONS: The development of silicosis is accompanied by macrophage polarization and MMT.

Paeoniflorin mitigates MMP-12 inflammation in silicosis via Yang-Yin-Qing-Fei Decoction in murine models.

BACKGROUND: Silicosis presents a significant clinical challenges and economic burdens, with Traditional Chinese Medicine (TCM) emerging as a potential therapeutic avenue. However, the precise effects and mechanisms of TCM in treating silicosis remain uncertain and subject to debate. OBJECTIVE: The study aims to elucidate the therapeutic role and mechanisms of the Yang-Yin-Qing-Fei Decoction (YYQFD) and its key component, paeoniflorin, in silicosis using a murine model. METHODS: Silicotic mice were treated with YYQFD, pirfenidone (PFD), or paeoniflorin. RAW264.7 cells and mouse lung fibroblasts (MLF) were stimulated with silica, matrix metalloproteinase-12 (MMP-12), or TGF-ß1, followed by treatment with paeoniflorin, PFD, or relevant inhibitors. YYQFD constituents were characterized using High-Performance Liquid Chromatography (HPLC). Lung fibrosis severity was assessed via histopathological examination, micro-CT imaging, lung functions, and Western blot analysis. Transcriptome sequencing and bioinformatics analysis were employed to delineate the gene expression profile and target genes modulated by YYQFD in silicosis. RESULTS: Treatment with YYQFD ameliorated silica-induced lung fibrosis. Transcriptome sequencing identified MMP-12 as a potential common target of YYQFD and PFD. Additionally, a potential pro-inflammatory role of MMP-12, regulated by silica-induced TLR4 signaling pathways, was revealed. Paeoniflorin, one of the most distinctive compounds in YYQFD, attenuated silica-induced MMP-12 increase and its derived inflammatory factors in macrophages through a direct binding effect. Notably, paeoniflorin treatment exerted anti-fibrotic effects by inhibiting MMP-12-derived inflammatory factors and TGF-ß1-induced myofibroblast differentiation in silica-exposed mice. CONCLUSIONS: This study underscores paeoniflorin as one of the most principal bioactive compounds in YYQFD, highlighting its capacity to attenuate lung inflammation driven by macrophage-derived MMP-12 and reduce lung fibrosis both in vivo and in vitro.

The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A.

Lung epithelial cells and fibroblasts poorly express angiotensin-converting enzyme 2, and the study aimed to investigate the role of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on inflammation and epithelial-mesenchymal transition (EMT) in two lung cell lines and to understand the potential mechanism. Lung epithelial cells (BEAS-2B) and fibroblasts (MRC-5) were treated with the spike protein, then inflammatory and EMT phenotypes were detected by enzyme-linked immunosorbent assay, Transwell, and western blot assays. RNA-sequence and bioinformatic analyses were performed to identify dysregulated genes. The roles of the candidate genes were further investigated. The results showed that treatment with 1,000 ng/mL of spike protein in two lung cell lines caused increased levels of IL-6, TNF-α, CXCL1, and CXCL3, and the occurrence of EMT. RNA-sequence identified 4,238 dysregulated genes in the spike group, and 18 candidate genes were involved in both inflammation- and EMT-related processes. GADD45A had the highest verified fold change (abs), and overexpression of GADD45A promoted the secretion of cytokines and EMT in the two lung cell lines. In conclusion, the spike protein induces inflammation and EMT in lung epithelial cells and fibroblasts by upregulating GADD45A, providing a new target to inhibit inflammation and EMT.

Ac-SDKP promotes KIF3A-mediated ß-catenin suppression through a ciliary mechanism to constrain silica-induced epithelial-myofibroblast transition.

Kinesin family member 3 A (KIF3A) decrease have been reported in silicotic patients and rats. However, the detailed mechanisms of KIF3A in silicosis remain unknown. In this study, we demonstrated that KIF3A effectively blocked the expression of ß-catenin and downstream myocardin-related transcription factor (MRTF)-A/serum response factor (SRF) signaling, thus inhibiting silica-induced epithelial-myofibroblast transition (EMyT). Moreover, KIF3A was identified as a downstream mediator of an antifibrotic tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Knockdown of KIF3A expression reactivated ß-catenin/myocardin-related transcription factor (MRTF)-A/serum response factor (SRF) signaling that was attenuated by Ac-SDKP in vitro. Collectively, our findings suggest that Ac-SDKP plays its anti-fibrosis role via KIF3A-mediated ß-catenin suppression, at least in part, in both in vivo model of silicosis and in vitro model of EMyT.

Exercise training inhibits macrophage-derived IL-17A-CXCL5-CXCR2 inflammatory axis to attenuate pulmonary fibrosis in mice exposed to silica.

Exposure to crystalline silica leads to health effects beyond occupational silicosis. Exercise training's potential benefits on pulmonary diseases yield inconsistent outcomes. In this study, we utilized experimental silicotic mice subjected to exercise training and pharmacological interventions, including interleukin-17A (IL-17A) neutralizing antibody or clodronate liposome for macrophage depletion. Findings reveal exercise training's ability to mitigate silicosis progression in mice by suppressing scavenger receptor B (SRB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Toll-like receptor 4 (TLR4) pathways. Macrophage-derived IL-17A emerges as primary source and trigger for silica-induced pulmonary inflammation and fibrosis. Exercise training effectively inhibits IL-17A-CXC motif chemokine ligand 5 (CXCL5)-Chemokine (C-X-C motif) Receptor 2 (CXCR2) axis in silicotic mice. Our study evidences exercise training's potential to reduce collagen deposition, preserve elastic fibers, slow pulmonary fibrosis advancement, and enhance pulmonary function post silica exposure by impeding macrophage-derived IL-17A-CXCL5-CXCR2 axis.

Effectiveness of Pentavalent Rotavirus Vaccine in Shanghai, China: A Test-Negative Design Study.

OBJECTIVE: To evaluate vaccine effectiveness (VE) of a live oral pentavalent rotavirus vaccine (RotaTeq, RV5) among young children in Shanghai, China, via a test-negative design study. STUDY DESIGN: We consecutively recruited children visiting a tertiary children's hospital for acute diarrhea from November 2021 to February 2022. Information on clinical data and rotavirus vaccination was collected. Fresh fecal samples were obtained for rotavirus detection and genotyping. To evaluate VE of RV5 against rotavirus gastroenteritis among young children, unconditional logistic regression models were conducted to compare ORs for vaccination between rotavirus-positive cases and test-negative controls. RESULTS: A total of 390 eligible children with acute diarrhea were enrolled, including 45 (11.54%) rotavirus-positive cases and 345 (88.46%) test-negative controls. After excluding 4 cases (8.89%) and 55 controls (15.94%) who had received the Lanzhou lamb rotavirus vaccine, 41 cases (12.39%) and 290 controls (87.61%) were included for the evaluation of RV5 VE. After adjustment for potential confounders, the 3-dose RV5 vaccination showed 85% (95% CI, 50%-95%) VE against mild to moderate rotavirus gastroenteritis among children aged 14 weeks to ≤4 years and 97% (95% CI, 83%-100%) VE among children aged 14 weeks to ≤2 years with genotypes G8P8, G9P8, and G2P4 represented 78.95%, 18.42%, and 2.63% of circulation strains, respectively. CONCLUSIONS: A 3-dose vaccination of RV5 is highly protective against rotavirus gastroenteritis among young children in Shanghai. The G8P8 genotype prevailled in Shanghai after RV5 introduction.

Quercetin Alleviates Pulmonary Fibrosis in Silicotic Mice by Inhibiting Macrophage Transition and TGF-ß-Smad2/3 Pathway.

Silicosis is a pulmonary disease caused by the inhalation of silica. There is a lack of early and effective prevention, diagnosis, and treatment methods, and addressing silicotic fibrosis is crucial. Quercetin, a flavonoid with anti-carcinogenic, anti-inflammatory, and antiviral properties, is known to have a suppressive effect on fibrosis. The present study aimed to determine the therapeutic effect of quercetin on silicotic mice and macrophage polarity. We found that quercetin suppressed silicosis in mice. It was observed that SiO2 activated macrophage polarity and the macrophage-to-myofibroblast transition (MMT) by transforming the growth factor-ß (TGF-ß)-Smad2/3 signaling pathway in silicotic mice and MH-S cells. Quercetin also attenuated the MMT and the TGF-ß-Smad2/3 signaling pathway in vivo and in vitro. The present study demonstrated that quercetin is a potential therapeutic agent for silicosis, which acts by regulating macrophage polarity and the MMT through the TGF-ß-Smad2/3 signaling pathway.

Household transmission of SARS-CoV-2 during the Omicron wave in Shanghai, China: A case-ascertained study.

OBJECTIVES: We used a case-ascertained study to determine the features of household transmission of SARS-CoV-2 Omicron variant in Shanghai, China. METHODS: In April 2022, we carried out a household transmission study from 309 households of 335 SARS-CoV-2 pediatric cases referred to a designated tertiary Children's Hospital. The detailed information can be collected from the 297 households for estimating the transmission parameters. The 236 households were qualified for estimating the secondary infection attack rates (SARI ) and secondary clinical attack rates (SARC ) among adult household contacts, characterizing the transmission heterogeneities in infectivity and susceptibility, and assessing the vaccine effectiveness. RESULTS: We estimated the mean incubation period and serial interval of Omicron variant to be 4.6 ± 2.1 and 3.9 ± 3.7 days, respectively, with 57.2% of the transmission events occurring at the presymptomatic phase. The overall SARI and SARC among adult household contacts were 77.11% (95% confidence interval [CI]: 73.58%-80.63%) and 67.03% (63.09%-70.98%). We found higher household susceptibility in females. Infectivity was not significantly different between children and adults and symptomatic and asymptomatic cases. Two-dose and booster-dose of inactivated COVID-19 vaccination were 14.8% (5.8%-22.9%) and 18.9% (9.0%-27.7%) effective against Omicron infection and 21.5% (10.4%-31.2%) and 24.3% (12.3%-34.7%) effective against the symptomatic disease. CONCLUSIONS: We found high household transmission during the Omicron wave in Shanghai due to presymptomatic and asymptomatic transmission despite implementation of strict interventions, indicating the importance of early detection and timely isolation of SARS-CoV-2 infections. Marginal effectiveness of inactivated vaccines against Omicron infection poses a great challenge for outbreak containment.

Common issues and improvement solution of vaccine hesitancy in children with underlying neurological conditions: Experience from one National Children's Medical Center in China.

BACKGROUND: Parents and healthcare providers usually defer or avoid immunization for children with neurological conditions. This study was conducted to investigate the common issues of immunization among these special children and the impact of specialists' recommendation on improving immunization practice. METHOD: We included 2,221 children with underlying neurological conditions seeking vaccination consultation at the first Immunization Advisory Clinic in China during 2017-2019. The primary neurological conditions and immunization status were analyzed. All parents were informed to self-report the adverse events following catch-up immunization. For specially concerned children with hereditary disorders, immune-related encephalopathy and epilepsy, we conducted the active follow-up to monitor the compliance with recommendation and the adverse events. RESULT: All counselling children were assessed as not having any contraindication of immunization. A total of 2,019 (90.9%) children with underlying neurological conditions had delayed immunization and 99 (4.5%) had non-immunization. The coverage rate of age-appropriate vaccines was 56.1%. The most concerned vaccines were diphtheria, tetanus and acellular pertussis combined vaccine, diphtheria and tetanus combined vaccine, meningococcal polysaccharide vaccine and Japanese encephalitis vaccine. Resuming immunization was recommended for the 2,048 (92.2%) children. Most of counselling children complied with the specialists' recommendation. Neither progress nor flaring of the neurological medical conditions was reported from parents. CONCLUSION: Vaccine hesitancy was a common issue for Chinese children with all kinds of neurological conditions. Specialized consultation on immunization is helpful to build vaccine confidence for the special children. Immunization for children with underlying neurological conditions is generally safe.

Thalidomide Attenuates Skin Lesions and Inflammation in Rosacea-Like Mice Induced by Long-Term Exposure of LL-37.

Purpose: Most of the existing studies focus on the early inflammation of rosacea, with few interventions on the later development of fibrosis and the relationship between thalidomide and rosacea. The purpose of this study was to construct a long-term induction model and explore the effects of thalidomide on the later stage of inflammation and early stage of fibrosis in rosacea. Patients and Methods: BALB/c male mice were randomly divided into four groups: control group, control plus thalidomide group, LL-37 group and LL-37 plus thalidomide group, Intradermal and intraperitoneal injections were given. After repeated induction, skin changes were recorded by taking photos. The animals were sacrificed, the back skin was used for HE staining and VG staining to detect histomorphological characteristics. Immunofluorescence staining and Western blot were used to detect the expression of inflammatory and fibrosis-related factors. Results: The results were compared with the early stage of the model, wherein the skin inflammation of the 20-day mice was more obvious with a trend of fibrosis. Compared with the control group, histopathological examination showed that the inflammatory cell infiltration in the LL-37 group was significantly increased, and the skin was thickened with collagen deposition. LL-37 induction significantly increased the expression of inflammatory markers (eg, TNF-α and IL-1ß) and fibrotic markers (eg, COL1, α-SMA, vimentin and N-Cadherin). Intervention with thalidomide significantly reduced erythema, inflammatory cell infiltration, collagen deposition, and down-regulate the expression of inflammation and fibrosis related factors in rosacea mice. Conclusion: The long-term continuous induction of LL-37 in mice could simulate the occurrence and development of rosacea, and thalidomide could ameliorate the rosacea induced by long-term exposure to LL-37 by regulating inflammatory infiltration, collagen deposition and fibrosis-related processes.

Effect of Sex Differences in Silicotic Mice.

Mechanisms of silicosis, caused by the inhalation of silica are still unclear, and the effect of sex on silicosis has rarely been reported. The purpose of this study was to investigate whether sex affects the silicotic lesions and the progressive fibrotic responses in silicosis. Our study showed that sex had no significant effect on the area of silicon nodules and the collagen deposition after a one-time bronchial perfusion of silica. Immunohistochemical staining showed that CD68 and the transforming growth factor-ß1 (TGF-ß1) were positive in male and female silicotic mice. In addition, the western blot results showed that the fibrosis-related factors type I collagen (COL I), α-smooth muscle actin (α-SMA), vimentin, TGF-ß1, p-SMAD2/3, inflammatory-related factors interleukin 6 (IL 6), interleukin 1ß (IL 1ß), and senescence-related factors p16 and p21 were up-regulated in silicotic mice and there was no difference between female or male mice exposed to silica. The expression of TGF-ß1, p-SMAD2/3, p16, and p21 were downregulated in the early stage of female silicotic mice, compared to the males. Thus, despite differences in the expression of certain factors, there was no overall difference in the progressive fibrosis between female and male mice in silicosis. These results thus provide a new perspective for studying the pathological development of silicosis.

Quercetin Alleviates Pulmonary Fibrosis in Mice Exposed to Silica by Inhibiting Macrophage Senescence.

Quercetin exerts anti-inflammatory, anti-oxidant and other protective effects. Previous studies have shown that senescent cells, such as fibroblasts and type II airway epithelial cells, are strongly implicated in the development of pulmonary fibrosis pathology. However, the role of senescent macrophages during silicosis remains unclear. We investigated the effects of quercetin on macrophage senescence and pulmonary fibrosis, and explored underlying mechanisms. Mice were randomized to six model groups. Vitro model was also established by culturing RAW264.7 macrophages with silica (SiO2). We examined the effects of quercetin on fibrosis, senescence-associated ß-galactosidase (SA-ß-Gal) activity, and senescence-specific genes (p16, p21, and p53). We showed that quercetin reduced pulmonary fibrosis and inhibited extracellular matrix (ECM) formation. Quercetin also attenuated macrophage senescence induced by SiO2 both in vitro and in vivo. In addition, quercetin significantly decreased the expressions of the senescence-associated secretory phenotype (SASP), including proinflammatory factors (interleukin-1α (Il-1α), Il-6, tumor necrosis factor-α (TNF-α), and transforming growth factor-ß1 (TGF-ß1)) and matrix metalloproteinases (MMP2, MMP9, and MMP12). In conclusion, quercetin mediated its anti-fibrotic effects by inhibiting macrophage senescence, possibly via SASP.

Epidemiological and clinical features of SARS-CoV-2 infection in children during the outbreak of Omicron variant in Shanghai, March 7-31, 2022.

OBJECTIVES: This study aimed to understand the epidemiological and clinical characteristics of pediatric SARS-CoV-2 infection during the early stage of Omicron variant outbreak in Shanghai. METHODS: This study included local COVID-19 cases <18 years in Shanghai referred to the exclusively designated hospital from March 7 to March 31, 2022. Clinical data, epidemiological exposure, and COVID-19 vaccination status were collected. Relative risks (RRs) were calculated to assess the effect of vaccination on symptomatic infection and febrile disease. RESULTS: A total of 376 pediatric cases of COVID-19 (median age: 6.0 ± 4.2 years) were referred to the designated hospital, including 257 (68.4%) symptomatic cases and 119 (31.6%) asymptomatic cases. Of the 307 (81.6%) children ≥3 years eligible for COVID-19 vaccination, 110 (35.8%) received two doses of vaccines. The median interval between the completion of two-dose vaccination and infection was 3.5 (interquartile range [IQR]: 3, 4.5) months. Compared with no vaccination, two-dose COVID-19 vaccination reduced the risks of symptomatic infection and febrile disease by 35% (RR 0.65, 95% confidence interval [CI]: 0.53-0.79) and 33% (RR 0.64, 95% CI: 0.51-0.81) among confirmed cases. Eighty-four percent of symptomatic cases had fever (mean duration: 1.7 ± 1.0.8 days), 40.5% had cough, and 16.4% had transient leukopenia. Three hundred and seven (81.6%) had an epidemiological exposure in household (69.1%), school (21.8%), and residential area (8.8%). CONCLUSION: The surge of pediatric COVID-19 cases and multiple transmission model reflect wide dissemination of Omicron variant in the community. Asymptomatic infection is common among Omicron-infected children. COVID-19 vaccination can offer some protection against symptomatic infection and febrile disease.

MicroRNA-411-3p inhibits bleomycin-induced skin fibrosis by regulating transforming growth factor-ß/Smad ubiquitin regulatory factor-2 signalling.

Skin fibrosis, which is characterized by fibroblast proliferation and increased extracellular matrix, has no effective treatment. An increasing number of studies have shown that microRNAs (miRNAs/miRs) participate in the mechanism of skin fibrosis, such as in limited cutaneous systemic sclerosis and pathological scarring. The objective of the present study was to determine the role of miR-411-3p in bleomycin (BLM)-induced skin fibrosis and skin fibroblast transformation. Using Western blot analysis and real-time quantitative polymerase chain reaction assess the expression levels of miR-411-3p, collagen (COLI) and transforming growth factor (TGF)-ß/Smad ubiquitin regulatory factor (Smurf)-2/Smad signalling factors both in vitro and in vivo with or without BLM. To explore the regulatory relationship between miR-411-3p and Smurf2, we used the luciferase reporter assay. Furthermore, miR-411-3p overexpression was identified in vitro and in vivo via transfection with Lipofectamine 2000 reagent and injection. Finally, we tested the dermal layer of the skin using haematoxylin and eosin and Van Gieson's staining. We found that miR-411-3p expression was decreased in bleomycin (BLM)-induced skin fibrosis and fibroblasts. However, BLM accelerated transforming growth factor (TGF)-ß signalling and collagen production. Overexpression of miR-411-3p inhibited the expression of collagen, F-actin and the TGF-ß/Smad signalling pathway factors in BLM-induced skin fibrosis and fibroblasts. In addition, miR-411-3p inhibited the target Smad ubiquitin regulatory factor (Smurf)-2. Furthermore, Smurf2 was silenced, which attenuated the expression of collagen via suppression of the TGF-ß/Smad signalling pathway. We demonstrated that miR-411-3p exerts antifibrotic effects by inhibiting the TGF-ß/Smad signalling pathway via targeting of Smurf2 in skin fibrosis.

Correlation Between Prevalence of Selected Enteropathogens and Diarrhea in Children: A Case-Control Study in China.

BACKGROUND: The application of nucleic acid detection methods improves the ability of laboratories to detect diarrheal pathogens, but it also poses new challenges for the interpretation of results. It is often difficult to attribute a diarrhea episode to the detected pathogens. Here we investigated the prevalence of 19 enteropathogens among diarrheal and nondiarrheal children and provided support for understanding the clinical significance of the pathogens. METHODS: A total of 710 fecal samples were collected from children under 5 years old in 2 different regions of China from May 2017 to March 2018, comprising 383 mild to moderate diarrheal cases and 327 nondiarrheal controls. The enteropathogens were detected using real-time polymerase chain reaction (PCR) or real-time reverse transcription PCR (RT-PCR). RESULTS: Enteropathogens were detected in 68.9% of cases and 41.3% of controls. Rotavirus A (adjusted OR [aOR], 9.91; 95% CI, 4.99-19.67), norovirus GI and GII (aOR, 3.82; 95% CI, 2.12-6.89), and Campylobacter jejuni (aOR, 20.12; 95% CI, 2.57-157.38) were significantly associated with diarrhea (P < .05). Adenovirus, norovirus GII, rotavirus A, and enteroaggregative Escherichia coli (pCVD432) gave lower cycle threshold (Ct) values in cases than in controls (P < .05). Rotavirus A and norovirus GII were associated with diarrhea when the Ct values were ≤30 and ≤25, respectively. CONCLUSIONS: The types and loads of enteropathogens are likely to influence the interpretation of the clinical significance of positive results.

OC-STAMP Overexpression Drives Lung Alveolar Epithelial Cell Type II Senescence in Silicosis.

Cellular senescence has been considered an important driver of many chronic lung diseases. However, the specific mechanism of cellular senescence in silicosis is still unknown. In the present study, silicotic rats and osteoclast stimulatory transmembrane protein (Ocstamp) overexpression of MLE-12 cells were used to explore the mechanism of OC-STAMP in cellular senescence in alveolar epithelial cell type II (AEC2). We found an increasing level of OC-STAMP in AEC2 of silicotic rats. Overexpression of Ocstamp in MLE-12 cells promoted epithelial-mesenchymal transition (EMT), endoplasmic reticulum (ER) stress, and cellular senescence. Myosin heavy chain 9 (MYH9) was a potential interacting protein of OC-STAMP. Knockdown of Ocstamp or Myh9 inhibited cellular senescence in MLE-12 cells transfected with pcmv6-Ocstamp. Treatment with 4-phenylbutyrate (4-PBA) to inhibit ER stress also attenuated cellular senescence in vitro or in vivo. In conclusion, OC-STAMP promotes cellular senescence in AEC2 in silicosis.

Ac-SDKP Attenuates Activation of Lung Macrophages and Bone Osteoclasts in Rats Exposed to Silica by Inhibition of TLR4 and RANKL Signaling Pathways.

BACKGROUND: Silica-induced inflammatory activation is associated with silicosis and various non-respiratory conditions. The present study was designed to examine the anti-inflammatory effects of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on lung macrophages and bone osteoclasts after silica inhalation in rats. METHODS: Wistar rats and NR8383 and RAW 264.7 cell lines were used in the present study. The receptor activator of nuclear factor kappa-B ligand (RANKL) and toll-like receptor 4 (TLR4) signaling pathways was measured in the lung tissue of rats or NR8383/RAW 264.7 cells exposed to silica. The microarchitecture of the trabecular bone in the tibia and femur was evaluated in silicotic rats. Furthermore, the roles of Ac-SDKP on silicotic rats, silica-treated NR8383/RAW 264.7 cells, and RANKL-induced osteoclast differentiation were studied. RESULTS: The data indicated that silica inhalation might activate the RANKL and TLR4 signaling pathways in lung macrophages, thus inducing the lung inflammatory and proteolytic phenotype of macrophages and osteoclasts in lung and bone. Ac-SDKP maintained the lung elastin level by inhibiting lung inflammation and macrophage activation via the RANKL and TLR4 signaling pathways. Ac-SDKP also attenuated the reduction in femoral bone mineral density in silicotic rats by inhibiting osteoclast differentiation via the RANKL signaling pathway. CONCLUSION: Our findings support the hypothesis that inhalation of crystalline silica induces activation of lung macrophages and bone osteoclasts via the RANKL and TLR4 signaling pathways. Ac-SDKP has the potential to stabilize lung homeostasis and bone metabolism.

Aetiology of acute diarrhoea in children in Shanghai, 2015-2018.

Diarrhoea remains a major cause of childhood morbidity and mortality worldwide. This study aimed to monitor the aetiology of acute diarrhoea in children in Shanghai. Paediatric outpatients with acute diarrhoea were enrolled in the study from Jan 2015 to Dec 2018. Faecal samples were collected for testing. Enteric bacteria were identified and typed by culture and serotyping, respectively. Enteric viruses were identified by real-time PCR. Enteric pathogens were identified in 1572 (58.4%) of the 2692 enrolled children with acute diarrhoea. Viruses were detected more frequently than bacteria (41.3% versus 25.0%). Nontyphoidal Salmonella spp. (NTS) was the most common (10.3%) bacteria isolated, followed by enteropathogenic Escherichia coli (EPEC) (6.5%), enteroaggregative Escherichia coli (EAEC) (6.2%), Campylobacter spp. (3.6%), enterotoxigenic Escherichia coli (ETEC) (1.1%), Shigella spp. (0.2%), and enterohemorrhagic Escherichia coli (EHEC) (0.1%). Rotavirus was the most common (16.0%) virus detected, followed by norovirus (15.5%), adenovirus (7.2%), sapovirus (3.0%) and astrovirus (2.7%). Rotavirus, norovirus and NTS were the major pathogens responsible for diarrhoea in Shanghainese children. Improving uptake of the rotavirus vaccine and strengthening foodborne-pathogen prevention will aid in reducing the burden of diarrhoeal disease in children in Shanghai.

Matrix stiffness regulates α-TAT1-mediated acetylation of α-tubulin and promotes silica-induced epithelial-mesenchymal transition via DNA damage.

Silicosis is characterized by silica exposure-induced lung interstitial fibrosis and formation of silicotic nodules, resulting in lung stiffening. The acetylation of microtubules mediated by α-tubulin N-acetyltransferase 1 (α-TAT1) is a posttranslational modification that promotes microtubule stability in response to mechanical stimulation. α-TAT1 and downstream acetylated α-tubulin (Ac-α-Tub) are decreased in silicosis, promoting the epithelial-mesenchymal transition (EMT); however, the underlying mechanisms are unknown. We found that silica, matrix stiffening or their combination triggered Ac-α-Tub downregulation in alveolar epithelial cells, followed by DNA damage and replication stress. α-TAT1 elevated Ac-α-Tub to limit replication stress and the EMT via trafficking of p53-binding protein 1 (53BP1, also known as TP53BP1). The results provide evidence that α-TAT1 and Ac-α-Tub inhibit the EMT and silicosis fibrosis by preventing 53BP1 mislocalization and relieving DNA damage. This study provides insight into how the cell cycle is regulated during the EMT and why the decrease in α-TAT1 and Ac-α-Tub promotes silicosis fibrosis.This article has an associated First Person interview with the first authors of the paper.