The causal relationship and potential mediators between plasma lipids and atopic dermatitis: a bidirectional two-sample, two-step mendelian randomization.

BACKGROUND: Observational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals. However, the causal relationship between these differences remains unclear due to the inherent limitations of observational studies. Our objective was to explore the causal effects between 179 plasma lipid species and atopic dermatitis, and to investigate whether circulating inflammatory proteins serve as mediators in this causal pathway. METHODS: We utilized public genome-wide association studies data to perform a bidirectional two-sample, two-step mendelian randomization study. The inverse variance-weighted method was adopted as the primary analysis technique. MR-Egger and the weighted median were used as supplementary analysis methods. MR-PRESSO, Cochran's Q test, and MR-Egger intercept test were applied for sensitivity analyses to ensure the robustness of our findings. RESULTS: The Mendelian randomization analysis revealed that levels of Phosphatidylcholine (PC) (18:1_20:4) (OR: 0.950, 95% CI: 0.929-0.972, p = 6.65 × 10- 6), Phosphatidylethanolamine (O-18:1_20:4) (OR: 0.938, 95% CI: 0.906-0.971, p = 2.79 × 10- 4), Triacylglycerol (TAG) (56:6) (OR: 0.937, 95% CI: 0.906-0.969, p = 1.48 × 10- 4) and TAG (56:8) (OR: 0.918, 95% CI: 0.876-0.961, p = 2.72 × 10- 4) were inversely correlated with the risk of atopic dermatitis. Conversely, PC (18:1_20:2) (OR: 1.053, 95% CI: 1.028-1.079, p = 2.11 × 10- 5) and PC (O-18:1_20:3) (OR: 1.086, 95% CI: 1.039-1.135, p = 2.47 × 10- 4) were positively correlated with the risk of atopic dermatitis. The results of the reverse directional Mendelian randomization analysis indicated that atopic dermatitis exerted no significant causal influence on 179 plasma lipid species. The level of circulating IL-18R1 was identified as a mediator for the increased risk of atopic dermatitis associated with higher levels of PC (18:1_20:2), accounting for a mediation proportion of 9.07%. CONCLUSION: Our research suggests that plasma lipids can affect circulating inflammatory proteins and may serve as one of the pathogenic factors for atopic dermatitis. Targeting plasma lipid levels as a treatment for atopic dermatitis presents a potentially novel approach.

Unconventional Polarization-Switching Mechanism in (Hf, Zr)O_{2} Ferroelectrics and Its Implications.

HfO_{2}-based ferroelectric thin films are promising for their application in ferroelectric devices. Predicting the ultimate magnitude of polarization and understanding its switching mechanism are critical to realize the optimal performance of these devices. Here, a generalized solid-state variable cell nudged elastic band method is employed to predict the switching pathway associated with domain-wall motion in (Hf,Zr)O_{2} ferroelectrics. It is found that the polarization reversal pathway, where threefold coordinated O atoms pass across the nominal unit-cell boundaries defined by the Hf/Zr atomic planes, is energetically more favorable than the conventional pathway where the O atoms do not pass through these planes. This finding implies that the polarization orientation in the orthorhombic Pca2_{1} phase of HfO_{2} and its derivatives is opposite to that normally assumed, predicts the spontaneous polarization magnitude of about 70 µC/cm^{2} that is nearly 50% larger than the commonly accepted value, signifies a positive intrinsic longitudinal piezoelectric coefficient, and suggests growth of ferroelectric domains, in response to an applied electric field, structurally reversed to those usually anticipated. These results provide important insights into the understanding of ferroelectricity in HfO_{2}-based ferroelectrics.

Ionic-Liquid-Assisted One-Step Construction of Mesoporous Metal-Organic Frameworks.

The synthesis of ionic-mesoporous-metal-organic frameworks (ionic-meso-MOFs) has received considerable interest in the fields of macromolecular adsorption, acid-base catalysis, ionic conductivity, etc.; yet, their synthesis still presents significant difficulties. In this study, functionalized mesoporous MIL-101-ILs (Cr) was facilely constructed via an in situ self-assembly method by using aromatic-anion-functionalized ionic liquids (ILs) as competitive ligands. It has been demonstrated that the inclusion of an aromatic moiety into an IL improves the coordination ability and is advantageous for the anchoring of ILs on Cr3+ via amino-metal coordination. Thus, ionic-meso-MOFs with a specific surface area of 441.9-624.9 cm2/g and an average pore diameter of 5.5 to 8.4 nm were successfully synthesized. Because of the presence of open Lewis acidic metal sites on the MOFs and basic active sites on the ILs, the resulting ionic-meso-MOFs demonstrated both an acid-base cooperative effect and a mesoporous structure, indicating a high potential for acid-base catalysis. This in situ synthesis procedure for ionic mesoporous MOFs offers a simple method for developing and fabricating multifunctional mesoporous materials.

LncRNA RPPH1 acts as a molecular sponge for miR-122 to regulate Wnt1/ß-catenin signaling in hepatocellular carcinoma.

This study aimed to explore the role of lncRNA RPPH1 in hepatocellular carcinoma. The expression of RPPH1 and miR-122 was determined by Real-time PCR. Cell proliferation and colony formation assays were employed to monitor cell growth in vitro. Wound healing and Transwell assays were applied to detect cell migration and invasion. A dual-luciferase reporter assay was used to verify the interaction between RPPH1 and miR-122. The in vivo function of RPPH1 was illustrated by xenograft tumor models. The results showed that the expression of RPPH1 was markedly upregulated in human HCC specimens and cell lines compared to normal controls. However, the trend of miR-122 was the opposite. RPPH1 facilitates the proliferation, migration, and invasion of HCC cells and synchronously suppresses cell apoptosis. The dual-luciferase assay confirmed the relationship between RPPH1 and miR-122. Rescue experiments showed that RPPH1 acted as a competing endogenous RNA (ceRNA) by sponging miR-122 in HCC cells. Moreover, RPPH1 positively regulated the expression of Wnt1 and its downstream targets through miR-122. Our study demonstrates for the first time that RPPH1 promotes HCC progression via the miR-122/Wnt1/ß-catenin axis, which may represent a valuable therapeutic target for patients with HCC.

Joint QTL Mapping and Transcriptome Sequencing Analysis Reveal Candidate Seed-Shattering-Related Genes in Common Buckwheat.

Common buckwheat (Fagopyrum esculentum M.) is an important traditional miscellaneous grain crop. However, seed-shattering is a significant problem in common buckwheat. To investigate the genetic architecture and genetic regulation of seed-shattering in common buckwheat, we constructed a genetic linkage map using the F2 population of Gr (green-flower mutant and shattering resistance) and UD (white flower and susceptible to shattering), which included eight linkage groups with 174 loci, and detected seven QTLs of pedicel strength. RNA-seq analysis of pedicel in two parents revealed 214 differentially expressed genes DEGs that play roles in phenylpropanoid biosynthesis, vitamin B6 metabolism, and flavonoid biosynthesis. Weighted gene co-expression network analysis (WGCNA) was performed and screened out 19 core hub genes. Untargeted GC-MS analysis detected 138 different metabolites and conjoint analysis screened out 11 DEGs, which were significantly associated with differential metabolites. Furthermore, we identified 43 genes in the QTLs, of which six genes had high expression levels in the pedicel of common buckwheat. Finally, 21 candidate genes were screened out based on the above analysis and gene function. Our results provided additional knowledge for the identification and functions of causal candidate genes responsible for the variation in seed-shattering and would be an invaluable resource for the genetic dissection of common buckwheat resistance-shattering molecular breeding.

Low-SNR Infrared Point Target Detection and Tracking via Saliency-Guided Double-Stage Particle Filter.

Low signal-to-noise ratio (SNR) infrared point target detection and tracking is crucial to study regarding infrared remote sensing. In the low-SNR images, the intensive noise will submerge targets. In this letter, a saliency-guided double-stage particle filter (SGDS-PF) formed by the searching particle filter (PF) and tracking PF is proposed to detect and track targets. Before the searching PF, to suppress noise and enhance targets, the single-frame and multi-frame target accumulation methods are introduced. Besides, the likelihood estimation filter and image block segmentation are proposed to extract the likelihood saliency and obtain proper proposal density. Guided by this proposal density, the searching PF detects potential targets efficiently. Then, with the result of the searching PF, the tracking PF is adopted to track and confirm the potential targets. Finally, the path of the real targets will be output. Compared with the existing methods, the SGDS-PF optimizes the proposal density for low-SNR images. Using a few accurate particles, the searching PF detects potential targets quickly and accurately. In addition, initialized by the searching PF, the tracking PF can keep tracking targets using very few particles even under intensive noise. Furthermore, the parameters have been selected appropriately through experiments. Extensive experimental results show that the SGDS-PF has an outstanding performance in tracking precision, tracking reliability, and time consumption. The SGDS-PF outperforms the other advanced methods.

Spectroscopic Investigation into the Binding of Ferulic Acid with Sodium Deoxycholate: Hydrophobic Force Versus Hydrogen Bonding.

The binding of ferulic acid (FA) with sodium deoxycholate (NaDC) has been investigated using fluorescence and absorption measurements. The fluorescence probe technique of pyrene reveals that the presence of FA favors the micellization of NaDC, leading to the decreased critical micelle concentrations for the formation of NaDC micelles. As NaDC molecules change gradually from monomers via primary micelles into secondary micelles, the intensities of absorption and fluorescence spectra of FA increase at low NaDC concentrations, but decrease suddenly at intermediate NaDC concentrations, and finally increase again at high NaDC concentrations. These results corroborated well with FA fluorescence lifetime data suggesting that the aryl ring of FA hydrophobically binds to the convex surface of NaDC monomers, whereas the hydrogen bonding between FA and NaDC is significantly involved in NaDC primary micelles, which is gradually overcome by the hydrophobic interaction between FA and NaDC secondary micelles. The absorption and fluorescence spectra as well as the binding constant value of FA indicate the strong binding of FA in the large hydrophobic core of NaDC secondary micelles. At low FA concentrations, the measurement of FA anisotropy suggests that FA can increase the packing order of hydrophobic surfaces in NaDC secondary micelles, whereas the high amount of FA can greatly disrupt the packing structure of NaDC secondary micelles which is ascribed to the formation of FA dimers. The spectroscopic experiments outlined here present the binding events of FA with NaDC monomers and primary and secondary micelles, which are significantly related with the hydrophobic force and hydrogen bonding as well as the unique structural characteristics of bile salt.

Liver kinase B1 attenuates liver ischemia/reperfusion injury via inhibiting the NLRP3 inflammasome.

Liver ischemia/reperfusion injury (IRI), a serious inflammatory response driven by innate immunity, occurs in liver surgeries such as liver resection and liver transplantation, leading to liver dysfunction, liver failure, and even rejection after transplantation. Liver kinase B1 (LKB1) plays a pivotal anti-inflammatory role in IRI. One of the most important factors involved in liver IRI is the aberrant activation of the nucleotide binding oligomerization domain like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome in Kupffer cells. However, the mechanisms underlying the effect of LKB1 on the NLRP3 inflammasome in liver IRI remain elusive. In this study, we found that the expression of LKB1 was decreased in liver IRI, while the NLRP3 inflammasome level was increased as shown, as revealed by RT-qPCR and western blot analysis. Furthermore, upregulation of LKB1 abrogated the expression of the NLRP3 inflammasome, which improved liver function and liver pathology in the liver IRI model in vivo. In vitro, overexpression of LKB1 inhibited the activation of NLRP3 inflammasome and nuclear factor-κB, while the inhibitory effect was reversed by silencing the expression of the forkhead box protein O1 in the RAW264.7 macrophage hypoxia/reoxygenation model. In conclusion, our results suggest that LKB1 exerts a protective effect against liver IRI by downregulating the NLRP3 inflammasome.

OTUD4 alleviates hepatic ischemia-reperfusion injury by suppressing the K63-linked ubiquitination of TRAF6.

Hepatic ischemia-reperfusion (IR) injury can cause serious liver damage, leading to liver dysfunction after liver surgery, which is associated with NF-κB-mediated inflammation. The K63-linked auto-polyubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) is essential for the activation of NF-κB. Here, we found that OTU domain-containing protein 4 (OTUD4), a deubiquitinating enzyme (DUB), interacts with TRAF6 and decreases the K63 auto-polyubiquitination of TRAF6. In addition, the data showed that NF-κB activation was impaired and inflammatory factor levels were reduced after overexpressing OTUD4 in a hypoxia/reoxygenation (HR) model and a hepatic IR model. Additionally, the liver inflammatory response and tissue damage were ameliorated in mice overexpressing OTUD4.Taken together, these results show that OTUD4 can negatively regulate NF-κB activation by suppressing the K63-linked ubiquitination of TRAF6, thus alleviating hepatic ischemia-reperfusion injury.

Tle1 attenuates hepatic ischemia/reperfusion injury by suppressing NOD2/NF-κB signaling.

Liver damage induced by ischemia/reperfusion (I/R) remains a primary issue in multiple hepatic surgeries. Innate immune-mediated inflammatory responses during the reperfusion stage aggravate the injury. Nevertheless, the detailed mechanism of hepatic I/R has not been fully clarified yet. Our research focuses on the role of Transducin-like enhancer of split-1 (Tle1) in the liver I/R injury and the relation between Tle1 and Nucleotide-binding oligomerization domain 2 (NOD2). To answer these questions, we constructed mouse models of I/R and cell models of hypoxia/reoxygenation (H/R). We found decreased Tle1 accompanied by increased NOD2 during reperfusion. Mice pro-injected with Tle1-siRNA emerged aggravated liver dysfunction. Repression of Tle1 had a significant impact on NOD2 and downstream NF-κB signaling in vitro. However, alteration of NOD2 failed to affect the expression of Tle1. To conclude, our study demonstrates that Tle1 shelters the liver from I/R injury through suppression of NOD2-dependent NF-κB activation and subsequent inflammatory responses.

miR-4458 inhibits the epithelial-mesenchymal transition of hepatocellular carcinoma cells by suppressing the TGF-ß signaling pathway via targeting TGFBR1.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. MicroRNAs play a pivotal role in the progression of various cancers. To date, very little attention has been paid to miR-4458. Therefore, the aim of our study was to explore the function and underlying molecular mechanism of miR-4458 in HCC. We found that the expression of miR-4458 was reduced in HCC tissues and cell lines. Forced overexpression of miR-4458 inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, while downregulation of miR-4458 promoted the aggressive phenotype. Furthermore, transforming growth factor beta receptor 1 (TGFBR1), the modulator of the TGF-ß signaling pathway, was verified to be a novel target gene of miR-4458 by dual-luciferase reporter gene assay. Upregulated miR-4458 dramatically abolished TGFBR1 and p-Smad2/3 expression, thus blocking the TGF-ß signaling pathway. Moreover, restoration of TGFBR1 partially rescued the miR-4458-mediated suppressive effect on the migration, invasion, and EMT and reactivated the TGF-ß signaling pathway in HCC cells. In summary, our findings first demonstrated a mechanism of miR-4458 in HCC cell migration, invasion, and EMT by regulating the TGF-ß signaling pathway via directly targeting TGFBR1.

Ferroelectric Tunnel Junctions Enhanced by a Polar Oxide Barrier Layer.

Ferroelectric tunnel junctions (FTJs) have recently aroused significant interest due to the interesting physics controlling their properties and potential application in nonvolatile memory devices. In this work, we propose a new concept to design high-performance FTJs based on ferroelectric/polar-oxide composite barriers. Using density functional theory calculations, we model electronic and transport properties of LaNiO3/PbTiO3/LaAlO3/LaNiO3 tunnel junctions and demonstrate that an ultrathin polar LaAlO3(001) layer strongly enhances their performance. We predict a tunneling electroresistance (TER) effect in these FTJs with an OFF/ON resistance ratio exceeding a factor of 104 and ON state resistance as low as about 1 kΩµm2. Such an enhanced performance is driven by the ionic charge at the PbTiO3/LaAlO3 interface, which significantly increases transmission across the FTJ when the ferroelectric polarization of PbTiO3 is pointing against the intrinsic electric field produced by this ionic charge. This is due to the formation of a two-dimensional (2D) electron or hole gas, depending on the LaAlO3 termination being (LaO)+ or (AlO2)-, respectively, which is formed to screen the polarization charge of the nonuniform polarization state. This 2D electron (hole) gas can be switched ON and OFF by the reversal of ferroelectric polarization, resulting in the giant TER effect. The proposed design suggests a new direction for creating FTJs with a stable and reversible ferroelectric polarization, a sizable TER effect, and a low-resistance-area product, as required for memory applications.

De novo transcriptome assembly and identification of genes related to seed size in common buckwheat (Fagopyrum esculentum M.).

Common buckwheat (Fagopyrum esculentum M.) belongs to the eudicot family Polygonaceae, Fagopyrum Mill, and its seeds have high nutritional value. The mechanism of seed development of common buckwheat remains unclear at the molecular level and no genes related to seed size have been identified. In this study, we performed genome-wide transcriptome sequencing and analysis using common buckwheat seeds at 5 days post anthesis (DPA) and 10 DPA from two cultivars (large-seeded and small-seeded). A total of 259,895 transcripts were assembled, resulting in 187,034 unigenes with average length of 1097 bp and N50 of 1538 bp. Based on gene expression profiles, 9127 differentially expressed genes (DEGs) were identified and analyzed in GO enrichment and KEGG analysis. In addition, genes related to seed size in the IKU pathway, ubiquitin-proteasome pathway, MAPK signaling pathway, TFs and phytohormones were identified and analyzed. AP2 and bZIP transcription factors, BR-signal and ABA were considered to be important regulators of seed size. This study provides a valuable genetic resource for future identification and functional analysis of candidate genes regulating seed size in common buckwheat and will be useful for improving seed yield in common buckwheat through molecular breeding in the future.

An ecophysiological perspective on likely giant panda habitat responses to climate change.

Threatened and endangered species are more vulnerable to climate change due to small population and specific geographical distribution. Therefore, identifying and incorporating the biological processes underlying a species' adaptation to its environment are important for determining whether they can persist in situ. Correlative models are widely used to predict species' distribution changes, but generally fail to capture the buffering capacity of organisms. Giant pandas (Ailuropoda melanoleuca) live in topographically complex mountains and are known to avoid heat stress. Although many studies have found that climate change will lead to severe habitat loss and threaten previous conservation efforts, the mechanisms underlying panda's responses to climate change have not been explored. Here, we present a case study in Daxiangling Mountains, one of the six Mountain Systems that giant panda distributes. We used a mechanistic model, Niche Mapper, to explore what are likely panda habitat response to climate change taking physiological, behavioral and ecological responses into account, through which we map panda's climatic suitable activity area (SAA) for the first time. We combined SAA with bamboo forest distribution to yield highly suitable habitat (HSH) and seasonal suitable habitat (SSH), and their temporal dynamics under climate change were predicted. In general, SAA in the hottest month (July) would reduce 11.7%-52.2% by 2070, which is more moderate than predicted bamboo habitat loss (45.6%-86.9%). Limited by the availability of bamboo and forest, panda's suitable habitat loss increases, and only 15.5%-68.8% of current HSH would remain in 2070. Our method of mechanistic modeling can help to distinguish whether habitat loss is caused by thermal environmental deterioration or food loss under climate change. Furthermore, mechanistic models can produce robust predictions by incorporating ecophysiological feedbacks and minimizing extrapolation into novel environments. We suggest that a mechanistic approach should be incorporated into distribution predictions and conservation planning.

Identification of 4-Aminopyrazolopyrimidine Metabolite That May Contribute to the Hypolipidemic Effects of LY2584702 in Long Evans Diet-Induced Obese Rats.

LY2584702 is an inhibitor of p70 S6 kinase-1 previously developed for the treatment of cancer. In two phase 1 trials in oncology patients, significant reductions of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride were observed. In the current study, we sought to understand the potential mechanism of action of this compound in regulating lipid metabolism. In Long Evans diet-induced obese (DIO) rats, oral administration of LY2584702 for 3-4 weeks led to robust reduction of LDL-C up to 60%. An unexpected finding of liver triglyceride (TG) increase implicated a metabolite of LY2584702, 4-aminopyrazolo[3,4-day]pyrimidine (4-APP), in modulation of lipid metabolism in these rats. We showed that low-dose 4-APP, when administered orally for 3-4 weeks to Long Evans DIO rats, produced lipoprotein profile changes that were strikingly similar to LY2584702. Kinetic studies suggested that both LY2584702 and 4-APP had no effect on chylomicron-TG secretion and only exerted a modest effect on hepatic very low-density lipoprotein (VLDL)-TG secretion. In human hepatoma HepG2 cells, 4-APP, but not LY2584702, increased LDL uptake. We hypothesize that generation of the 4-APP metabolite may contribute to the efficacy of LY2584702 in lowering LDL-C in rats and potentially in humans as well. This mechanism of LDL-C lowering may include inhibition of VLDL production and increase in LDL clearance.

Increased expression of TROP2 in airway basal cells potentially contributes to airway remodeling in chronic obstructive pulmonary disease.

BACKGROUND: The airway epithelium of chronic obstructive pulmonary disease (COPD) patients undergoes aberrant repair and remodeling after repetitive injury following exposure to environmental factors. Abnormal airway regeneration observed in COPD is thought to originate in the stem/progenitor cells of the airway epithelium, the basal cells (BCs). However, the molecular mechanisms underlying these changes remain unknown. Here, trophoblast cell surface antigen 2 (TROP2), a protein implicated in the regulation of stem cell activity, was examined in lung tissue samples from COPD patients. METHODS: The expression of TROP2 and hyperplasia index Ki67 was assessed in lung epithelium specimens from non-smokers (n = 24), smokers (n = 24) and smokers with COPD (n = 24). Primary airway BCs were isolated by bronchoscopy from healthy individuals and COPD patients and subsequently transfected with pcDNA3.1-TROP2 or siRNA sequence in vitro. The functional consequences of TROP2 overexpression in BCs were explored. RESULTS: Immunohistochemistry and immunofluorescence revealed increased TROP2 expression in airway BCs in smokers with COPD compared to nonsmokers and smokers without COPD, and staining was highly localized to hyperplastic regions containing Ki67 positive cells. TROP2 expression was also inversely correlated with airflow limitation in patients with COPD (r = -0.53, P < 0.01). pcDNA3.1-TROP2-BCs in vitro exhibited improved proliferation with activation of ERK1/2 phosphorylation signaling pathway. In parallel, changes in vimentin and E-cadherin in pcDNA3.1-TROP2-BCs were consistent with an epithelial-mesenchymal transition (EMT)-like change, and secretion of inflammatory factors IL-1ß, IL-8 and IL-6 was increased. Moreover, down-regulation of TROP2 by siRNA significantly attenuated the proliferation of BCs derived from COPD patients. EMT-like features and cytokine levels of COPD basal cells were also weakened following the down-regulation of TROP2. CONCLUSION: The results indicate that TROP2 may play a crucial role in COPD by affecting BC function and thus airway remodeling through increased BC hyperplasia, EMT-like change, and introduction of inflammatory molecules into the microenvironment.

Involvement of urokinase in cigarette smoke extract-induced epithelial-mesenchymal transition in human small airway epithelial cells.

Urokinase-type plasminogen activator (uPA) augments inflammation and tissue remodeling during lung injury and repair. The uPA expression in small airway epithelium of chronic obstructive pulmonary disease (COPD) increases. Epithelial-mesenchymal transition (EMT) is important in the small airway fibrosis of COPD. This study shows the uPA regulation in cigarette smoke extract (CSE)-induced EMT in human small airway epithelial cell lines (HSAEpiCs). uPA is overexpressed in the small airway epithelium of COPD patients and CSE-treated cell lines. Furthermore, uPA expression correlated with vimentin expression in the small airway epithelium of COPD patients. uPA inhibition blocks CSE-induced EMT by reversing E-cadherin and α-catenin expression and retarding the induction of N-cadherin and vimentin, resulting in reduction in migration. uPA overexpression in HSAEpiC cells also promotes EMT and migration. EMT is partly reversed in uPA-overexpressing HSAEpiC cells through the silencing expression of uPA receptor. In conclusion, this study provides new insights into the contribution of uPA upregulation to EMT associated with small airway remodeling in COPD.

LL-37 secreted by epithelium promotes fibroblast collagen production: a potential mechanism of small airway remodeling in chronic obstructive pulmonary disease.

Emerging evidence suggests that the process of small airway remodeling is mediated by profibrotic growth factors produced by epithelium, which are capable of activating the underlying mesenchymal cells with excessive collagen production. It has been demonstrated that human cathelicidin antimicrobial protein LL-37 is highly expressed in small airway epithelium from COPD patients. However, it is unknown whether the increased levels of LL-37 in epithelium are involved in the pathogenesis of small airway remodeling in COPD. In this study, we examined the expression of LL-37 in small airways from smokers with COPD and controls (non-smokers and smokers without COPD) by immunohistochemistry, and then the association between LL-37 expression in epithelium and the structural changes of small airway remodeling was analyzed. In vitro, the effect of CSE-induced epithelial secretion of LL-37 on collagen production in human lung fibroblasts (HFL-1 cell line) was studied in a co-culture system. Finally, the signaling pathways involved in the effect of LL-37 on fibroblast collagen production were evaluated. The results showed that LL-37 immunoreactivity in airway epithelium was significantly elevated in smokers with COPD compared with controls. In addition, the magnitude of LL-37 expression in epithelium was positively correlated with airway wall thickness and collagen deposition. In vitro, CSE-induced epithelial secretion of LL-37 promoted fibroblast collagen production. Finally, we showed that formyl peptide receptor-like 1 (FPRL1)-dependent extracellular signal-regulated kinase (ERK) signaling pathway was essential for LL-37-induced collagen production in HFL-1 cells. These results suggest that after cigarette smoke exposure, the increased levels of LL-37 in airway epithelium could stimulate collagen production in the underlying lung fibroblasts and may contribute to small airway remodeling in COPD.

The human cathelicidin LL-37 enhances airway mucus production in chronic obstructive pulmonary disease.

Airway mucus overproduction is a distinguishing feature of chronic obstructive pulmonary disease (COPD). LL-37 is the only member of human cathelicidins family of antimicrobial peptides and plays a central role in many immune and inflammatory reactions. Increasing evidence suggests the involvement of LL-37 in the pathogenesis of COPD. Here, we investigated the effects of LL-37 on airway mucus overproduction in COPD. We observed overexpression of both LL-37 and MUC5AC mucin (a major mucin component of mucus) in airways of COPD patients and found a correlation between them. We showed in vitro that LL-37 induces MUC5AC mucin production by airway epithelial NCI-H292 cells in the absence and presence of cigarette smoke extract, with TNF-α converting enzyme (TACE)-EGFR-ERK1/2 pathway and IL-8 required for the induction. Therefore, we concluded that LL-37 enhances the mucus production in COPD airways, thus contributing to the progression of COPD.