Inflammation In Chronic Pulmonary Disease Research Articles

Protective effect of amygdalin on epithelial-mesenchymal transformation in experimental chronic obstructive pulmonary disease mice.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory pulmonary disease characterized by continuous, progressive limitation of airflow. Airway remodelling, which is correlated with epithelial-mesenchymal transitions (EMTs), is a typical pathophysiological change of COPD. Amygdalin, an active ingredient in the traditional Chinese medicine bitter almond with extensive pharmacological effects, was shown to inhibit tissue fibrosis in recent studies. In this study, a human bronchial epithelial cell line (BEAS-2B) and mice were exposed to cigarette smoke, and EMT levels were investigated after treatment with different concentrations of amygdalin. Morphology was assessed by immunohistochemical staining. Evaluation of the expression of TGF-β1, smad2/3, and p-smad2/3 in lung tissue was conducted out via ELISA, Western blot, and real-time PCR. The results showed that E-cadherin expression was significantly increased, whereas vimentin, TGF-β1, and phosphorylated smad2/3 (p-smad2/3) expression was markedly decreased in the amygdalin-treated groups compared with the model group. Therefore, our study demonstrated a protective role of amygdalin in the murine EMT process after COPD.

Munc13‑4 mediates human neutrophil elastase‑induced airway mucin5AC hypersecretion by interacting with syntaxin2.

The overexpression and hypersecretion of mucus is a hallmark of chronic pulmonary inflammatory disease. Mucin5AC (MUC5AC) is a major component of airway gel‑forming mucin. Members of the Unc13 (Munc13) protein family act as important activators of granule exocytosis from various types of mammalian cells. The present study aimed to determine the role of Munc13 family proteins in MUC5AC secretion via an invitro study with BEAS‑2B and Calu‑3 cell lines. Reverse transcription‑quantitative polymerase chain reaction and western blotting indicated that stimulation of the cells with 100nM human neutrophil elastase (hNE) for 1h did not affect the expression of either unc13 homolog B (Munc13‑2) or unc13 homolog D (Munc13‑4), but immunofluorescence analysis demonstrated that hNE treatment was associated with the recruitment of Munc13‑4 to the plasma membrane. Co‑immunoprecipitation analysis indicated increased binding between Munc13‑4 and syntaxin2 followingh NE stimulation; however, Munc13‑2 formed a stable interaction with syntaxin2 with or without hNE stimulation. Subsequently, Munc13‑2 and Munc13‑4 expression levels were downregulated in BEAS‑2B and Calu‑3 cells using small interfering RNA (siRNA). ELISAs and immunofluorescence analysis were performed to assess MUC5AC secretion and intracellular retention, respectively. Munc13‑2 siRNA transfection did not alter the expression levels of intracellular or secreted MUC5AC following hNE stimulation in either cell line; however, it increased the baseline intracellular levels of MUC5AC and decreased the amount of secreted MUC5AC. Conversely, Munc13‑4 siRNA transfection increased the intracellular levels of MUC5AC and decreased the amount of secreted MUC5AC following hNE stimulation, but did not affect their baseline quantities. The results of the present study indicate that Munc13‑2 may be an essential regulator of basal MUC5AC exocytosis, while Munc13‑4 appears to be a Munc13 protein subtype that may to be sensitive to hNE stimulation during airway MUC5AC hypersecretion.

Seventeen-Year Nationwide Trends in Use of Long-acting Bronchodilators and Inhaled Corticosteroids among Adults - A Danish Drug Utilization Study.

Long-acting bronchodilators and inhaled corticosteroids (ICS) are the cornerstones in treatment of chronic obstructive and inflammatory pulmonary diseases. However, non-adherence to guidelines is widespread. Detailed information on real-life treatment patterns is needed to promote rational use. We aimed to investigate nationwide time trends in individual-level treatment patterns of long-acting bronchodilators and ICS. Using nationwide Danish health registries, we identified all Danish adults with a prescription for long-acting bronchodilators and/or ICS from 2000 to 2016. We investigated the total use of long-acting bronchodilators and ICS, the proportion of current users and the rate of new users over time. Finally, we assessed treatment persistence. We included 23,061,681 prescriptions for long-acting bronchodilators and ICS issued to 805,860 individuals from 2000 to 2016. Over this period, the total annual amount of prescribed long-acting bronchodilators and ICS increased by 39%. Similarly, the proportion of adult users increased from 2.6% to 4.5%, mainly driven by the introduction of combination therapy and long-acting muscarinic antagonist (LAMA). Although the rate of new users of fixed-dose combination drugs increased substantially over time, the overall rate of new users was stable. In general, the proportion of patients on therapy after 1 year was low (25-53%), especially among young individuals and users of ICS. We document a pronounced increase in the total use of long-acting bronchodilators and ICS over time, mainly driven by the introduction of combination drugs and LAMA. Special attention should be paid to the low level of persistence, especially among young individuals and users of ICS.

Sex-bias in allergic asthma: androgens and group 2 innate lymphoid cells

Allergic asthma is a chronic pulmonary inflammatory disease initiated by exposure to normally harmless allergens and marked by bronchial hyperreactivity. It affects more than 300 million people worldwide. Asthma often starts in childhood. Epidemiological studies show that there are sexual disparities in the prevalence and severity of asthma. Before the age of 10, the disease is more common in boys. This tendency reverses at puberty suggesting a regulating role of the sex hormones. In this synthesis, we summarize current knowledge on the role of sex hormones in allergic inflammation, with a particular focus on the impact of androgens on the development and function of recently introduced group 2 innate lymphoid cell subsets (ILC2) as critical actors in the initiation of allergic responses.♢.

Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma.

Pediatric asthma is a chronic pulmonary inflammatory disease featuring hypersecretion of mucus and inflammation in the airway, resulting in dysfunction of the airway smooth muscle. Previous evidence demonstrated that latrophilins, a novel family of receptors, present a beneficial effect on airway smooth muscle cells. In the present study, the therapeutic effects of recombinant human latrophilin 3 (rhLPHN3) antibody (Ab) in patients with pediatric asthma were investigated, and the molecular mechanism underlying the function of LPHN3 in the treatment of asthma in clinical practice was examined. A total of 342 pediatric asthma cases were recruited and randomly divided into three groups, receiving treatment with rhLPHN3 Ab (n=134), salbutamol (n=108) or montelukast (n=100) by nasal aerosolization. Each group received the respective clinically tested dose for 16 weeks. Inflammatory factors interleukin (IL)-10, IL-17, IL-4, matrix metallopeptidase-9 (MMP-9), interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) levels in peripheral blood mononuclear cells were analyzed prior to and post treatment. The clinical outcomes revealed that pathological alterations were significantly improved following treatment with rhLPHN3 Ab for patients with pediatric asthma when compared with those receiving salbutamol and montelukast. It was also observed that rhLPHN3 Ab downregulated the plasma concentration levels of IL-10, IL-17, IL-4 and MMP-9, and upregulated IFN-γ and TGF-β levels in the three groups. In addition, clinical data demonstrated that rhLPHN3 Ab significantly promoted E-selectin and mucin 5AC expression, as well as improved the activation of nuclear factor (NF)-κB p65 DNA binding activity and the phosphorylation levels of protein kinase A. Furthermore, rhLPHN3 Ab markedly improved adhesion and proliferation of airway smooth muscle cells, which led to promotion of the contraction of these cells. In conclusion, these clinical data suggest that rhLPHN3 Ab serves an important role in the inhibition of inflammatory mediators through downregulation of NF-κB signaling pathway, which contributes to airway remodeling and bronchodilation in patients with pediatric asthma.

Hydrogen Sulfide: A Novel Player in Airway Development, Pathophysiology of Respiratory Diseases, and Antiviral Defenses.

Hydrogen sulfide (H2S) is a biologically relevant signaling molecule in mammals. Along with the volatile substances nitric oxide (NO) and carbon monoxide (CO), H2S is defined as a gasotransmitter. It plays a physiological role in a variety of functions, including synaptic transmission, vascular tone, angiogenesis, inflammation, and cellular signaling. The generation of H2S is catalyzed by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). The expression of CBS and CSE is tissue specific, with CBS being expressed predominantly in the brain, and CSE in peripheral tissues, including lungs. CSE expression and activity are developmentally regulated, and recent studies suggest that CSE plays an important role in lung alveolarization during fetal development. In the respiratory tract, endogenous H2S has been shown to participate in the regulation of important functions such as airway tone, pulmonary circulation, cell proliferation or apoptosis, fibrosis, oxidative stress, and inflammation. In the past few years, changes in the generation of H2S have been linked to the pathogenesis of a variety of acute and chronic inflammatory lung diseases, including asthma and chronic obstructive pulmonary disease. Recently, our laboratory made the critical discovery that cellular H2S exerts broad-spectrum antiviral activity both in vitro and in vivo, in addition to independent antiinflammatory activity. These findings have important implications for the development of novel therapeutic strategies for viral respiratory infections, as well as other inflammatory lung diseases, especially in light of recent significant efforts to generate controlled-release H2S donors for clinical therapeutic applications.

Mucoadhesive solid lipid microparticles for controlled release of a corticosteroid in the chronic obstructive pulmonary disease treatment.

Therapeutic efficacy of pulmonary diseases is often limited and drug delivery systems offer new solutions to clinical problems. Solid lipid microparticles (SLMs) are suggested as systems for the delivery of therapeutics to the lung as, because of their size, they are able to deposit into secondary bronchi. Here, we describe two novel different SLMs using chitosan and alginate such as mucoadhesive polymers and we also studied their biocompatibility and their effectiveness compared with the free drug in controlling senescence and inflammatory processes in cigarette smoke extracts. Data reported show that fluticasone propionate (FP)-loaded SLMs are more effective than FP alone in controlling oxidative stress. The therapeutic approach using FP-loaded microparticles could be a promising strategy for the treatment of the chronic inflammatory pulmonary diseases.

α-Asarone suppresses the proliferation and migration of ASMCs through targeting the lncRNA-PVT1/miR-203a/E2F3 signal pathway in RSV-infected rats.

Asthma is a chronic inflammatory pulmonary disease and respiratory syncytial virus (RSV) infection is a common cause of lower respiratory tract illness in infants and young children. α-Asarone presents many pharmacological effects and has been demonstrated to be useful in treating asthma. However, the functional mechanism of α-asarone in RSV-infected asthma has not been investigated. Long non-coding RNAs (lncRNAs) have been reported to play critical roles in many biological processes. Although many lncRNAs have been characterized, few were reported in asthma, especially in RSV-induced asthma. Currently, a novel post-transcriptional regulation has been proposed in which lncRNAs function as competing endogenous RNAs (ceRNAs) to competitively sponge miRNAs, thereby regulating the target genes. In the present study, we established an RSV-infected Sprague-Dawley rat model and demonstrated that lncRNA-PVT1 is involved in the mechanism of α-asarone in treating RSV-induced asthma, and lncRNA-PVT1 regulates the expression of E2F3 by functioning as a ceRNA which competitively sponges miR-203a.

RETRACTED: Efficacy of novel antibody-based drugs against rhinovirus infection: In vitro and in vivo results

Rhinoviruses (RVs) cause the common cold and are associated with exacerbations of chronic inflammatory respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). We have assessed the antiviral drugs Anaferon for Children (AC) and Ergoferon (containing AC as one of the active pharmaceutical ingredients) in invitro and invivo experimental models, in order to evaluate their anti-rhinoviral and immunomodulatory potential. HeLa cells were pretreated with AC, and levels of the interferon-stimulated gene (ISG), 2'-5'-oligoadenylate synthetase 1 (OAS1-A) and viral replication were analyzed. In a mouse model of RV-induced exacerbation of allergic airway inflammation we administered Ergoferon and analyzed its effect on type I (IFN-β), type II (IFN-γ) and type III (IFN-λ) IFNs induction, cell counts in bronchoalveolar lavage (BAL), cytokine (interleukin (IL)-4; IL-6) and chemokine (CXCL10/IP-10; CXCL1/KC) levels. It was shown that AC increased OAS1-А production and significantly decreased viral replication invitro. Increased IFNs expression together with reduced neutrophils/lymphocytes recruitment and correlated IL-4/IL-6 declination was demonstrated for Ergoferon invivo. However, there was no effect on examined chemokines. We conclude that AC and Ergoferon possess effects against RV infection and may have potential as novel therapies against RV-induced exacerbations of asthma.

Prevalence of osteoporosis and osteopenia in stable patients of chronic obstructive pulmonary disease in Sub-Himalayan region of Himachal Pradesh, India.

Background:Chronic obstructive pulmonary disease (COPD) is a lifestyle-related chronic inflammatory pulmonary disease and a major cause of morbidity and mortality globally. Osteoporosis and osteopenia are common observations in COPD and degree of the loss of bone mineral density (BMD) has been found to be proportionate to the severity of the disease.Objectives:Our objective was to study the prevalence of osteoporosis and osteopenia in stable COPD patients in Indian Sub-Himalayan population.Materials and Methods:This study was performed on 84 patients of COPD attending as outpatient in the Pulmonary Medicine Department after application of inclusion and exclusion criteria. A control group of 60 healthy controls was selected for comparison with COPD group. Spirometry was done on patients to stage the severity of COPD according to global initiative for chronic obstructive lung disease criteria. Dual-energy X-ray absorptiometry scan of the lumbar spine was done using bone densitometer to determine the severity of reduced BMD. The patients were categorized according to the World Health Organization criterion for definition of reduced BMD.Results:In the present study, a total of 45.2% patients had osteoporosis, 41.6% patients had osteopenia while the rest 13% patients had normal bone density in the COPD group. The prevalence of low bone density was about 4 times higher in COPD group as compared to control group. There were 15.48 times higher chances of low BMD in COPD patients as compared to healthy controls.Conclusions:Reduced BMD is a common comorbid entity in COPD patients which leads to increase in bone fragility and susceptibility to fracture. It is recommended that all the patients with COPD should be screened for osteoporosis to initiate the treatment for the disorder before they develop fractures.

A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models.

Emphysema is a typical component of chronic obstructive pulmonary disease (COPD), a progressive and inflammatory airway disease. However, no effective treatment currently exists. Here, we show that keratan sulfate (KS), one of the major glycosaminoglycans produced in the small airway, decreased in lungs of cigarette smoke-exposed mice. To confirm the protective effect of KS in the small airway, a disaccharide repeating unit of KS designated L4 ([SO3--6]Galβ1-4[SO3--6]GlcNAc) was administered to two murine models: elastase-induced-emphysema and LPS-induced exacerbation of a cigarette smoke-induced emphysema. Histological and microcomputed tomography analyses revealed that, in the mouse elastase-induced emphysema model, administration of L4 attenuated alveolar destruction. Treatment with L4 significantly reduced neutrophil influx, as well as the levels of inflammatory cytokines, tissue-degrading enzymes (matrix metalloproteinases), and myeloperoxidase in bronchoalveolar lavage fluid, suggesting that L4 suppressed inflammation in the lung. L4 consistently blocked the chemotactic migration of neutrophils in vitro. Moreover, in the case of the exacerbation model, L4 inhibited inflammatory cell accumulation to the same extent as that of dexamethasone. Taken together, L4 represents one of the potential glycan-based drugs for the treatment of COPD through its inhibitory action against inflammation.

CHI25243, a novel potent inhaled inhibitor of neutrophil elastase for the treatment of bronchiectasis and other chronic inflammatory lung disease

Neutrophil elastase (NE) is a key proteolytic enzyme implicated in the pathogenesis and progression of chronic neutrophil-driven inflammatory lung diseases, including bronchiectasis, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). A number of clinical observations indicate that targeting NE might be beneficial for treating such inflammatory lung diseases. Here we studied the pharmacological profile of CHI25243, a novel inhaled NE inhibitor designed for inhaled treatment of neutrophil-driven inflammatory lung diseases such as bronchiectasis.

Extracellular High mobility group box 1-induced epithelial mesenchymal transition through β-catenin pathway in human airway epithelial cells

Abstract High mobility group box 1 (HMGB1) protein belongs to late inflammatory phase cytokine which shows a crucial role in the pathology of chronic pulmonary inflammatory diseases. Epithelial–mesenchymal transition (EMT) is implicated in airway remodeling and lung dysfunction in chronic inflammatory airway diseases. At present, the effects and mechanisms of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we found that HMGB1 treatment modulated EMT-related gene expression in human primary airway epithelial cells by RNA sequencing assay. HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. To dissect the mechanisms of HMGB1-induced EMT in human airway epithelial cells, we used western blotting, RNA interference and chemical inhibitors to investigate. Treatment with PI3K inhibitor (LY294006) and β-catenin shRNA reversed HMGB1-induced EMT. HMGB1 caused AKT phosphorylation, resulting in GSK3β inactivation, cytoplasmic accumulation, and nuclear translocation of β-catenin to induce EMT in human airway epithelial cells. Additionally, HMGB1 upregulated expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA attenuated HMGB1-induced EMT in human airway epithelial cells. In conclusion, we found that extracellular HMGB1 induced EMT through RAGE and β-catenin signaling pathway which might deteriorate bronchial epithelium which enhance disease severity and steroid resistance of airway.

Assessment of Treg/Th17 axis role in immunopathogenesis of chronic injuries of mustard lung disease

Purpose: Sulfur mustard (SM) lung is a heterogeneous disease associated with abnormal inflammatory immune responses. The Th17/Treg axis imbalance is associated with the pathogenesis of chronic inflammatory pulmonary disease. We aimed to determine the distribution of different Th17 and Treg cells in patients with SM lung and chronic obstructive pulmonary disease (COPD) and evaluate the clinical implications in this homeostasis. Methods: In this analytical cross-sectional study, CD4 + Foxp3+ Treg and CD4+ IL-17+ Th17 cells were measured in peripheral blood mononuclear cells (PBMCs) and transbronchial biopsy (TBB) samples of 15 SM-exposed patients, 12 COPD and 13 healthy controls (HCs). The potential correlation between the ratio of Th17/Tregs and lung function was evaluated with multivariate logistic regression (MLR) analysis. Results: The frequency of CD4 + FoxP3+ Tregs and CD4 + IL-17+ Th17 was increased ∼1.7-fold (8.71/4.95) and ∼2.7-fold (1.028/0.371) respectively, in the PBMC of SM patients compared with the health controls (p < 0.001). The results indicated that there were increases in the frequency of Th17 and Tregs cells in the patients with COPD versus the HC, that is, ∼2.6-fold (0.987/0.371) and ∼1.4-fold (7.12/4.95), respectively; but they did not reach to SM level (p ≥ 0.05). Moreover, in the TBB samples, the CD4 + IL-17+ Th17 and CD4+ FoxP3+ Tregs numbers were significantly higher in SM and COPD patients than HC (p < 0.05). The Th17 and Treg cells were inversely correlated with forced expiratory volume in 1s (FEV1%) (r = −0.351, p = 0.001; r = −0.344, p = 0.021) and FEV1/FVC (r = −0.44, p = 0.001; r = −0.302, p = 0.011), respectively. Instead, positive correlations were found between Treg/Th17 ratios and forced FEV1%pred (r = 0.156, p = 0.007), as well as FEV1/FVC ratio (r = 0.334, p = 0.006). Conclusions: The imbalance of Th17/Treg has a key role in immunopathogenesis of chronic phase of mustard lung disease.

High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells.

Epithelial–mesenchymal transition (EMT) is implicated in bronchial remodeling and loss of lung function in chronic inflammatory airway diseases. Previous studies showed the involvement of the high mobility group box 1 (HMGB1) protein in the pathology of chronic pulmonary inflammatory diseases. However, the role of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we used RNA sequencing to show that HMGB1 treatment regulated EMT-related gene expression in human primary-airway epithelial cells. The top five upregulated genes were SNAI2, FGFBP1, VIM, SPARC (osteonectin), and SERPINE1, while the downregulated genes included OCLN, TJP1 (ZO-1), FZD7, CDH1 (E-cadherin), and LAMA5. We found that HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. Additionally, we observed that HMGB1 induced AKT phosphorylation, resulting in GSK3β inactivation, cytoplasmic accumulation, and nuclear translocation of β-catenin to induce EMT in human airway epithelial cells. Treatment with PI3K inhibitor (LY294006) and β-catenin shRNA reversed HMGB1-induced EMT. Moreover, HMGB1 induced expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA inhibited HMGB1-induced EMT in human airway epithelial cells. In conclusion, we found that HMGB1 induced EMT through RAGE and the PI3K/AKT/GSK3β/β-catenin signaling pathway.

Endoplasmic Reticulum Stress Is a Danger Signal Promoting Innate Inflammatory Responses in Bronchial Epithelial Cells

Endoplasmic reticulum (ER) stress is associated with chronic pulmonary inflammatory diseases. We hypothesized that the combined activation of both Toll-like receptor (TLR) signaling and ER stress might increase inflammatory reactions in otherwise tolerant airway epithelial cells. Indeed, ER stress resulted in an increased response of BEAS-2B and human primary bronchial epithelial cells to pathogen-associated molecular pattern stimulation with respect to IL6 and IL8 production. ER stress elevated p38 and ERK MAP kinase activation, and pharmacological inhibition of these kinases could inhibit the boosting effect. Knockdown of unfolded protein response signaling indicated that mainly PERK and ATF6 were responsible for the synergistic activity. Specifically, PERK and ATF6 mediated increased MAPK activation, which is needed for effective cytokine secretion. We conclude that within airway epithelial cells the combined activation of TLR signaling and ER stress-mediated MAPK activation results in synergistic proinflammatory activity. We speculate that ER stress, present in various chronic pulmonary diseases, boosts TLR signaling and therefore proinflammatory cytokine production, thus acting as a costimulatory danger signal.

非手術入院患者（慢性閉塞性肺疾患，感染症，炎症性疾患）における深部静脈血栓症の発現頻度

要約：安静期間4 日以上，年齢60 歳以上で，慢性閉塞性肺疾患の急性増悪，感染症または炎症性疾患で入院し，静脈血栓塞栓症（VTE）予防ガイドラインで示されたリスクの組み合わせより高リスクと判断された入院患者の深部静脈血栓症（DVT）発現頻度を前向きに超音波検査で調査した．安静の3 カ月前以降に手術または外傷があった患者，入院時にVTE と診断されていた患者，抗凝固薬を使用していた患者は除外した．4 施設より25 名の患者が登録され，平均年齢は83.1（標準偏差6.8）歳であった．理学的予防法が行われていた患者はなく，抗血小板薬を使用していた患者は5 名であった．25 名中8 名（32.0％）にDVT（全て無症候性，新しい血栓は6 例，中枢型は3 例）が認められた．急性内科疾患入院患者には無症候性DVT が潜んでいることが示唆された．今後，より多くの患者を対象とした前向き研究でさらに検討すべきと考えた．

Evaluation of D-Dimer in Screening Deep Vein Thrombosis in Hospitalized Japanese Patients with Acute Medical Diseases/Episodes.

Objective: To investigate the usefulness of D-dimer as a screening method as well as to explore potent predictors of deep vein thrombosis (DVT) in hospitalized Japanese patients with acute medical diseases/episodes. Methods and Subjects: This study was a multi-center, prospective, observational study. The inclusion criteria were hospitalized patients at high risk of developing venous thromboembolism with; (1) congestive heart failure, acute exacerbation of chronic obstructive pulmonary disease, infectious diseases, or inflammatory diseases, (2) bed rest ≥4 days, and (3) ≥60 years old. D-dimer was measured on the same day as ultrasonography. Multivariate logistic regression analysis was performed to investigate predictors associated with the presence of DVT. Results: Sixty-nine patients were enrolled. The prevalence of DVT was 33.3% (23/69; 95% C.I., 19.4% to 47.3%). D-dimer was measured in 42 patients and the sensitivity and negative predictive value reached 100%, while the specificity (13.3%) and positive predictive value (31.6%) were low (cut-off value: 0.9 or 1.0 µg/mL). Statistically significant predictor was not assigned. Conclusion: As the sensitivity and negative predictive value of D-dimer reached 100%, D-dimer have a role in excluding patients who might otherwise undergo diagnostic imaging for DVT in hospitalized Japanese patients with acute medical diseases/episodes.

Intensive care unit length of stay can be longer due to the low serum vitamin D levels in patients with chronic obstructive pulmonary disease

Vitamin D is an immune modulator hormone which has major effects on nearly all cells of the immune system. The deficiency of vitamin D has been found to be associated with many diseases. Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory pulmonary disease asociated with significant mortality and morbidity. Immune system disorders may aggravate the COPD due to the increased morbidity.

MicroRNA response of inhalation exposure to hexanal in lung tissues from Fischer 344 rats.

In previous studies, we have investigated the relationships between environmental chemicals and health risk based on omics analysis and identified significant biomarkers. Our current findings indicate that hexanal may be an important toxicant of the pulmonary system in epigenetic insights. MicroRNA (miRNA) is an important indicator of biomedical risk assessment and target identification. Hexanal is highly detectable in the exhaled breath of patients with chronic obstructive pulmonary disease (COPD) and chronic inflammatory lung disease. In this study, we aimed to identify hexanal-characterized miRNA-mRNA correlations involved in lung toxicity. Microarray analysis identified 56 miRNAs that commonly changed their expression more than 1.3-fold in three doses (600, 1000, and 1500 ppm) within hexanal-exposed Fischer 344 rats by inhalation, and 226 genes were predicted to be target genes of miRNAs through TargetScan analysis. By integrating analyses of miRNA and mRNA expression profiles, we identified one anti-correlated target gene (Chga; chromogranin A; parathyroid secretory protein 1). Comparative toxicogenomics database (CTD) analysis of this gene showed that Chga is involved with several disease categories such as cancer, respiratory tract disease, nervous system disease, and cardiovascular disease. Further research is necessary to elucidate the mechanisms of hexanal-responsive toxicologic pathways at the molecular level. This study concludes that our integrated approach to miRNA and mRNA enables us to identify molecular events in disease development induced by hexanal in an in vivo rat model. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1909-1921, 2016.