Exposure to fine particulate matter (PM2.5) represents a leading environmental cause of pulmonary inflammation and diseases, yet the underlying cellular mechanisms remain incompletely understood. Here, we identify histone deacetylase 10 (HDAC10) in macrophages as a critical regulator of PM2.5-induced airway inflammation by governing autophagic flux. PM2.5 exposure upregulated HDAC10 expression specifically in lung macrophages both in vivo and in vitro. Myeloid-specific Hdac10 deletion markedly attenuated PM2.5-induced airway inflammation and inflammatory cytokine production by inhibiting macrophage autophagy. Mechanistically, HDAC10 interacted with Beclin1 and deacetylated it at lysine 5 (K5), a modification critical for autophagic flux and subsequent inflammatory responses. Pharmacological inhibition of HDAC10 with salvianolic acid B reduced Beclin1 deacetylation, suppressed macrophage autophagy, and ameliorated PM2.5-induced lung inflammation. Clinically, elevated HDAC10 expression and reduced Beclin1 acetylation were observed in lung tissues from chronic obstructive pulmonary disease (COPD) patients, where HDAC10 mRNA levels correlated positively with the heightened lung inflammation. Our findings reveal a previously unrecognized HDAC10-Beclin1 axis that links PM2.5 exposure to macrophage autophagy and pulmonary inflammation, providing potential therapeutic targets for PM2.5-related respiratory diseases.

Metastasis is a principal factor in the poor prognosis of colorectal cancer. Recent studies have found microbial metabolites regulate colorectal cancer metastasis. By analyzing metabolomics data, we identified an essential fecal metabolite citraconate that potentially promotes colorectal cancer metastasis. Next, we tried to reveal its effect on colorectal cancer and the underlying mechanism. Firstly, the response of colorectal cancer cells (HCT116 and MC38 cells) to citraconate was assessed by Cell Counting Kit-8 assay, clonogenic assay, transwell migration and invasion assay. Moreover, we utilized an intra-splenic injection model to evaluate the effect of citraconate on colorectal cancer liver metastasis in vivo. Then molecular approaches were employed, including RNA sequencing, mass spectrometry-based metabolomics, western blot, quantitative real-time PCR, cell ferrous iron colorimetric assay and intracellular malondialdehyde measurement. In vitro, citraconate promotes the growth of colorectal cancer cells. In vivo, citraconate aggravated liver metastasis of colorectal cancer. Mechanistically, downstream genes of NRF2, NQO1, GCLC, and GCLM high expression induced by citraconate resulted in resistance to ferroptosis of colorectal cancer cells. In summary, citraconate promotes the malignant progression of colorectal cancer through NRF2-mediated ferroptosis resistance in colorectal cancer cells. Furthermore, our study indicates that fecal metabolite may be crucial in colorectal cancer development.

Purpose: Particulate matter (PM2.5) is a common risk factor for airway inflammation. Alveolar macrophages play a critical role in airway inflammation. Sirtuin 6 (SIRT6) is a class Ill histone deacetylase that exerts an anti-inflammatory effect in airway diseases. However, the role of SIRT6 on PM2.5-induced airway inflammation in macrophages remains unclear. We aimed to determine whether SIRT6 protects against PM2.5-induced airway inflammation in macrophages. Methods: The effect of SIRT6 on PM2.5-induced airway inflammation was assessed by using THP1 cells or bone marrow-derived macrophages (BMDMs) exposed to PM2.5 in vitro and myeloid cell-specific SIRT6 conditional knockout mice (Sirt6fl/fl-LysMCre) in vivo. Results: PM2.5 increased SIRT6 expression in THP1 cells, but SIRT6 gene silencing decreased PM2.5 induced inflammatory cytokines in THP1 cells. Moreover, the expression of SIRT6 and inflammatory cytokines was also decreased in BMDMs with myeloid-specific deletion of SIRT6 after stimulation of PM2.5. In vivo, Sirt6fl/fl-LysMCre mice substantially decreased airway inflammation in response to PM2.5 exposure. Conclusion: Our results revealed that SIRT6 promotes the PM2.5-induced airway inflammation in macrophages and indicated that inhibition of SIRT6 in macrophages may represent therapeutic strategy for airway disorders induced by airborne particulate pollution.

BACKGROUND:Mammalian Claudin-5 is the main endothelial tight junction component maintaining blood-brain barrier (BBB) permeability, while Claudin-1 and -3 seal the paracellular space of choroid plexus (CP) epithelial cells contributing to the blood-cerebrospinal fluid barrier (BCSFB). In zebrafish, two paralogs of claudin-5a and -5b are expressed while their roles in the formation of BBB and BCSFB are unclear.METHODS:The expression patterns of Claudin-5a and -5b in zebrafish brains were systematically analyzed by immunofluorescence (IF) assay. The developmental functions of Claudin-5a and -5b were characterized by generating of claudin-5a and -5b mutants respectively. Meanwhile, the cerebral inflammation and cell apoptosis in claudin-5a-/- were assessed by live imaging of transgenic zebrafish, RT-qPCR, IF, and TUNEL assay. The integrity of BBB and BCSFB was evaluated by in vivo angiographic and dye permeation assay. Finally, RT-qPCR, whole-mount RNA in situ hybridization (WISH), and transmission electron microscopy (TEM) analyses were performed to investigate the development of cerebral vessels and choroid plexus.RESULTS:We showed that Claudin-5a and -5b are both expressed in zebrafish cerebrovascular endothelial cells (ECs). In addition, Claudin-5a was strongly expressed in CP epithelial cells. Loss of Claudin-5b showed no effect on zebrafish vasculogenesis or BBB function. In contrast, the knockout of claudin-5a caused a lethal phenotype of severe whole-brain oedema, ventricular dilatation, and cerebral hernia in zebrafish larvae, although the cerebral vasculogenesis and the development of CP were not altered. In claudin-5a-/- , although ultrastructural analysis of CP and cerebral capillary showed intact integrity of epithelial and endothelial tight junctions, permeability assay indicated a disruption of both BBB and BCSFB functions. On the molecular level, it was found that ZO-1 was upregulated in the CP epithelium of claudin-5a-/-, while the notch and shh pathway responsible for CP development was not affected due to loss of Claudin-5a.CONCLUSIONS:Our findings verified a non-functional role of zebrafish Claudin-5b in the BBB and identified Claudin-5a as the ortholog of mammalian Claudin-5, contributing to the development and the functional maintenance of both BBB and BCSFB.

The blood-brain barrier (BBB) protects the central nervous system (CNS) from harmful elements, while it also restricts efficient drug delivery into the CNS. Previously, we generated a mutated fragment of Clostridium perfringens enterotoxin (cCPEYWSH ) which specifically binds to the endothelial tight junction protein claudin-5. Here, we explore the mechanisms regulating the dynamics of membranous claudin-5 and BBB permeability. Following cCPEYWSH binding to claudin-5, caveolin-1 mediates the redistribution of claudin-5 to the cytosol. This abnormal cytosolic aggregation triggers the autophagic degradation of claudin-5, leading to an increase in BBB permeability. Enhancement or inhibition of autophagy accelerates or inhibits the degradation of cytosolic claudin-5, respectively. Our findings may pave the way for improving BBB permeability for drug delivery.

Stroke is a devastating disease with high morbidity and mortality. Animal models are indispensable tools that can mimic stroke processes and can be used for investigating mechanisms and developing novel therapeutic regimens. As a heterogeneous disease with complex pathophysiology, mimicking all aspects of human stroke in one animal model is impossible. Each model has unique strengths and weaknesses. Models such as transient or permanent intraluminal thread occlusion middle cerebral artery occlusion (MCAo) models and thromboembolic models are the most commonly used in simulating human ischemic stroke. The endovascular filament occlusion model is characterized by easy manipulation and accurately controllable reperfusion and is suitable for studying the pathogenesis of focal ischemic stroke and reperfusion injury. Although the reproducibility of the embolic model is poor, it is more convenient for investigating thrombolysis. Rats are the most frequently used animal model for stroke. This review mainly outlines the stroke models of rats and discusses their strengths and shortcomings in detail.

目的 探讨膜联蛋白A1(Annexin A1)对肺成纤维细胞炎症反应、增殖及胶原沉积的作用.方法 分离小鼠原代肺成纤维细胞,利用不同浓度的Annexin A1干预肺成纤维细胞24h或48 h后,检测炎症因子、细胞增殖及胶原沉积表达.将C57/BL6小鼠分为对照组、Annexin A1干预组,每组6～8只.Annexin A1干预组每只小鼠气管滴注1 μg/50 μL Annexin A1重组因子,对照组每只小鼠气道滴注50 μL生理盐水,连续干预7d后取检.检测肺组织炎症因子、Ⅲ型胶原(CollagenⅢ)及气道平滑肌肌动蛋白(α-SMA)的表达.结果 与对照组比较,Annexin A1能促进肺成纤维细胞分泌IL-6、IL-8等炎症因子(均P＜0.05),促进成纤维细胞的增殖,CollagenⅢ合成和α-SMA表达增加(均P＜0.05).与对照组小鼠比较,Arnexin A1干预组小鼠的肺泡灌洗液细胞总数[(2.91±0.26)×104/mL vs.(7.03 ±0.48)×104/mL,t=7.432,P=0.008]及中性粒细胞数目明显升高[(0.12±0.04)×104/mL vs.(1.01±0.05)×104/mL,t=13.810,P＜0.001],炎症因子、胶原沉积及平滑肌表达也显著增加(均P ＜0.05).结论 Annexin A1具有诱导肺成纤维细胞的炎症反应、增殖及胶原沉积作用,提示可能在气道重构发病中起重要作用.

Hypoxic injury to cerebrovascular endothelial cells (ECs) after stroke leads to blood-brain barrier (BBB) dysfunction, which is commonly associated with disruptions of endothelial tight junctions (TJs) and increased permeability. Therefore, maintaining the structural integrity and proper function of the BBB is essential for the homeostasis and physiological function of the central nervous system (CNS). Our previous study revealed that autophagy functions on protecting the BBB by regulating the dynamics of Claudin-5, the essential TJ protein, under short-term starvation or hypoxia conditions. Here, we show that in zebrafish and in vitro cells, loss of membranous Claudin-5 conversely determine the occurrence of hypoxia-induced autophagy in cerebrovascular ECs. Absence of endothelial Claudin-5 could partly attenuate endothelial cell apoptosis caused by short-term hypoxic injury. Mechanism studies revealed that under hypoxic conditions, the existence of membranous Claudin-5 affects the stimulation of hypoxia inducible factor 1 subunit alpha (HIF-1a) and the inducible nitric oxide synthase (iNOS), which are responsible for the translocation of and endocytosis of caveole-packaged Claudin-5 into cytosol. Meanwhile, loss of Claudin-5 affects the generation of reactive oxygen species (ROS) and the downstream expression of BCL2/adenovirus E1B 19kDa protein interacting protein 3 (Bnip3). These together suppress the endothelial autophagy under hypoxia. This finding provides a theoretical basis for clarifying the mechanism of hypoxia-induced BBB injury and its potential protection mechanisms.

Background We have reported that heparin-binding epidermal growth factor (HB-EGF) is increased in patients with chronic obstructive pulmonary disease (COPD) and associated with collagen deposition, but the mechanisms remain unclear. In the present study, we aimed to investigated the inflammatory cytokines secreted by bronchial epithelial cells following exposure to HB-EGF that promoted proliferation and migration of human lung fibroblast. Methods HB-EGF-induced inflammatory cytokines were assayed in two airway epithelial cells (primary human bronchial epithelial cells [HBECs] and BEAS-2B cells). Moreover, the culture supernatants derived from HB-EGF-treated HBECs and BEAS-2B cells were added to human primary lung fibroblasts. The effect of culture supernatants on proliferation and migration of fibroblasts was assessed. Results IL-8 expression was significantly increased in bronchial epithelial cells treated with HB-EGF, which was at least partially dependent on NF-kB pathways activation. HB-EGF-induced IL-8 was found to further promote lung fibroblasts proliferation and migration, and the effects were attenuated after neutralizing IL-8. Conclusions These findings suggest that HB-EGF may be involved in the pathology of airway fibrosis by induction of IL-8 from airway epithelium, subsequently causing lung fibroblasts proliferation and migration. Thus, inhibition of HBEGF and/or IL-8 production could prevent the development of airway fibrosis by modulating fibroblast activation.

Objective:To investigate the clinical effect of the transverse rectus abdominismuscle (TRAM) on reconstruction of the breast.Methods:The clinical data of 23 patients receiving TRAM breast reconstruction in our department from Jan. 2018 to Dec. 2019 were retrospectively analyzed.Results:The operation time of 23 patients ranged from 240 to 360 mins, andthe average time was about 300 mins. Intraoperative bleeding was about 120 to 200 ml, with an average of 170 ml. All the flaps survived successfully, but 2 cases were complicated with local fat necrosis. The postoperative period was between 6 and 12 months. No local tumor recurrence or metastasis was found inall patients during postoperative follow-up, and the breast shape was maintained in good condition.Conclusion:TRAM can make up for the regret of breast loss caused by breast cancer in female patients. It can bring confidence in life and work to female patients, and the technology is safe and reliable, which is worthy of promotion.

Steinberg's differential adhesion hypothesis suggests that adhesive mechanisms are important for sorting of cells and tissues during morphogenesis (Steinberg, 2007). During zebrafish vasculogenesis, endothelial cells sort into arterial and venous vessel beds but it is unknown whether this involves adhesive mechanisms. Claudins are tight junction proteins regulating the permeability of epithelial and endothelial tissue barriers. Previously, the roles of claudins during organ development have exclusively been related to their canonical functions in determining paracellular permeability. Here, we use atomic force microscopy to quantify claudin-5-dependent adhesion and find that this strongly contributes to the adhesive forces between arterial endothelial cells. Based on genetic manipulations, we reveal a non-canonical role of Claudin-5a during zebrafish vasculogenesis, which involves the regulation of adhesive forces between adjacent dorsal aortic endothelial cells. In vitro and in vivo studies demonstrate that loss of claudin-5 results in increased motility of dorsal aorta endothelial cells and in a failure of the dorsal aorta to lumenize. Our findings uncover a novel role of claudin-5 in limiting arterial endothelial cell motility, which goes beyond its traditional sealing function during embryonic development.

Objective We investigate the molecular mechanism underlying inhibitory effects of cordycepin on proliferation,apoptosis,migration and invasion of breast cancer.We focus on the role of HOXD10 in inhibitory effects of cordycepin.Methods Two individual breast cancer cell lines,MCF-7 and MDA-MB-231,were used in this study to investigate the effects of cordycepin on proliferation,apoptosis,migration and invasion of breast cancer,by cell counting kit-8 (CCK-8) assays,flow cytometry and Transwell assays.The small interfering RNAs (siRNAs) targeted HOXD10 were transfected into MCF-7 and MDA-MB-231 cells to knock down HOXD10.We investigate the role of HOXD10 by comparing the difference between group NC and group siRNAs.Results The A values of cordycepin treated MCF-7 and MDA-MB-231 cells were significantly lower than those of control group (DMSO group) (MCF-7cells:0.665 ± 0.004 vs.0.733 ± 0.005,t =10.450,and MDA-MB-231cells:0.632 ± 0.005 vs.0.722 ± 0.005,t =13.330,P ＜ 0.05),which means the proliferation of breast cancer cells was significantly inhibited,The apoptosis rateof cordycepin treated MCF-7 and MDA-MB-231 cells were significantly higher than those of control group (MCF-7cells:20.200 ± 0.322 vs.5.500 ± 0.000,t =45.730,MDA-MB-231 cells:21.800 ± 1.493 vs.5.367 ± 0.318,t =10.760,P ＜ 0.05).There were significantly fewer migrated MCF-7 and MDA-MB-231 cells in cordycepin group than in control group(MCF-7 cells:28.670 ± 1.764 vs.83.330 ± 2.186,t=19.460,MDA-MB-231cells:29.000 ± 2.646 vs.114.700 ± 3.180,t =20.710,P ＜ 0.05).There were significantly fewer invasive MCF-7 and MDA-MB-231 cells in eordycepin group than control group(MCF-7cells:24.670 ± 2.603 vs.49.000 ± 1.528,t =8.0620,MDA-MB-231cells:12.330 ± 1.453 vs.36.670 ± 2.728,t =7.872,P ＜ 0.05).After transfection of MCF-7 and MDA-MB-231 cells with siRNA and intervention with cordycepin,the proliferation of breast cancer cells was inhibited (MCF-7cells:0.627 ± 0.004 vs.0.648 ±0.006,t=2.951,MDA-MB-23 cells:0.620 ±0.006 vs.0.635 ±0.004,t=2.087,P ＜ 0.05).The apoptosis rate of the treatment group was significantly higher than the control group (MCF-7 cells:20.470 ± 0.260 vs.16.300 ± 0.153,t =13.800,MDA-MB-23 cells:19.170 ± 0.167 vs.17.030 ±0.186,t =8.5520,P ＜0.05).There were significantly fewer migrated MCF-7 andMDA-MB-231 cells in siRNA group than in control group (MCF-7cells:11.000 ± 2.082 vs.30.330 ± 2.028,t =6.653,MDA-MB-23cells:11.330 ± 1.4530 vs.23.000 ± 1.528,t =5.534,P ＜0.05).There were significantly fewer invasive MCF-7 and MDA-MB-231cells in siRNA group than control group(MCF-7 cells:16.330 ± 1.764 vs.23.670 ± 1.760,t =2.940,MDA-MB-2 cells:9.333 ± 1.453 vs.19.670 ± 2.333,t =3.759,P ＜ 0.05).Those values above are statistically significant.Conclusion Cordycepin induces apoptosis and inhibits proliferation,migration and invasion of breast cancer.2.Suppression of HOXD10 promptes the effects of cordycepin on proliferation,apoptosis,migration and invasion of breast cancer.

目的:观察延龄草总皂苷对乳腺癌细胞MDA-MB-231裸鼠皮下移植瘤的影响及相关机制.方法:培养乳腺癌细胞MDA-MB-231,接种至BALB/c裸鼠背部皮下.接种后第5天通过腹腔注射的方式给裸鼠予延龄草总皂苷治疗,每隔3天测量移植瘤的体积以及裸鼠的体重;实验结束时,采用TUNEL试剂盒检测移植瘤细胞的凋亡情况;Western blot法检测凋亡相关蛋白剪切型caspase-3,8,9表达的变化.结果:延龄草总皂苷可有效地抑制裸鼠移植瘤的增殖,实验结束时,肿瘤的体积分别为:模型组(1142.24±164.32)mm3,延龄草总皂苷(5 mg/kg)(552.90±49.71)mm3,延龄草总皂苷(10 mg/kg)(269.78±48.84)mm3.延龄草总皂苷能诱导移植瘤细胞的凋亡,可浓度依赖性地促进细胞中剪切型caspase-3,9的表达.结论:延龄草总皂苷可有效地抑制MDA-MB-231裸鼠移植瘤的增殖,其方式可能通过caspase依赖的方式促使MDA-MB-231发生凋亡.

Although airway fibrosis and epithelial-mesenchymal transition (EMT) contribute to airway remodeling in chronic obstructive pulmonary disease (COPD), the mechanisms underlying their development have not been fully elucidated. In the present study, we aimed to assess heparin-binding epidermal growth factor (HB-EGF) expression in the airways of patients with COPD and to elucidate the possible role of HB-EGF in the pathology of COPD. Sputum and lung tissue HB-EGF expression was evaluated in control subjects and patients with COPD. The relationships between HB-EGF expression, disease severity, collagen deposition (fibrosis), and EMT were investigated. In vitro, human bronchial epithelial (HBE) cells and lung fibroblast cells exposed to the recombinant HB-EGF, collagen deposition and EMT were assessed. We found that sputum HB-EGF expression was significantly increased in patients with COPD compared with non-smokers and smokers without COPD. There was a significant positive correlation between sputum HB-EGF and COPD assessment test (CAT) score. HB-EGF expression was significantly increased in the lung tissue samples of patients with COPD and associated with collagen deposition and N- and E-cadherin, and vimentin expression. In vitro, HB-EGF promoted collagen production in lung fibroblasts. Moreover, HB-EGF induced the EMT process through induction of N-and E-cadherin, and vimentin expression in HBE cells. Collectively, HB-EGF induces airway remodeling by modulating airway fibrosis and pulmonary EMT, and contributes to the COPD severity. The current data may provide insight into the underlying pathogenesis of COPD, in which HB-EGF has an important pathogenic role.

Objective To observe the effect of cigarette smoke extract (CSE) on the expression of human silencing information regulator protein 6 (SIRT6) and Caspase-9 in human bronchial epithelial cells (16HBE).Methods In vitro culture of 16HBE,we added different concentrations of fresh CSE to induce cells.The expression of SIRT6 and Caspase-9 were detected by fluorescence quantitative polmerase chain reaction (PCR) and Western blotting.The effects of (0 ％,5 ％,7.5 ％,10 ％)CSE on the expression of SIRT6 and Caspase-9 in 16HBE were compared.Results After 16HBE treatment with different concentrations (0 ％,5 ％,7.5 ％,10 ％) of CSE,the SIRT6 mRNA expression showed significant difference (P ＜0.01).The differences between each two groups were statistically significant except for 5 ％ CSE vs 7.5 ％ CSE (P ＞ 0.05).Caspase-9 mRNA expression between groups showed significant difference (P ＜0.01).The differences between each two groups were statistically significant (P ＜0.01).After 16HBE treatment with different concentrations (0 ％,5 ％,7.5 ％,10 ％) of CSE,the SIRT6 protein expression and Caspase-9 protein showed significant difference between groups (P ＜0.01).The differences between each two groups were statistically significant (P ＜0.01 or＜0.05).Conclusions CSE can cause SIRT6,Caspase-9 of 16HBE expression changes.

沉默信息调节因子2 (Sirt2) 是1986年Ivy等人在酵母菌中发现的和长寿相关的基因[1],后来发现在哺乳动物中也存在和 Sirt2同源蛋白,命名为SIRT1-SIRT7,其中SIRT1和酵母的 Sirt2同源性最高.SIRT1作为细胞内重要的调节因子,广泛分布于人类多种细胞的胞浆和胞核,参与调节炎症、细胞周期、衰老和凋亡、应激等重要生理过程.与多种肺部疾病的发生发展密切相关,例如慢性阻塞性肺疾病、支气管哮喘(简称哮喘)、肺纤维化、肺癌等.然而,目前SIRT1在哮喘中发病机制的研究报道较少.本文主要从SIRT1与哮喘关系进行综述.

Purpose Fibrosis in peripheral airways is responsible for airflow limitation in chronic obstructive pulmonary disease (COPD). Annexin A1 modulates several key biological events during inflammation. However, little is known about its role in airway fibrosis in COPD. We investigated whether levels of Annexin A1 were upregulated in patients with COPD, and whether it promoted airway fibrosis. Methods We quantified serum Annexin A1 levels in never-smokers (n=12), smokers without COPD (n=11), and smokers with COPD (n=22). Correlations between Annexin A1 expression and clinical indicators (eg, lung function) were assessed. In vitro, human bronchial epithelial (HBE) cells were exposed to cigarette smoke extract (CSE) and Annexin A1 expression was assessed. Primary human lung fibroblasts were isolated from patients with COPD and effects of Annexin A1 on fibrotic deposition of lung fibroblasts were evaluated. Results Serum Annexin A1 was significantly higher in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines stage III or IV than in those with GOLD stages I or II (12.8±0.8 ng/mL versus 9.8±0.7 ng/mL; p=0.016). Annexin A1 expression was negatively associated with airflow obstruction (forced expiratory volume in one second % predicted; r=−0.72, p<0.001). In vitro, Annexin A1 was significantly increased in CSE-exposed HBE cells in a time- and concentration-dependent manner. Annexin A1 promoted lung fibroblasts proliferation, migration, differentiation, and collagen deposition via the ERK1/2 and p38 mitogen-activated protein kinase pathways. Conclusion Annexin A1 expression is upregulated in patients with COPD and affects lung fibroblast function. However, more studies are needed to clarify the role of Annexin A1 in airway fibrosis of COPD.

目的 探讨白藜芦醇(Res)对PM2.5诱导气道上皮细胞IL-8表达的影响.方法 先用不同浓度PM2.5刺激人气道上皮细胞株16HBE,再将16HBE细胞分为PM2.5组(75 mg/L)、Res+PM2.5组(100 μtmol/L Res+75 mg/L PM2.5)、空白对照组,分别用荧光定量PCR、ELISA检测IL-8表达.结果 PM2.5呈浓度和时间依赖性刺激16HBE细胞表达IL-8,Res+PM2.5组中IL-8表达明显低于PM2.5组(P＜0.05).结论 Res可能通过抑制气道上皮细胞表达IL-8,进而减轻PM2.5诱导的气道炎症反应.

The increased expression of placental growth factor (PlGF) in chronic obstructive pulmonary disease and allergy-related asthma suggests its role in the pathogenesis of these diseases. In asthmatic smokers, airway remodelling is accompanied by an accelerated decline in lung function. However, whether PlGF contributes to the persistent airflow obstruction and vascular remodelling typically seen in asthmatic smokers is unknown. In this study we measured lung function, airway-wall thickening, and PlGF levels in serum and induced sputum in 74 asthmatic and 42 healthy smokers and never-smokers. Using human lung microvascular endothelial cells (HLMECs), we evaluated the in vitro effects of PlGF on each step of vascular remodelling, including proliferation, migration, stress-fibre expression, and tubule formation. Our data showed significantly higher serum and sputum PlGF levels in asthma patients, especially asthmatic smokers, than in healthy controls. Serum and sputum PlGF levels correlated negatively with post-bronchodilator forced expiratory volume in 1 s (FEV1) and the FEV1/forced vital capacity, but positively with airway-wall thickening. Stimulation of HLMECs with rhPlGF promoted all of the steps of airway-microvascular remodelling. These findings provide insights into the influence of cigarette smoking on the structural changes in the airways of asthmatics and the important pathogenic role played by PlGF.