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We studied the influence of the fellow‐villager relationship between the independent directors and the chairman of the board and found that the above relationship significantly eased the shareholder's encroachment. Furthermore, the above suppression effect is more significant in the poor formal institutional environment, and higher equity balance will weaken the restraining effect. At last, we revealed that the reputation mechanism presented the key factor that urged independent directors to exert influence on the decision of the chairman through the fellow‐villager relationship and, in turn, inhibited the encroachment.

Deficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease. Using ASMKO mice, we report that ASM deficiency is associated with a complex inflammatory phenotype characterized by marked accumulation of monocyte-derived CD11b(+) macrophages and expansion of airspace/alveolar CD11c(+) CD11b(−) macrophages, both with increased size, granularity, and foaminess. Both the alternative and classical pathways were activated, with decreased in situ phagocytosis of opsonized (Fc-coated) targets, preserved clearance of apoptotic cells (efferocytosis), secretion of Th2 cytokines, increased CD11c(+)/CD11b(+) cells, and more than a twofold increase in lung and plasma proinflammatory cytokines. Macrophages, neutrophils, eosinophils, and noninflammatory lung cells of ASMKO lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, which formed large eosinophilic polygonal Charcot-Leyden–like crystals. In addition to providing insight into novel features of lung inflammation that may be associated with NPD, our report provides a novel connection between ASM and the development of crystal-associated lung inflammation with alterations in macrophage biology.

Objective: MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. Conclusions: miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.

Purpose At present, the number of corporates certified by ISO14001 in China is ranked first in the world. This paper aims to explore the effectiveness of ISO14001 certification and the moderating effect of financial performance and external institutional pressures on the effectiveness. Design/methodology/approach This paper selects Shenzhen and Shanghai A-share listed companies in the heavy polluting industry from 2010 to 2017 as the research sample, and studies the impact of ISO14001 certification on corporate environmental performance and the moderating effect of financial performance and external institutional pressures. Findings This paper finds that ISO14001 certification has a positive impact on corporate environmental performance; corporate financial performance has a positive moderating effect in the relationship between ISO14001 certification and corporate environmental performance; government regulation, industry competition and media supervision also have positive moderating effects; and corporate environmental information disclosure has not yet had a positive moderating effect. Originality/value Most of the current empirical research on this topic are carried out in the context of developed countries, and lack empirical evidence from developing countries. This paper will help to make up for this deficiency. In addition, this paper will help explain why the effectiveness of ISO14001 certification generates variation in different corporates and under what conditions it will play a positive role.

Rationale: The loss of pulmonary endothelial cells in emphysema is associated with increased lung ceramide. Ceramide perturbations may cause adaptive alterations in other bioactive sphingolipids, with pathogenic implications. We previously reported a negative correlation between emphysema and circulating glycosphingolipids (GSLs). Glucosylceramide (GlcCer), the initial GSL synthesized from ceramide by GCS (GlcCer synthase), is required for embryonic survival, but its role in the lung is unknown.Objectives: To determine if cigarette smoke (CS) alters lung GlcCer and to elucidate the role of GCS in lung endothelial cell fate.Methods: GlcCer was measured by tandem mass spectrometry in BAL fluid of CS- or elastase-exposed mice, and GCS was detected by Western blotting in chronic obstructive pulmonary disease lungs and CS extract-exposed primary human lung microvascular endothelial cells (HLMVECs). The role of GlcCer and GCS on mTOR (mammalian target of rapamycin) signaling, autophagy, lysosomal function, and cell death were studied in HLMVECs with or without CS exposure.Measurements and Main Results: Mice exposed to chronic CS or to elastase, and patients with chronic obstructive pulmonary disease, exhibited significantly decreased lung GlcCer and GCS. In mice, lung GlcCer levels were negatively correlated with airspace size. GCS inhibition in HLMVEC increased lysosomal pH, suppressed mTOR signaling, and triggered autophagy with impaired lysosomal degradation and apoptosis, recapitulating CS effects. In turn, increasing GlcCer by GCS overexpression in HLMVEC improved autophagic flux and attenuated CS-induced apoptosis.Conclusions: Decreased GSL production in response to CS may be involved in emphysema pathogenesis, associated with autophagy with impaired lysosomal degradation and lung endothelial cell apoptosis.

A better understanding of the pathogenesis of distinct chronic obstructive pulmonary disease (COPD) phenotypes will improve diagnostic and therapeutic options for this common disease. We present evidence that sphingolipids such as ceramides are involved in the emphysema pathogenesis. Whereas distinct ceramide species cause cell death by apoptosis and necroptosis, cell adaptation leads to accumulation of other sphingolipid metabolites that extend cell survival by triggering autophagy. Cigarette smoke-released sphingolipids have been involved in both the initiation and persistence of lung injury via intracellular signaling and paracrine effects mediated via exosomes and plasma membrane-bound microparticles. Strategies to control sphingolipid metabolite production may promote cellular repair and maintenance to treat COPD.

Alpha-1 antitrypsin (A1AT), a circulating acute-phase reactant antiprotease, is produced and secreted by cells of endodermal epithelial origin, primarily hepatocytes, and by immune cells. Deficiency of A1AT is associated with increased risk of excessive lung inflammation and injury, especially following chronic cigarette smoke (CS) exposure. Exogenous administration of mesenchymal progenitor cells, including adipose tissue-derived stromal/stem cells (ASC), alleviates CS-induced lung injury through paracrine effectors such as growth factors. It is unknown, however, if mesodermal ASC can secrete functional A1AT and if CS exposure affects their A1AT production. Human ASC collected via liposuction from nonsmoking or smoking donors were stimulated by inflammatory cytokines tumor necrosis alpha (TNFα), oncostatin M (OSM), and/or dexamethasone (DEX) or were exposed to sublethal concentrations of ambient air control or CS extract (0.5%-2%). We detected minimal expression and secretion of A1AT by cultured ASC during unstimulated conditions, which significantly increased following stimulation with TNFα or OSM. Furthermore, TNFα and OSM synergistically enhanced A1AT expression and secretion, which were further increased by DEX. The A1AT transcript variant produced by stimulated ASC resembled that produced by bronchial epithelial cells rather than the variant produced by monocytes/macrophages. While the cigarette smoking status of the ASC donor had no measurable effect on the ability of ASC to induce A1AT expression, active exposure to CS extract markedly reduced A1AT expression and secretion by cultured ASC, as well as human tracheobronchial epithelial cells. ASC-secreted A1AT covalently complexed with neutrophil elastase in control ASC, but not in cells transfected with A1AT siRNA. Undifferentiated ASC may require priming to secrete functional A1AT, a potent antiprotease that may be relevant to stem cell therapeutic effects.

Histologic scoring of ALI lungs. A. Formalin-fixed, paraffin-embedded mice lungs (4 day post LPS instillation) were stained with hematoxylin and eosin and scored at high power fields (400X magnification). Neutrophils marked with blue arrowhead. B. Representative images of lung sections from LPS injured TSG-6 KO and WT mice compared to PBS control taken at lower power fields (100X and 200X). Scale bars: 25 μm (400X), 50 μm (200X), and 100 μm (100X). (DOCX 984 kb)

HC-modification of HA after LPS and PA injury. A. HC-modified HA following LPS injury at 1 and 4 dpi measured as in Fig. 1a. B. HC-modified HA following PA injury (2*106Â CFU) at 2 and 4 dpi measured as in Fig. 1b. HT denotes heterozygous TSG-6 control littermate. (DOCX 110 kb)

Effect of TSG-6 deficiency on lung HA molecular weight distribution and lavage HA levels following LPS injury. A. HA was extracted from lung tissue (LPS 1 dpi), separated by agarose gel, and visualized as described in Fig. 3. HT and KO denote TSG-6 heterozygous and knockout mice. Select-HA consisting of 2500, 1000, 500, and 250 kDa HA was used to determine the molecular weight. B. HA levels in bronchoalveolar lavage were measured by ELISA. n = 5–10 mice per group. (DOCX 87 kb)

TSG-6 is conserved for catalyzing HC-modification of HA. A. Modifying HA with heavy chains (HC) of the serum protein inter alpha inhibitor (IaI), also known as serum-derived HA-associated protein (SHAP), is the only covalent modification HA can undergo. B. TNFα-stimulated gene-6 (TSG-6) is an inflammation-induced secreted protein that exclusively mediates formation of HC-modified HA. Through two transesterification reactions, TSG-6 transfers HC from IαI onto itself and then onto HA. To form the TSG-6-HC intermediate, HC is covalently linked to a conserved serine residue adjacent to the TSG-6 Link domain that binds HA and facilitates HC transfer [1–5]. The serum protein IaI consists of a chondroitin sulfate that is covalently linked to the light chain bikunin and two heavy chains (HC1 and HC2) that can be removed by TSG-6. C. Alignment of TSG-6 pro-protein (residues 1–47 depicted, hTSG-6 numbering) containing the signal peptide (highlighted in gray) and start of the HA-binding Link domain (highlighted in green). The serine residue (highlighted in yellow) responsible for removing HC from serum IaI and transferring HC onto HA is evolutionarily conserved across all vertebrates including fish, reptile, and bird: Homo sapiens (human), Mus musculus (mouse), Equus caballus (horse), Bos taurus (cattle), Pelodiscus sinensis (chinese softshell turtle), and Danio rerio (zebrafish). CLUSTAL multiple sequence alignment by MUSCLE 3.8 (MUltiple Sequence Comparison by Log-Expectation); “*” (asterisk) indicates fully conserved residue. “:” (colon) indicates residues with strongly similar properties (>0.5 in Gonnet PAM 250); “.” (period) indicates residues with weakly similar properties (≤0.5 in Gonnet PAM 250). (DOCX 95 kb)

Correlation between HC-HA and markers of alveolar permeability. Correlation plot of HC-HA abundance, measured in arbitrary units (AU) versus BAL fluid albumin (A) or RAGE (B) levels in individual mice exposed to LPS for 1 or 4Â days compared to PBS control with simple linear regression line and coefficient of determination (R-squared). (DOCX 36 kb)

Background Several inflammatory lung diseases display abundant presence of hyaluronic acid (HA) bound to heavy chains (HC) of serum protein inter-alpha-inhibitor (IαI) in the extracellular matrix. The HC-HA modification is critical to neutrophil sequestration in liver sinusoids and to survival during experimental lipopolysaccharide (LPS)-induced sepsis. Therefore, the covalent HC-HA binding, which is exclusively mediated by tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6), may play an important role in the onset or the resolution of lung inflammation in acute lung injury (ALI) induced by respiratory infection. Methods Reversible ALI was induced by a single intratracheal instillation of LPS or Pseudomonas aeruginosa in mice and outcomes were studied for up to six days. We measured in the lung or the bronchoalveolar fluid HC-HA formation, HA immunostaining localization and roughness, HA fragment abundance, and markers of lung inflammation and lung injury. We also assessed TSG-6 secretion by TNFα- or LPS-stimulated human alveolar macrophages, lung fibroblast Wi38, and bronchial epithelial BEAS-2B cells. Results Extensive HC-modification of lung HA, localized predominantly in the peri-broncho-vascular extracellular matrix, was notable early during the onset of inflammation and was markedly decreased during its resolution. Whereas human alveolar macrophages secreted functional TSG-6 following both TNFα and LPS stimulation, fibroblasts and bronchial epithelial cells responded to only TNFα. Compared to wild type, TSG-6-KO mice, which lacked HC-modified HA, exhibited modest increases in inflammatory cells in the lung, but no significant differences in markers of lung inflammation or injury, including histopathological lung injury scores. Conclusions Respiratory infection induces rapid HC modification of HA followed by fragmentation and clearance, with kinetics that parallel the onset and resolution phase of ALI, respectively. Alveolar macrophages may be an important source of pulmonary TSG-6 required for HA remodeling. The formation of HC-modified HA had a minor role in the onset, severity, or resolution of experimental reversible ALI induced by respiratory infection with gram-negative bacteria. Electronic supplementary material The online version of this article (10.1186/s12931-018-0812-1) contains supplementary material, which is available to authorized users.

Circulating endothelial microparticles (EMPs) are emerging as biomarkers of chronic obstructive pulmonary disease (COPD) in individuals exposed to cigarette smoke (CS), but their mechanism of release and function remain unknown. We assessed biochemical and functional characteristics of EMPs and circulating microparticles (cMPs) released by CS. CS exposure was sufficient to increase microparticle levels in plasma of humans and mice and in supernatants of primary human lung microvascular endothelial cells. CS-released EMPs contained predominantly exosomes that were significantly enriched in let-7d, miR-191; miR-126; and miR125a, microRNAs that reciprocally decreased intracellular in CS-exposed endothelium. CS-released EMPs and cMPs were ceramide-rich and required the ceramide-synthesis enzyme acid sphingomyelinase (aSMase) for their release, an enzyme which was found to exhibit significantly higher activity in plasma of COPD patients or of CS-exposed mice. The ex vivo or in vivo engulfment of EMPs or cMPs by peripheral blood monocytes-derived macrophages was associated with significant inhibition of efferocytosis. Our results indicate that CS, via aSMase, releases circulating EMPs with distinct microRNA cargo and that EMPs affect the clearance of apoptotic cells by specialized macrophages. These targetable effects may be important in the pathogenesis of diseases linked to endothelial injury and inflammation in smokers.

With the continuous development of economic globalization and regional economic integration, the economic ties between the countries and regions are increasingly close, the economic cooperation between the regions has become a common economic phenomenon. The organic combination of the basic principle of system dynamics and modern logistics, probing into the new concept of regional logistics system dynamics and modeling method. According to the characteristics of the regional logistics system, the establishment of regional logistics system dynamics model, through the example of regional logistics system analysis, prove the model is practical and guiding significance, and proved that the established model of regional logistics system is the study of regional logistics problem is feasible and effective method.

The rapid development of business activities to accelerate the development of logistics industry. As the global economy and the advancement of electronic business logistics costs in the proportion of the whole cost is more and more big, the effectiveness of the logistics problems have become more and more prominent. As information technology, communication technology and the development of artificial intelligence technology, fully tap existing logistics resources potential, improve logistics resource utilization, conform to the requirements of the current development. Detail in this paper, the logistics in the matching problem of vehicle scheduling problem is studied, and effective integration of vehicle transportation, goods and transport resources effectively, make full use of limited resources of vehicles, improve the quality of service, cost savings, reduce the energy consumption and reducing exhaust gas pollution, achieve the sustainable development of social and economic benefits.

Effect of LPS on HA staining. A. Representative images of paraformaldehyde-fixed, frozen lung sections immunostained as described for Fig. 4 shown here in detail. Changes in HA staining can be seen in the peri-broncho-vascular interstitium (white arrow). B. Representative sections from independent animals (n = 3 mice per group). Br depicts a bronchial airway and V pulmonary vessels. Scale bar 50 μm. (DOCX 821 kb)

TSG-6 expression in resident and recruited mouse alveolar macrophages. Resident and recruited mouse alveolar macrophages (msAM) were isolated from bronchoalveolar lavage of LPS treated mice (20 μg intratracheal; 0, 3, 6, 9, and 12 dpi). Expression level of msTSG-6 was assessed by RNA-seq and shown as transcripts per million (TPM). Mean (n = 3 independently pooled samples per time point, 4–7 mice for each pool) and error bar (SD) plotted. ND, not detected; NA, not applicable; SD, standard deviation. (DOCX 42 kb)

Effect of LPS on HA staining. A. Representative images of paraformaldehyde-fixed, frozen lung sections immunostained as described for Fig. 4 shown here in detail. Changes in HA staining can be seen in the peri-broncho-vascular interstitium (white arrow). B. Representative sections from independent animals (n = 3 mice per group). Br depicts a bronchial airway and V pulmonary vessels. Scale bar 50 μm. (DOCX 821 kb)

TSG-6 expression in resident and recruited mouse alveolar macrophages. Resident and recruited mouse alveolar macrophages (msAM) were isolated from bronchoalveolar lavage of LPS treated mice (20 μg intratracheal; 0, 3, 6, 9, and 12 dpi). Expression level of msTSG-6 was assessed by RNA-seq and shown as transcripts per million (TPM). Mean (n = 3 independently pooled samples per time point, 4–7 mice for each pool) and error bar (SD) plotted. ND, not detected; NA, not applicable; SD, standard deviation. (DOCX 42 kb)