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Fang-Yi Yu,* Kua Zheng,* Yin-Fang Wu,* Shen-Wei Gao, Qing-Yu Weng, Chen Zhu, Yan-Ping Wu, Miao Li, Zhong-Nan Qin, Jia-Fei Lou, Zhi-Hua Chen, Song-Min Ying, Hua-Hao Shen, Wen Li Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Li, Tel +86-571-87783729, Fax +86-571-87068001, Email liwen@zju.edu.cnPurpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism.Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models.Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia.Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.Keywords: Staphylococcus aureus, pneumonia, macrophage, rapamycin, mTOR- ribosomal protein S6 signaling pathway

Yong Wang,1 Jie-Sen Zhou,1 Xu-Chen Xu,1 Zhou-Yang Li,1 Hai-Pin Chen,1 Song-Min Ying,1 Wen Li,1 Hua-Hao Shen,1,2 Zhi-Hua Chen1 1Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 2State Key Laboratory of Respiratory Disease, Guangzhou, People’s Republic of China Introduction: Bronchial epithelial cell death and airway inflammation induced by cigarette smoke (CS) have been involved in the pathogenesis of COPD. GRP78, belonging to heat shock protein 70 family, has been implicated in cell death and inflammation, while little is known about its roles in COPD. Here, we demonstrate that GRP78 regulates CS-induced necroptosis and injury in bronchial epithelial cells.Materials and methods: GRP78 and necroptosis markers were examined in human bronchial epithelial (HBE) cell line, primary mouse tracheal epithelial cells, and mouse lungs. siRNA targeting GRP78 gene and necroptosis inhibitor were used. Expression of inflammatory cytokines, mucin MUC5AC, and related signaling pathways were detected.Results: Exposure to CS significantly increased the expression of GRP78 and necroptosis markers in HBE cell line, primary mouse tracheal epithelial cells, and mouse lungs. Inhibition of GRP78 significantly suppressed CS extract (CSE)-induced necroptosis. Furthermore, GRP78–necroptosis cooperatively regulated CSE-induced inflammatory cytokines such as interleukin 6 (IL6), IL8, and mucin MUC5AC in HBE cells, likely through the activation of nuclear factor (NF-κB) and activator protein 1 (AP-1) pathways, respectively.Conclusion: Taken together, our results demonstrate that GRP78 promotes CSE-induced inflammatory response and mucus hyperproduction in airway epithelial cells, likely through upregulation of necroptosis and subsequent activation of NF-κB and AP-1 pathways. Thus, inhibition of GRP78 and/or inhibition of necroptosis could be the effective therapeutic approaches for the treatment of COPD. Keywords: cigarette smoke, airway epithelium, glucose-regulated protein 78, necroptosis, airway injury

Asthma is a heterogeneous disease characterized by chronic airway inflammation. More than half of asthma cases are induced by allergens. Eosinophils accumulate in large numbers in the airways, and their number is closely related to the severity of asthma. In recent years, extensive research has been conducted on the pathogenesis of eosinophils in asthma and the targeted therapeutic drugs for them. This article mainly reviews the research progress on the important role of eosinophil heterogeneity in the occurrence and development of asthma, and provides ideas for the personalized and precise treatment of asthma in the future.

MOF-808, owing to the synergistic effect of its large surface area and surface charge matching, showed a diclofenac sodium (DCF) removal capacity as high as 630 mg g -1 , and the ability to adsorb 436 mg g -1 DCF in two hours, outperforming many common Zr-MOFs under the same conditions. Importantly, a series of free-standing mixed-matrix membranes made by combining polyacrylonitrile with MOF-808 were fabricated and exhibited high efficiency of removing DCF from water via an easily accessible filtration method., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: To evaluate the awareness, diagnosis and treatment of chest tightness variant asthma (CTVA) among pediatricians in China. Methods: The survey was conducted by convenient sampling method. Pediatricians with professional title of attending physician and above from different grades hospitals in 30 provinces were invited to conduct online questionnaire surveys through WeChat, pediatricians scan QR codes to complete electronic questionnaires in the mini program from January 16th to February 4th, 2021. The contents of questionnaire included the awareness, diagnosis and treatment of CTVA, and comparing the differences between pediatricians in secondary hospitals and tertiary hospitals. Results: A total of 1 529 pediatricians participated in the survey, and 1 484 (97.06%) pediatricians completed the questionnaire and included in the analysis, including 420 males (28.30%). The awareness rate of CTVA among pediatricians was 77.83 % (1 155/1 484). Pediatricians in tertiary hospitals had higher rates of awareness of CTVA than pediatricians in secondary hospitals [81.86% (898/1 097) vs 66.41% (257/387), P <0.001] and had better execution of the guidelines [89.15% (978/1 097) vs 79.59% (308/387), P <0.001]. A total of 93.06 % (1 381/1 484) of pediatricians' first-line treatment included inhaled corticosteroids (ICS) for CTVA. Among them, a higher proportion of pediatricians in tertiary hospitals used ICS included regimens for first-line treatment of CTVA compared with pediatricians in secondary hospitals [94.90% (1 041/1 097) vs 87.86% (340/387), P <0.001]. The reported well control rate of CTVA was 32.08% (476/1 484), which was significantly lower in secondary hospitals than that in tertiary hospitals [17.31% (67/387) vs 37.28% (409/1 097), P <0.001]. Conclusion: Most pediatricians are well aware of CTVA, among which there is a certain gap in clinical practice between pediatricians in secondary hospitals and tertiary hospitals in terms of understanding, diagnosis, and treatment of CTVA.

Polymorphs of ZnHPO 3 ·2H 2 O with centrosymmetry ( Cmcm ) and noncentrosymmetry ( C 2) structures were prepared by modified solution evaporation and seed-crystal-induced secondary nucleation methods. In Cmcm -ZnHPO 3 ·2H 2 O, the zinc atoms are only octahedrally coordinated, while in C 2-ZnHPO 3 ·2H 2 O, they feature both tetrahedral and octahedral coordination. As a result, Cmcm -ZnHPO 3 ·2H 2 O features a 2D layered structure with lattice water molecules located in the interlayer space, while C 2-ZnHPO 3 ·2H 2 O features a 3D electroneutral framework of tfa topology connected by Zn(1)O 4 , Zn(2)O 6 , and HPO 3 units. The UV-visible diffuse reflectance spectra associated with Tauc's analyses give a direct bandgap of 4.24 and 4.33 eV for Cmcm -ZnHPO 3 ·2H 2 O and C 2-ZnHPO 3 ·2H 2 O, respectively. Moreover, C 2-ZnHPO 3 ·2H 2 O exhibits a weak second harmonic generation (SHG) response and a moderate birefringence for phase matching, indicating its potential as a nonlinear optical material. Detailed dipole moment calculation and analysis confirmed that the SHG response mainly derived from the HPO 3 pseudo-tetrahedra.

Data and clinical guidelines on the management of osteoporosis in nonagenarians are lacking. The aim of this study was to assess the characteristics of osteoporosis management and identify any gaps or trends in a cohort of nonagenarians who were newly diagnosed with osteoporosis during an inpatient admission. A retrospective analysis of nonagenarians admitted to the medicine department of a tertiary hospital who were newly diagnosed with osteoporosis based on extracted ICD-10 codes. Baseline demographics, frailty based on the clinical frailty scale, comorbidities, initiation, compliance and adverse effects on osteoporosis medication were analysed. Mean age of the study group was 93.0 ± 2.5 years. There was a high prevalence of frailty (71.7%), cognitive impairment (34.2%) and recurrent falls (30.0%). 82.5% were started on osteoporosis treatment with denosumab (43.4%) being the most prescribed, followed by alendronate (41.4%). Cognitive impairment and male gender were associated with less likelihood of being on osteoporosis treatment on multivariate analysis. Having a previous fracture was associated with a higher likelihood of being on osteoporosis treatment. There was a discontinuation rate of 49.5% with a mean time to discontinuation of 26.3 ± 22.9 months. There was a high rate of osteoporosis treatment in nonagenarians with osteoporosis. The presence of previous fractures was associated with initiation of osteoporosis medications, whereas frailty and falls had no impact on treatment decisions. Cognitive impairment and males were associated with a lower rate of initiation of osteoporosis medication., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Major histocompatibility complex class II (MHC II) is an essential immune regulatory molecule that plays an important role in antigen presentation and T-cell development. Abnormal MHC II expression can lead to immunodeficiency, clinically termed as type II bare lymphocyte syndrome (BLS), which usually results from mutations in the MHC II transactivator (CIITA) and other coactivators. Here, we present a new paradigm for MHC II deficiency in mice that involves a spontaneous point mutation on H2-Aa. A significantly reduced population of CD4 + T cells was observed in mice obtained from the long-term homozygous breeding of autophagy-related gene microtubule-associated protein 1 light chain 3 β (Map1 lc3b , Lc3b ) knockout mice; this phenotype was not attributed to the original knocked-out gene. MHC II expression was generally reduced, together with a marked deficiency of H2-Aa in the immune cells of these mice. Using cDNA and DNA sequencing, a spontaneous H2-Aa point mutation that led to false pre-mRNA splicing, deletion of eight bases in the mRNA, and protein frameshift was identified in these mice. These findings led to the discovery of a new type of spontaneous MHC II deficiency and provided a new paradigm to explain type II BLS in mice., Competing Interests: JX was employed by Qihan Bio Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Xiong, Chen, Zhang, Zhou, Wu, Li, Fei, Li, Zhu, Li, Ying, Wang, Chen and Shen.)

Cigarette smoke (CS)-induced macrophage activation and airway epithelial injury are both critical for the development of chronic obstructive pulmonary disease (COPD), while the eventual functions of autophagy in these processes remain controversial. We have recently developed a novel COPD mouse model which is based on the autoimmune response sensitized by CS and facilitated by elastin. In the current study, we therefore utilized this model to investigate the roles of autophagy in different stages of the development of bronchitis-like airway inflammation. Autophagic markers were increased in airway epithelium and lung tissues, and Becn +/- or Lc3b -/ - mice exhibited reduced neutrophilic airway inflammation and mucus hyperproduction in this COPD mouse model. Moreover, treatment of an autophagic inhibitor 3-methyladenine (3-MA) either during CS-initiated sensitization or during elastin provocation significantly inhibited the bronchitis-like phenotypes in mice. Short CS exposure rapidly induced expression of matrix metallopeptidase 12 (MMP12) in alveolar macrophages, and treatment of doxycycline, a pan metalloproteinase inhibitor, during CS exposure effectively attenuated the ensuing elastin-induced airway inflammation in mice. CS extract triggered MMP12 expression in cultured macrophages, which was attenuated by autophagy impairment ( Becn +/- or Lc3b -/ - ) or inhibition (3-MA or Spautin-1). These data, taken together, demonstrate that autophagy mediates both the CS-initiated MMP12 activation in macrophages and subsequent airway epithelial injury, eventually contributing to development COPD-like airway inflammation. This study reemphasizes that inhibition of autophagy as a novel therapeutic strategy for CS-induced COPD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Li, Li, Jing, Liu, Xu, Chen, Dong, Zhang, Ying, Li, Shen, Li and Chen.)

Introduction: Acute lung injury (ALI) is a fatal but undertreated condition with severe neutrophilic inflammation, although little is known about the functions of eosinophils in the pathogenesis of ALI. Our objectives were to investigate the roles and molecular mechanisms of eosinophils in ALI., Methods: Pulmonary eosinophils were identified by flow cytometry. Mice with abundant or deficient eosinophils were used. Cellularity of eosinophils and neutrophils in bronchoalveolar lavage fluid, inflammatory assessment, and survival rate were determined. Human samples were also used for validating experimental results., Results: Blood eosinophils were increased in surviving patients with acute respiratory distress syndrome (ARDS) independent of corticosteroid usage. There existed homeostatic eosinophils in lung parenchyma in mice and these homeostatic eosinophils, originating from the bone marrow, were predominantly CD101 - . More CD101 - eosinophils could be recruited earlier than lipopolysaccharide (LPS)-initiated neutrophilic inflammation. Loss of eosinophils augmented LPS-induced pulmonary injury. Homeostatic CD101 - eosinophils ameliorated, while allergic CD101 + eosinophils exacerbated, the neutrophilic inflammation induced by LPS. Likewise, CD101 expression in eosinophils from ARDS patients did not differ from healthy subjects. Mechanistically, CD101 - eosinophils exhibited higher levels of Alox15 and Protectin D1. Administration of Protectin D1 isomer attenuated the neutrophilic inflammation., Conclusions: Collectively, our findings identify an uncovered function of native CD101 - eosinophils in suppressing neutrophilic lung inflammation and suggest a potential therapeutic target for ALI., Competing Interests: Conflict of interest: C. Zhu has nothing to disclose. Conflict of interest: Q-Y. Weng has nothing to disclose. Conflict of interest: L-R. Zhou has nothing to disclose. Conflict of interest: C. Cao has nothing to disclose. Conflict of interest: F. Li has nothing to disclose. Conflict of interest: Y-F. Wu has nothing to disclose. Conflict of interest: Y-P. Wu has nothing to disclose. Conflict of interest: M. Li has nothing to disclose. Conflict of interest: Y. Hu has nothing to disclose. Conflict of interest: J-X. Shen has nothing to disclose. Conflict of interest: X-F. Xiong has nothing to disclose. Conflict of interest: F. Lan has nothing to disclose. Conflict of interest: L-X. Xia has nothing to disclose. Conflict of interest: B. Zhang has nothing to disclose. Conflict of interest: H. Zhang has nothing to disclose. Conflict of interest: M. Huang has nothing to disclose. Conflict of interest: S-M. Ying has nothing to disclose. Conflict of interest: H-H. Shen has nothing to disclose. Conflict of interest: Z-H. Chen has nothing to disclose. Conflict of interest: W. Li has nothing to disclose., (Copyright ©ERS 2020.)

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1 -/- , Mmp12 -/- , and Il17a -/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1 -/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD., Competing Interests: Conflict of interest: Jie-Sen Zhou has nothing to disclose. Conflict of interest: Zhou-Yang Li has nothing to disclose. Conflict of interest: Xu-Chen Xu has nothing to disclose. Conflict of interest: Yun Zhao has nothing to disclose. Conflict of interest: Yong Wang has nothing to disclose. Conflict of interest: Hai-Pin Chen has nothing to disclose. Conflict of interest: Min Zhang has nothing to disclose. Conflict of interest: Yin-Fang Wu has nothing to disclose. Conflict of interest: Tian-Wen Lai has nothing to disclose. Conflict of interest: Chun-Hong Di has nothing to disclose. Conflict of interest: Ling-Ling Dong has nothing to disclose. Conflict of interest: Juan Liu has nothing to disclose. Conflict of interest: Nan-Xia Xuan has nothing to disclose. Conflict of interest: Chen Zhu has nothing to disclose. Conflict of interest: Yan-Ping Wu has nothing to disclose. Conflict of interest: Hua-Qiong Huang has nothing to disclose. Conflict of interest: Fu-Gui Yan has nothing to disclose. Conflict of interest: Wen Hua has nothing to disclose. Conflict of interest: Yi Wang has nothing to disclose. Conflict of interest: Wei-Ning Xiong has nothing to disclose. Conflict of interest: Hui Qiu has nothing to disclose. Conflict of interest: Tao Chen has nothing to disclose. Conflict of interest: Dong Weng has nothing to disclose. Conflict of interest: Hui-Ping Li has nothing to disclose. Conflict of interest: Xiaobo Zhou has nothing to disclose. Conflict of interest: Lie Wang has nothing to disclose. Conflict of interest: Fang Liu has nothing to disclose. Conflict of interest: Xin Lin has nothing to disclose. Conflict of interest: Song-Min Ying has nothing to disclose. Conflict of interest: Wen Li has nothing to disclose. Conflict of interest: Mitsuru Imamura has nothing to disclose. Conflict of interest: M.E. Choi has nothing to disclose. Conflict of interest: M.R. Stampfli has nothing to disclose. Conflict of interest: A.M.K. Choi has nothing to disclose. Conflict of interest: Zhi-Hua Chen has nothing to disclose. Conflict of interest: Hua-Hao Shen has nothing to disclose., (Copyright ©ERS 2020.)

Particulate matter (PM) is able to induce airway epithelial injury, while the detailed mechanisms remain unclear. Here we demonstrated that PM exposure inactivated MTOR (mechanistic target of rapamycin kinase), enhanced macroautophagy/autophagy, and impaired lysosomal activity in HBE (human bronchial epithelial) cells and in mouse airway epithelium. Genetic or pharmaceutical inhibition of MTOR significantly enhanced, while inhibition of autophagy attenuated, PM-induced IL6 expression in HBE cells. Consistently, club-cell-specific deletion of Mtor aggravated, whereas loss of Atg5 in bronchial epithelium reduced, PM-induced airway inflammation. Interestingly, the augmented inflammatory responses caused by MTOR deficiency were markedly attenuated by blockage of downstream autophagy both in vitro and in vivo . Mechanistically, the dysregulation of MTOR-autophagy signaling was partially dependent on activation of upstream TSC2, and interacted with the TLR4-MYD88 to orchestrate the downstream NFKB activity and to regulate the production of inflammatory cytokines in airway epithelium. Moreover, inhibition of autophagy reduced the expression of EPS15 and the subsequent endocytosis of PM. Taken together, the present study provides a mechanistic explanation for how airway epithelium localized MTOR-autophagy axis regulates PM-induced airway injury, suggesting that activation of MTOR and/or suppression of autophagy in local airway might be effective therapeutic strategies for PM-related airway disorders. Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; ALI: air liquid interface; AP2: adaptor related protein complex 2; ATG: autophagy related; BALF: bronchoalveolar lavage fluid; COPD: chronic obstructive pulmonary disease; CXCL: C-X-C motif chemokine ligand; DOX: doxycycline; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EPS15: epidermal growth factor receptor pathway substrate 15; HBE: human bronchial epithelial; H&E: hematoxylin & eosin; IKK: IKB kinase; IL: interleukin; LAMP2: lysosomal-associated membrane protein 2; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTEC: mouse tracheal epithelial cells; MTOR: mechanistic target of rapamycin kinase; MYD88: MYD88 innate immune signal transduction adaptor; NFKB: nuclear factor of kappa B; NFKBIA: NFKB inhibitor alpha; PM: particulate matter; PtdIns3K: phosphatidylinositol 3-kinase; Rapa: rapamycin; RELA: RELA proto-oncogene, NFKB subunit; SCGB1A1: secretoglobin family 1A member 1; siRNA: small interfering RNAs; SQSTM1: sequestosome 1; TEM: transmission electronic microscopy; TLR4: toll like receptor 4; TSC2: TSC complex subunit 2.

Objective: To explore the role of S100A8, the receptor for advanced glycation endproducts (RAGE) and Caveolin-1 in neutrophilic asthmatic rats, and to further study the intervention of roxithromycin and the possible mechanisms. Methods: Male Brown Norway rats were randomly assigned to a control group, an asthma group and a Roxithromycin group. The asthmatic rat model was established by intraperitoneal injection of ovalbumin (OVA) and Freund's complete adjuvant (FCA) mixture, and aerosol inhalation of OVA. Rats in the Roxithromycin group were given roxithromycin injection 30 mg/kg 30 minutes before each challenge. Rats in the control and the asthma groups were replaced with equal volumes of saline, respectively. Bronchoalveolar lavage fluid (BALF) neutrophil percentage (Neu%) and pathological changes of pulmonary tissue (hematoxylin-eosin, HE staining) were measured to confirm the establishment of asthmatic models. The concentration of inflammatory cytokines and S100A8 were quantified by enzyme-linked immunosorbent assay (ELISA), and the expression of Caveolin-1 and RAGE at protein levels were detected by immunohistochemistry and Western blot. Results: Neu% in BALF of the asthma group was significantly higher than those of the control group, and Neu% in the Roxithromycin group was lower than the asthma group (all P< 0.01). Pulmonary histology revealed that there were a large number of inflammatory cells infiltrated in the bronchial and perivascular, pulmonary interstitial and alveolar spaces, and the bronchial wall and smooth muscles were thickened obviously in the asthma group. Rats in the Roxithromycin group showed milder inflammation and airway remodeling change than the asthma group. There was no obvious pathological damage in the control group. The concentration of IL-6 and IL-17 in BALF and serum of rats in the asthma group were significantly higher than those in the control group ( P< 0.01), and Roxithromycin inhibited the high expression of these cytokines ( P< 0.05). The expression of S100A8 and RAGE in the asthma group were significantly higher than those in the control group [(20.6±4.4) vs (7.1±2.0) ng/L; (885±118) vs (462±102) ng/L; (14.2±1.7) vs (7.6±1.8) ng/L; (774±166) vs (406±69) ng/L, all P< 0.05], and Roxithromycin inhibited the high expression of these proteins [(14.3±3.7) vs (20.6±4.4) ng/L; (650±53) vs (885±118) ng/L; (10.4±1.2) vs (14.2±1.7) ng/L; (560±64) vs (728±72) ng/L] (all P< 0.05). Meanwhile, the expression of Caveolin-1 in the asthma group was significantly lower than that in the control group ( P< 0.01), and Roxithromycin up-regulated its expression ( P< 0.01). Correlation analysis showed that there was a significantly positive correlation between the expression of S100A8 and RAGE ( r= 0.706, P< 0.01), while there was a significantly negative correlation between the expression of S100A8 and Caveolin-1 ( r= -0.775, P< 0.01), and between the expression of Caveolin-1 and RAGE ( r= -0.919, P< 0.01). Conclusion: S100A8 and Caveolin-1 may play an important role in neutrophilic asthma via RAGE, and Roxithromycin may exerts anti-inflammatory effects and inhibition of airway remodeling partly through this signaling pathway.

Objective: To observe the expression of the Receptor of Advanced glycation end products (RAGE) in asthmatic rats, and explore the intervention of Roxithromycin. Methods: A total of 18 Specific Pathogen Free-class Brown Norway male rats were randomly divided into control group, asthma model group and Roxithromycin group, with 6 rats in each group. The asthmatic model was sensitized by intraperitoneal injection of Ovalbumin (OVA)+Al(OH)(3), and challenged with OVA. Rats in Roxithromycin group were given Roxithromycin 30 mg/kg 30 minutes before each challenge. Rats in control group and asthma model group were treated with equal volume of saline. The concentrations of RAGE and interleukin (IL)-4 in serum and bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent (ELISA); the pathological changes of lung tissues were observed by HE-staining; the thickness of airway wall and airway smooth muscle were measured by Image-Pro Plus; the relative expression of RAGE in lung tissues were detected by Western blot. Results: In asthma model group, the concentrations of RAGE and IL-4 in the serum and BALF were obviously higher than those in control group [(494±32) vs (327±45) ng/L; (32.4±5.8) vs (13.1±2.9) ng/L; (553±38) vs (399±56) ng/L; (37.8±3.4) vs (19.4±2.5) ng/L] (all P< 0.01); in Roxithromycin group, the concentrations of RAGE and IL-4 in the serum and BALF were obviously lower than those in asthma model group [(438±18) vs (494±32) ng/L; (22.8±6.0) vs (32.4±5.8) ng/L; (444±42) vs (553±38) ng/L; (25.6±4.5) vs (37.8±3.4) ng/L] (all P< 0.05). In asthma model group, the bronchial wall was thickened, the lumen was narrow, the mucosal wrinkles were significantly increased, edema appeared under the mucosa, and a large number of inflammatory cells infiltrated and aggregated in the bronchi, perivascular and alveolar spaces; the thickness of airway wall and airway smooth muscle were significantly increased than those in control group ( P< 0.01); in Roxithromycin group, airway inflammation and remodeling were alleviated compared with those in asthma model group ( P< 0.05). In asthma model group, the expression of RAGE in lung tissues were significantly increased than those in control group ( P< 0.01); in Roxithromycin group, the expression of RAGE were significantly decreased than those in asthma model group ( P< 0.01). There were positive correlations between the expression of RAGE and IL-4 in BALF and serum ( r= 0.782, 0.804, all P< 0.01); there were positive correlations between RAGE and total white cell counts, eosinophil counts, smooth muscle thickness ( r= 0.897, 0.927, 0.860, all P< 0.01). Conclusions: The increasing of RAGE in asthmatic rats are positively correlated with airway inflammation and airway remodeling. Roxithromycin may inhibit the development of asthma by reducing the expression of RAGE.

Two new indium sulfate tellurites, namely, In 2 (SO 4 )(TeO 3 )(OH) 2 (H 2 O) and In 3 (SO 4 )(TeO 3 ) 2 F 3 (H 2 O), were synthesized by hydrothermal method in a one-pot reaction. Their pure phase yields have been successfully optimized to 76% and 21%, respectively. In 2 (SO 4 )(TeO 3 )(OH) 2 (H 2 O) crystallized in centrosymmetric (CS) space group P 2 1 / n , while In 3 (SO 4 )(TeO 3 ) 2 F 3 (H 2 O) formed a non-centrosymmetric (NCS) and chiral space group P 2 1 2 1 2 1 . The CS compound features a 2D layered structure composed of 2D indium oxide layers decorated by sulfate tetrahedra and tellurite groups. The NCS compound displays a 3D network consisting of indium tellurite layers bridged by sulfate tetrahedra. Powder second harmonic generation measurements disclosed that In 3 (SO 4 )(TeO 3 ) 2 F 3 (H 2 O) exhibits a weak frequency-doubling efficiency about 11% of the commercial KDP. Its powder laser damage threshold quantity was estimated to be 79.6 MW/cm 2 , which is about 36 times that of AGS. The two samples present wide optical band gaps of 4.86 and 4.10 eV, respectively, which were determined by Te, In, and O atoms based on density functional theory calculations.

Tissue factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI). In this study, we explored the roles of targeted endothelial anticoagulation in ALI using two strains of transgenic mice expressing either a membrane-tethered human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31 + cells, including vascular endothelial cells (ECs). ALI was induced by intratracheal injection of LPS, and after 24 h the expression of TF and protease-activated receptors (PARs) on EC in lungs were assessed, alongside the extent of inflammation and injury. The expression of TF and PARs on the EC in lungs was upregulated after ALI. In the two strains of transgenic mice, expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the levels of proinflammatory cytokines, and promoted survival after LPS-induced ALI. The beneficial outcomes were associated with inhibition of the expression of chemokine CCL2 in lung tissues. The protection observed in the CD31-TFPI-transgenic strain was abolished by injection of an anti-hTFPI antibody, but not by prior engraftment of the transgenic strains with WT bone marrow, confirming that the changes observed were a specific transgenic expression of anticoagulants by EC. These results demonstrate that the inflammation in ALI is TF and thrombin dependent, and that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment.

Background: Aerosolized antibiotics have been proposed as a novel and promising treatment option for the treatment of ventilator-associated pneumonia (VAP). However, the optimum aerosolized antibiotics for VAP remain uncertain., Methods: We included studies from two systematic reviews and searched PubMed, EMBASE, and Cochrane databases for other studies. Eligible studies included randomized controlled trials and observational studies. Extracted data were analyzed by pairwise and network meta-analysis., Results: Eight observational and eight randomized studies were identified for this analysis. By pairwise meta-analysis using intravenous antibiotics as the reference, patients treated with aerosolized antibiotics were associated with significantly higher rates of clinical recovery (risk ratio (RR) 1.21, 95% confidence interval (CI) 1.09-1.34; P = 0.001) and microbiological eradication (RR 1.42, 95% CI 1.22-1.650; P < 0.0001). There were no significant differences in the risks of mortality (RR 0.88, 95% CI 0.74-1.04; P = 0.127) or nephrotoxicity (RR 1.00, 95% CI 0.72-1.39; P = 0.995). Using network meta-analysis, clinical recovery benefits were seen only with aerosolized tobramycin and colistin (especially tobramycin), and microbiological eradication benefits were seen only with colistin. Aerosolized tobramycin was also associated with significantly lower mortality when compared with aerosolized amikacin and colistin and intravenous antibiotics. The assessment of rank probabilities indicated aerosolized tobramycin presented the greatest likelihood of having benefits for clinical recovery and mortality, and aerosolized colistin presented the best benefits for microbiological eradication., Conclusions: Aerosolized antibiotics appear to be a useful treatment for VAP with respect to clinical recovery and microbiological eradication, and do not increase mortality or nephrotoxicity risks. Our network meta-analysis in patients with VAP suggests that clinical recovery benefits are associated with aerosolized tobramycin and colistin (especially tobramycin), microbiological eradication with aerosolized colistin, and survival with aerosolized tobramycin, mostly based on observational studies. Due to the low levels of evidence, definitive recommendations cannot be made before additional, large randomized studies are carried out.

To study the short-term effects of air pollution on asthma visits and differences in susceptibility to various groups of people, data for asthma visits from January 1, 2013 to December 31, 2015 were obtained from a Hangzhou hospital. Considering the nonlinear relationships among concentration of air pollutants, respiratory hospital outpatient visits and meteorological factors, Generalized Additive Models (GAM) and stratification analysis were used to explore the lag effects and differences in people stratifications. The natural cubic spline function was used for smoothing the average temperature, the average relative humidity and the long-term trend, using dummy variables to control the effect of the day of the week and of holidays. Correlation of PM 2.5 , NO 2 and SO 2 daily mean concentrations were significant (under 0.01) in Spearman correlation analysis, while the correlations of daily mean temperature and 3 pollutants were significantly negative. The lag effects of PM 2.5 concentration on outpatient visits of asthma peaked at 3-5 days. The relative risk of asthma reached maximum at lag day 5 as 1.0056 (95% CI:1.0021-1.0091), with per 10 μg·m -3 increment of PM 2.5 concentration. The relative risk of asthma outpatient visits of all groups of patients were statistically significant ( P <0.05). The relative risk of asthma outpatient visits of males and young and middle-aged group were statistically significant at lag days 3-5, and for females and the elderly, were statistically significant at lag day 5. With the introduction of the effects of NO 2 , the relative risk of asthma outpatient visits increased at lag 5 day in co-pollutant models. The authors concluded that the increase of PM 2.5 may be related to the increase of asthma hospital outpatient visits within 3-5 days in Hangzhou, and the effects on male group and elderly group were more definite.

Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2-MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-κB pathway. Mice with a specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema-likely through modulation of autophagy, apoptosis, and necroptosis-and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Objective: The aim of this article was to evaluate the association of intracranial artery calcification (IAC) with acute downstream ischemic stroke (dAIS)/transient ischemic attack while considering stenosis., Methods: Consecutive stroke computed tomography angiography head/neck examinations from January 2010 to April 2010 were reviewed. Per-vessel IAC and stenosis of greater than or equal to 30% were documented by 2 neuroradiologists. Associations between calcification and dAIS were assessed using multivariate logistic regression, controlling for traditional risk factors and stenosis., Results: A total of 1287 arterial segments from 99 patients were reviewed. Intracranial artery calcification was significantly associated with dAIS (odds ratio [OR], 2.2; P = 0.009). This association persisted among nonstenotic arteries, with significantly higher likelihood of dAIS for arteries with IAC than those without (OR, 2.5; P = 0.009). However, among stenotic arteries, calcified stenoses had a lower association of dAIS than noncalcified stenoses (OR, 0.55; 95% confidence interval, 0.17-1.8; P = 0.33)., Conclusions: Without concurrent stenosis, IAC is a significant risk factor for dAIS. When stenosis is present, IAC does not increase the association with dAIS. Stenotic and nonstenotic calcifications may represent different disease processes, as represented in the histology literature.

Background: Increasing randomized controlled trials (RCTs) indicate that bronchoscopic lung volume reduction (BLVR) is effective for severe emphysema. In this meta-analysis, we investigated the efficacy and safety of BLVR in patients with severe emphysema., Methods: PubMed, Embase and the Cochrane Library and reference lists of related articles were searched, and RCTs that evaluated BLVR therapy VS conventional therapy were included. Meta-analysis was performed only when included RCTs ≥ 2 trials., Results: In total, 3 RCTs for endobronchial coils, 6 RCTs for endobronchial valves (EBV) and 2 RCTs for intrabronchial valves (IBV) were included. Compared with conventional therapy, endobronchial coils showed better response in minimal clinically important difference (MCID) for forced expiratory volume in 1s (FEV1) (RR = 2.37, 95% CI = 1.61 - 3.48, p < 0.0001), for 6-min walk test (6MWT) (RR = 2.05, 95% CI = 1.18 - 3.53, p = 0.01), and for St. George's Respiratory Questionnaire (SGRQ) (RR = 2.32, 95% CI = 1.77 - 3.03, p < 0.00001). EBV therapy also reached clinically significant improvement in FEV1 (RR = 2.96, 95% CI = 1.49 - 5.87, p = 0.002), in 6MWT (RR = 2.90, 95% CI = 1.24 - 6.79, p = 0.01), and in SGRQ (RR = 1.53, 95% CI = 1.22 - 1.92, p = 0.0002). Both coils and EBV treatment achieved statistically significant absolute change in FEV1, 6MWT, and SGRQ from baseline, also accompanied by serious adverse effects. Furthermore, subgroup analysis showed there was no difference between homogeneous and heterogeneous emphysema in coils group. However, IBV group failed to show superior to conventional group., Conclusions: Current meta-analysis indicates that coils or EBV treatment could significantly improve pulmonary function, exercise capacity, and quality of life compared with conventional therapy. Coils treatment could be applied in homogeneous emphysema, but further trials are needed., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Airway and lung inflammation is a fundamental hallmark of chronic obstructive pulmonary disease (COPD). Activating transcription factor 3 (ATF3) has been reported to negatively regulate many pro-inflammatory cytokines and chemokines. However, little is known about the impact of ATF3 on the inflammatory response of COPD. Since cigarette smoke (CS) is considered to be the most important risk factor in the etiology of COPD, we attempted to investigate the effects and molecular mechanisms of ATF3 in CS-induced inflammation. We observed an increase in the expression of ATF3 in the lung tissues of CS-exposed mice and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. In vitro results indicated that ATF3 inhibition significantly increased the expression of proinflammatory cytokines interleukin 6 (IL6) and interleukin 8 (IL8) in CSE-stimulated HBE cells. Furthermore, in vivo data verified that CS induced inflammatory cell recruitment around the bronchus. In addition, neutrophil infiltration in bronchoalveolar lavage fluid (BALF) of CS-exposed Atf3 -/- mice was markedly higher than in stimulated WT mice. Finally, ATF3 deficiency increased the in vitro and in vivo expression and phosphorylation of nuclear factor-κB (NF-κB), a positive mediator of inflammation. Thus, this study shows that ATF3 plays an important role in the negative regulation of CS-induced pro-inflammatory gene expression through downregulating NF-κB phosphorylation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mucus hypersecretion is an important pathologic feature of chronic obstructive pulmonary disease. Activating transcription factor 3 (ATF3) is an adaptive-response gene that participates in various cellular processes. However, little is known about its role in cigarette smoke (CS)-induced mucus hyperproduction. This study aimed to investigate the role and molecular mechanisms of ATF3 in CS-induced Mucin 5AC (MUC5AC) expression. ATF3 was elevated in lung tissues of mice exposed to CS for 12 weeks. Treatment with CS extract significantly induced ATF3 expression and MUC5AC production in human bronchial epithelial cells, NCI-H292, and mouse tracheal epithelial cells. Interference of ATF3 significantly attenuated CS-induced MUC5AC expression in NCI-H292 and human bronchial epithelial cells. Mouse tracheal epithelial cells isolated from Atf3 -/- mice also exhibited less MUC5AC production in response to CS extract treatment. In vivo, the Atf3 -/- mice also displayed a significantly reduced mucus production relative to wild-type controls in response to chronic CS exposure. Furthermore, a chromatin immunoprecipitation assay revealed increased ATF3 binding to the MUC5AC promoter after CS treatment, and this transcriptional binding was significantly inhibited by knockdown of JUN, a subunit of activator protein-1. These results demonstrate that ATF3 may be involved in activator protein-1 signaling and transcriptional promotion of CS-induced MUC5AC expression in airway epithelial cells., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

MTOR (mechanistic target of rapamycin [serine/threonine kinase]) plays a crucial role in many major cellular processes including metabolism, proliferation and macroautophagy/autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both MTOR and autophagy have been suggested to be involved in lung disorders, however, little is known about the role of MTOR and autophagy in pulmonary epithelium in the context of acute lung injury (ALI). In the present study, we observed that lipopolysaccharide (LPS) stimulation induced MTOR phosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-II, a hallmark of autophagy, in mouse lung epithelium and in human bronchial epithelial (HBE) cells. The activation of MTOR in HBE cells was mediated by TLR4 (toll-like receptor 4) signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, whereas inhibition of autophagy further augmented, LPS-induced expression of IL6 (interleukin 6) and IL8, through NFKB signaling in HBE cells. Mice with specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly attenuated airway inflammation, barrier disruption, and lung edema, and displayed prolonged survival in response to LPS exposure. Taken together, our results demonstrate that activation of MTOR in the epithelium promotes LPS-induced ALI, likely through downregulation of autophagy and the subsequent activation of NFKB. Thus, inhibition of MTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing ALI induced by certain bacteria.

Mucus hypersecretion is a common pathological feature of chronic airway inflammatory diseases including chronic obstructive pulmonary disease (COPD). However, the molecular basis for this condition remains incompletely understood. We have previously demonstrated a critical role of autophagy in COPD pathogenesis through mediating apoptosis of lung epithelial cells. In this study, we aimed to investigate the function of autophagy as well as its upstream and downstream signals in cigarette smoke-induced mucus production in human bronchial epithelial (HBE) cells and in mouse airways. Cigarette smoke extract (CSE), as well as the classical autophagy inducers starvation or Torin-1, significantly triggered MUC5AC expression, and inhibition of autophagy markedly attenuated CSE-induced mucus production. The CSE-induced autophagy was mediated by mitochondrial reactive oxygen species (mitoROS), which regulated mucin expression through the JNK and activator protein-1 pathway. Epidermal growth factor receptor (EGFR) was also required for CSE-induced MUC5AC in HBE cells, but it exerted inconsiderable effects on the autophagy-JNK signaling cascade. Airways of mice with dysfunctional autophagy-related genes displayed a markedly reduced number of goblet cells and attenuated levels of Muc5ac in response to cigarette smoke exposure. These results altogether suggest that mitoROS-dependent autophagy is essential for cigarette smoke-induced mucus hyperproduction in airway epithelial cells, and reemphasize autophagy inhibition as a novel therapeutic strategy for chronic airway diseases., (Copyright © 2016 the American Physiological Society.)

The somatotrophic axis plays important roles in influencing reproduction. All key members of this axis including growth hormone (GH, gh), GH receptors (ghra and ghrb), insulin-like growth factors (IGFs, igf1, igf2 and igf3) and IGF receptors (igf1ra and igf1rb) were detected in the zebrafish ovary. GH was exclusively expressed in the full-grown oocytes, while its receptors were detectable in both the follicle cells and oocytes. The IGFs and their receptors were all expressed in both compartments except igf3, which was expressed in the follicle cells only. During folliculogenesis, there was a sharp decrease of gh expression at follicle activation; however, the expression of its receptors increased significantly. The expression profiles of igf1, igf2a, and igf2b were similar to that of fshr, whereas igf3 expression was close to lhcgr, suggesting differential roles for different forms of IGFs in follicle development. To examine if the ovarian GH-IGF system is regulated by gonadotropins (e.g., hCG) and GH, we performed in vitro experiments using cultured zebrafish follicle cells. The expression of igf1 and igf1ra, but not others, was down-regulated by hCG (LH analog), whereas recombinant zebrafish GH stimulated igf1 expression. In addition, GH also increased the expression of activin βA subunit (inhbaa). In agreement with this, the stimulatory effect of GH but not IGF-I on oocyte maturation could be abolished by follistatin. In conclusion, the present study revealed an intrafollicular network involving GH-IGF mini-axis in the zebrafish ovary; however, it might not work in the same way as that of the systemic somatotrophic axis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

SHP2 participates in multiple signaling events by mediating T-cell development and function, and regulates cytokine-dependent granulopoiesis. To explore whether and how SHP2 can regulate bone-marrow eosinophil differentiation, we investigate the contribution of SHP2 in the bone-marrow eosinophil development in allergic mice. Blockade of SHP2 function by SHP2 inhibitor PHPS-1 or conditional shp2 knockdown by adenovirus-inhibited bone-marrow-derived eosinophil differentiation in vitro, with no detectable effects on the apoptosis of eosinophils. Furthermore, SHP2 induced eosinophil differentiation via regulation of the extracellular signal-regulated kinase pathway. Myeloid shp2 conditional knockout mice (LysM(cre)shp2(flox/flox)) failed to induce eosinophilia as well as airway hyper-responsiveness. The SHP2 inhibitor PHPS-1 also alleviated eosinophilic airway inflammation and airway hyper-responsiveness, accompanied by significantly reduced levels of systemic eosinophils and eosinophil lineage-committed progenitors in allergic mice. We demonstrate that inhibition of eosinophil development is SHP2-dependent and SHP2 is sufficient to promote eosinophil formation in vivo. Our data reveal SHP2 as a critical regulator of eosinophil differentiation, and inhibition of SHP2 specifically in myeloid cells alleviates allergic airway inflammation.

Suhuang antitussive capsule (Suhuang), a traditional Chinese medication, is found effective in treating chronic cough and cough variant asthma (CVA). This study aimed to determine the possible effects and underlying mechanisms of Suhuang on chronic ovalbumin (OVA)-induced airway hyperresponsiveness (AHR), inflammation, and remodeling in mice. Mice were randomly assigned to six experimental groups: control, OVA model with or without Suhuang (low dose: 3.5 g/kg, middle dose: 7.0 g/kg, high dose: 14.0 g/kg), or dexamethasone (2.5 mg/kg). AHR, inflammatory cells, cytokines in bronchoalveolar lavage fluid (BALF), lung pathology, mucus production, and airway remodeling were examined. We found Suhuang treated at lower doses effectively inhibited OVA-induced AHR, airway inflammation, mucus production and collagen deposition around the airway. High dose of Suhuang reduced most of the inflammatory hallmarks while exerted inconsiderable effects on the number of macrophages in BALF and AHR. At all doses, Suhuang significantly reduced the levels of interlukin (IL) -13 and transforming growth factor (TGF)-β1, but had little effects on IL-4, IL-5, IL-17A and interferon (IFN)-γ. Thus, Suhuang administration alleviates the pathological changes of chronic asthma likely through inhibition of IL-13 and TGF-β1. Suhuang might be a promising therapy for patients with allergic asthma in the future.

Environmental ultrafine particulate matter (PM) is capable of inducing airway injury, while the detailed molecular mechanisms remain largely unclear. Here, we demonstrate pivotal roles of autophagy in regulation of inflammation and mucus hyperproduction induced by PM containing environmentally persistent free radicals in human bronchial epithelial (HBE) cells and in mouse airways. PM was endocytosed by HBE cells and simultaneously triggered autophagosomes, which then engulfed the invading particles to form amphisomes and subsequent autolysosomes. Genetic blockage of autophagy markedly reduced PM-induced expression of inflammatory cytokines, e.g. IL8 and IL6, and MUC5AC in HBE cells. Mice with impaired autophagy due to knockdown of autophagy-related gene Becn1 or Lc3b displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Interference of the autophagic flux by lysosomal inhibition resulted in accumulated autophagosomes/amphisomes, and intriguingly, this process significantly aggravated the IL8 production through NFKB1, and markedly attenuated MUC5AC expression via activator protein 1. These data indicate that autophagy is required for PM-induced airway epithelial injury, and that inhibition of autophagy exerts therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction, although they are differentially orchestrated by the autophagic flux.

Asthma is one of the most common chronic inflammatory disorders, associated with reversible airflow obstruction, airway hyperresponsiveness, and airway remodeling. This disease has a significant impact on individuals, their families, and society. Standardized therapeutics such as inhaled corticosteroid in combination with long acting β2 agonist have been applied for asthma control; however, complementary and alternative medicines, especially herbal medicines, are still widely used all over the world. A growing body of literature suggests that various herbals or related products might be effective in inhibiting asthmatic inflammation. In this review, we summarize recent advances about the mechanistic studies of herbal medicines on allergic airway inflammation in animal models and their potential application into clinic for asthma control.

Metal-organic frameworks (MOFs) have potentially useful applications and an intriguing variety of architectures and topologies. Two homochiral coordination polymers have been synthesized by the hydrothermal method, namely poly[(μ-N-benzyl-L-phenylalaninato-κ(4)O,O':O,N)(μ-formato-κ(2)O:O')zinc(II)], [Zn(C16H16NO2)(HCOO)]n, (1), and poly[(μ-N-benzyl-L-leucinato-κ(4)O,O':O,N)(μ-formato-κ(2)O:O')zinc(II)], [Zn(C13H18NO2)(HCOO)]n, (2), and studied by single-crystal X-ray diffraction, elemental analyses, IR spectroscopy and fluorescence spectroscopy. Compounds (1) and (2) each have a two-dimensional layer structure, with the benzyl or isobutyl groups of the ligands directed towards the interlayer interface. Photoluminescence investigations show that both (1) and (2) display a strong emission in the blue region.

IL-17 is known to play important roles in immune and inflammatory disease, such as in asthma, but its functions in allergic airway inflammation are still controversial, and the molecular mechanisms mediating these functions remain unclear. Increased production of eosinophils in bone marrow and their emergence in the airway have been linked to the onset and progression of allergic asthma. In this study, we investigated the effects of exogenous IL-17 on allergic airway inflammation and explored the underlying molecular mechanisms through eosinophil generation. Exogenous IL-17 significantly attenuated the features of allergic inflammation induced by ovalbumin in mice. It inhibited eosinophil differentiation both in vivo and in vitro, accompanied by down-regulated expression of CC chemokine receptor 3, GATA binding protein 1 (GATA-1), and GATA binding protein 2 (GATA-2), as well as reduced formation of common myeloid progenitors and eosinophil progenitors, but without influencing eosinophil apoptosis. IL-17 also significantly decreased the number of eosinophils in IL-5-transgenic mice, although it notably increased the levels of IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor. In addition, IL-17 had little effect on secretion of the inflammatory cytokines by eosinophils. Neutralization of endogenous IL-17 significantly augmented eosinophil recruitment in the airways. Together, these findings suggest that exogenous IL-17 protects against allergic airway inflammation, most likely through inhibition of the eosinophil differentiation in bone marrow.

Two homochiral coordination polymers based on a chiral reduced Schiff base ligand, namely poly[(μ5-4-{[(NR,1S)-(1-carboxylato-2-phenylethyl)amino]methyl}benzoato)zinc(II)], [Zn(C17H15NO4)]n, (1), and poly[(μ5-4-{[(NR,1S)-(1-carboxylato-2-phenylethyl)amino]methyl}benzoato)cobalt(II)], [Co(C17H15NO4)]n, (2), have been obtained by hydrothermal methods and studied by single-crystal X-ray diffraction, elemental analyses, powder X-ray diffraction, thermogravimetric analysis, IR spectroscopy and fluorescence spectroscopy. Compounds (1) and (2) are isostructural and crystallize in the P2(1)2(1)2(1) space group. Both display a three-dimensional network structure with a one-dimensional channel, with the benzyl group of the ligand directed towards the channel. An investigation of photoluminescence properties shows that compound (1) displays a strong emission in the purple region.

The title compound, [Cd(C(8)H(18)NO(8)P(2))(2)](n), synthesized by hydrothermal methods, exhibits a layered structure in which the Cd(II) ion, occupying a centre of symmetry, is coordinated by six O atoms from four phosphonate ligands. The crosslinkage of CdO(6) octahedra by bridging phosphonate ligands results in a cadmium(II) phosphonate layer. Within the layer, there exists a 16-membered ring incorporating four -Cd-O-P-O- linkages. The uncoordinated carboxyl group of the ligand is oriented so that it penetrates the adjacent layer, taking part in hydrogen bonding to two uncoordinated phosphonate O atoms to form a CO(2)H/HO(2)P motif.

In the title complex, [CoCl(2)(C(12)H(8)N(2))(2)]·C(3)H(7)NO, which has twofold rotation symmetry, the Co(II) cation is coordinated by two 1,10-phenanthroline (phen) mol-ecules and two chloride ligands in a distorted octa-hedral geometry. In the crystal structure, a cavity is created by six complex mol-ecules connected by C-H⋯π inter-actions and non-classical C-H⋯Cl hydrogen bonds. The cavities are occupied by the disordered dimethyl-formamide solvent mol-ecule. The C and N atoms of the C-N bond in the solvent mol-ecule also lie on a crystallographic twofold rotation axis; the remaining atoms of the solvent are statistically disordered (ratio 0.5:0.5) about this axis.

The title complex, [Mn(C(6)H(5)N(2)O(4))(2)(H(2)O)(2)], was obtained by hydro-thermal synthesis. The Mn(II) atom, which lies on an inversion centre, displays a slightly distorted octa-hedral geometry. In the crystal packing, complex mol-ecules are linked by inter-molecular O-H⋯O and N-H⋯O hydrogen bonds to form a three-dimensional supramolecular structure. The title complex is isostructural with the corresponding cadmium(II) complex [Nie, Wen, Wu, Liu & Liu (2007 ▶). Acta Cryst. E63, m753-m755].

The title compound, [Mn(2)(HO(3)PCH(2)CH(2)COO)(2)(C(8)H(8)N(2))(2)(H(2)O)(2)], was obtained by hydro-thermal synthesis. The manganese(II) ions are six-coordinate and are linked by two 2-carboxy-ethyl-phospho-nate ligands, forming a centrosymmetric dimer. The Mn ions adopts a distorted octahedral coordination geometry. The dimers are further linked by O-H⋯O hydrogen bonds and π-π stacking inter-actions [centroid-centroid distance 4.2754 (4) Å].