GLUT3-mediated cigarette smoke-induced epithelial-mesenchymal transition in chronic obstructive pulmonary disease through the NF-kB/ZEB1 pathway.

BACKGROUND: Airway remodelling plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) is a significant process during the occurrence of airway remodelling. Increasing evidence suggests that glucose transporter 3 (GLUT3) is involved in the epithelial mesenchymal transition (EMT) process of various diseases. However, the role of GLUT3 in EMT in the airway epithelial cells of COPD patients remains unclear. METHODS: We detected the levels of GLUT3 in the peripheral lung tissue of COPD patients and cigarette smoke (CS)-exposed mice. Two Gene Expression Omnibus GEO datasets were utilised to analyse GLUT3 gene expression profiles in COPD. Western blot and immunofluorescence were used to detect GLUT3 expression. In addition, we used the AAV9-GLUT3 inhibitor to reduce GLUT3 expression in the mice model. Masson's staining and lung function measurement were used detect the collagen deposition and penh in the mice. A cell study was performed to confirm the regulatory effect of GLUT3. Inhibition of GLUT3 expression with siRNA, Western blot, and immunofluorescence were used to detect the expression of E-cadherin, N-cadherin, vimentin, p65, and ZEB1. RESULTS: Based on the GEO data set analysis, GLUT3 expression in COPD patients was higher than in non-smokers. Moreover, GLUT3 was highly expressed in COPD patients, CS exposed mice, and BEAS-2B cells treated with CS extract (CSE). Further research revealed that down-regulation of GLUT3 significantly alleviated airway remodelling in vivo and in vitro. Lung function measurement showed that GLUT3 reduction reduced airway resistance in experimental COPD mice. Mechanistically, our study showed that reduction of GLUT3 inhibited CSE-induced EMT by down-regulating the NF-κB/ZEB1 pathway. CONCLUSION: We demonstrate that CS enhances the expression of GLUT3 in COPD and further confirm that GLUT3 may regulate airway remodelling in COPD through the NF-κB/ZEB1 pathway; these findings have potential value in the diagnosis and treatment of COPD. The down-regulation of GLUT3 significantly alleviated airway remodelling and reduced airway resistance in vivo. Our observations uncover a key role of GLUT3 in modulating airway remodelling and shed light on the development of GLUT3-targeted therapeutics for COPD.

CircRNA_0026344 via miR-21 is involved in cigarette smoke-induced autophagy and apoptosis of alveolar epithelial cells in emphysema.

Cigarette smoke (CS), a main source of indoor air pollution, is a primary risk factor for emphysema, and aberrant cellular autophagy is related to the pathogenesis of emphysema. Circular RNAs (circRNAs) affect the expression of mRNAs via acting as microRNA (miRNA) sponges, but their role in emphysema progression is not established. In the present investigation, CS, acting on alveolar epithelial cells, caused higher levels of miR-21, p-ERK, and cleaved-caspase 3 and led to lower levels of circRNA_0026344 and PTEN, which induced autophagy and apoptosis. miR-21 suppressed the expression of PTEN, which was involved in the regulation of autophagy and apoptosis. Further, in alveolar epithelial cells, overexpression of circRNA_0026344 blocked cigarette smoke extract (CSE)-induced autophagy and apoptosis, but this blockage was reversed by upregulation of miR-21 with a mimic. These results demonstrated that, in alveolar epithelial cells, CS decreases circRNA_0026344 levels, which sponge miR-21 to inhibit the miR-21 target, PTEN, which, in turn, activates ERK and thereby promotes autophagy and apoptosis, leading to emphysema. Thus, for emphysema, circRNA_0026344 regulates the PTEN/ERK axis by sponging miR-21, which is associated with the CS-induced autophagy and apoptosis of alveolar epithelial cells. In sum, the present investigation identifies a novel mechanism for CS-induced emphysema and provides information useful for the diagnosis and treatment of CS-induced emphysema.

The aberrant cross-talk of epithelium-macrophages via METTL3-regulated extracellular vesicle miR-93 in smoking-induced emphysema.

Cigarette smoke (CS), a complex chemical indoor air pollutant, induces degradation of elastin, resulting in emphysema. Aberrant cross-talk between macrophages and bronchial epithelial cells is essential for the degradation of elastin that contributes to emphysema, in which extracellular vesicles (EVs) play a critical role. The formation of N6-methyladenosine (m6A) is a modification in miRNA processing, but its role in the development of emphysema remains unclear. Here, we established that production of excess mature microRNA-93 (miR-93) in bronchial epithelial cells via enhanced m6A modification was mediated by overexpressed methyltransferase-like 3 (METTL3) induced by CS. Mature miR-93 was transferred from bronchial epithelial cells into macrophages by EVs. In macrophages, miR-93 activated the JNK pathway by targeting dual-specificity phosphatase 2 (DUSP2), which elevated the levels of matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 12 (MMP12) and induced elastin degradation, leading to emphysema. These results demonstrate that METTL3-mediated formation of EV miR-93, facilitated by m6A, is implicated in the aberrant cross-talk of epithelium-macrophages, indicating that this process is involved in the smoking-related emphysema. EV miR-93 may use as a novel risk biomarker for CS-induced emphysema.

The correlation between volumetric bone mineral density and morphological parameters of the proximal femur and clinical outcomes in ankylosing spondylitis patients with hip involvement.

BACKGROUND: To measure volumetric bone mineral density (vBMD) with quantitative computed tomography (QCT) in the proximal femur of ankylosing spondylitis (AS) patients with hip involvement and analyze their correlations with radiographic and clinical parameters. METHODS: Sixty-five AS inpatients were enrolled in this study. The bone mineral density was measured by QCT and dual-energy x-ray absorptiometry (DXA), respectively. The morphological parameters of the proximal femur were measured on digital anteroposterior (AP) radiographs of the pelvis. The correlations between them were analyzed by SPSS software. RESULTS: The average trabecular vBMD measured at the femoral neck was 136.38 ± 25.58 mg/cm3. According to the BASRI-Hip score, group A consisted of 39 hips (0-2 score) and group B consisted of 26 hips (3-4 score). There were significant differences regarding trabecular CTXA equivalent T-score between group A and B at the femoral neck (p = 0.004); intertrochanteric region (p < 0.001) and greater trochanter (p = 0.001). The trabecular CTXA equivalent T-score at femoral neck had a negative correlation with disease duration (r = - 0.311, p = 0.012) and with CBR (r = - 0.319, p = 0.010). CONCLUSIONS: The low trabecular bone density at the site of the hip was associated with the duration of disease progression and degree of hip involvement. Meanwhile, it had a correlation with hip function status although we failed to confirm a significant relationship between hip vBMD and disease activity.

Which serum markers predict the success of reimplantation after periprosthetic joint infection?

PURPOSE: In clinical practice, serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels are routinely used to screen for periprosthetic joint infection (PJI), but the effectiveness of predicting the success of reimplantation is variable. This study aimed to evaluate the diagnostic effectiveness of serum CRP, ESR, plasma D-dimer, and fibrinogen values in groups achieving treatment success or failure for PJI. METHODS: A total of 119 PJI cases between January 2012 and January 2017 were identified and included in this study. The most recent serum CRP, ESR, plasma D-dimer, and fibrinogen values obtained prior to performing second-stage revision or spacer exchange were collected for analysis. Treatment failure was defined as having been unable to undergo reimplantation due to clinically persistent infection or reinfection after reimplantation. RESULTS: All these tests showed significantly lower values in the treatment success group than in the treatment failure group. The optimal cutoff serum CRP, ESR, plasma D-dimer, and fibrinogen levels for predicting the success of reimplantation were 9.4 mg/L, 29 mm/h, 1740 ng/mL, and 365.6 mg/dL, respectively. All tests had the same sensitivity (72.7%) except for ESR (63.6%), while their specificities were 92.6%, 88.0%, 72.3%, and 83.2%, respectively. Plasma fibrinogen had the highest AUC value of 0.831 [95% confidence interval (CI), 0.685 to 0.978], followed by serum CRP (0.829) and ESR (0.795); plasma D-dimer had the lowest AUC value of 0.716 (95% CI, 0.573 to 0.859). CONCLUSION: Plasma CRP and fibrinogen are good tests for predicting reimplantation success after two-stage revision procedures for patients with PJI.

Let-7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL-6.

BACKGROUND: Myofibroblast differentiation and extracellular matrix (ECM) deposition are observed in chronic obstructive pulmonary disease (COPD). However, the mechanisms of regulation of myofibroblast differentiation remain unclear. MATERIALS AND METHODS: We detected let-7 levels in peripheral lung tissues, serum and primary bronchial epithelial cells of COPD patients and cigarette smoke (CS)-exposed mice. IL-6 mRNA was explored in lung tissues of COPD patients and CS-exposed mice. IL-6 protein was detected in cell supernatant from primary epithelial cells by ELISA. We confirmed the regulatory effect of let-7 on IL-6 by luciferase reporter assay. Western blotting assay was used to determine the expression of α-SMA, E-cadherin and collagen I. In vitro, cell study was performed to demonstrate the role of let-7 in myofibroblast differentiation and ECM deposition. RESULTS: Low expression of let-7 was observed in COPD patients, CS-exposed mice and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. Increased IL-6 was found in COPD patients, CS-exposed mice and CSE-treated HBE cells. Let-7 targets and silences IL-6 protein coding genes through binding to 3' untranslated region (UTR) of IL-6. Normal or CSE-treated HBE cells were co-cultured with human embryonic lung fibroblasts (MRC-5 cells). Reduction of let-7 in HBE cells caused myofibroblast differentiation and ECM deposition, while increase of let-7 mimics decreased myofibroblast differentiation phenotype and ECM deposition. CONCLUSION: We demonstrate that CS reduced let-7 expression in COPD and, further, identify let-7 as a regulator of myofibroblast differentiation through the regulation of IL-6, which has potential value for diagnosis and treatment of COPD.

Extracorporeal membrane oxygenation as a bridge vs. non-bridging for lung transplantation: A systematic review and meta-analysis.

Whether extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) can achieve a similar survival to non-BTT remains controversial. We conducted this meta-analysis to compare the outcomes between ECMO BTT and non-BTT to facilitate better clinical decision-making. Seven databases were searched for eligible studies comparing ECMO BTT and non-BTT. The primary endpoints included survival, intraoperative indicators, postoperative hospitalization indicators, and postoperative complications. Nineteen studies (involving 7061 participants) were included in the final analysis. The outcomes of overall survival, overall survival rate, graft survival rate, in-hospital mortality, postoperative hospital days, postoperative intensive care unit days, postoperative ventilation time, blood transfusion volume, and postoperative complications were all better in the non-BTT group. The total mortality in ECMO bridging was 23.03%, in which the top five causes of death were right heart failure (8.03%), multiple organ failure (7.03%), bleeding (not cranial) (4.67%), cranial bleeding (3.15%), and sepsis (2.90%). In summary, Non-BTT is associated with better survival and fewer complications compared to BTT. When ECMO may be the only option, the patient and medical team need to realize the increased risk of ECMO by complications and survival.

Dynamic evolution of emphysema and airway remodeling in two mouse models of COPD.

BACKGROUND: Establishment of a mouse model is important for investigating the mechanism of chronic obstructive pulmonary disease (COPD). In this study, we observed and compared the evolution of the pathology in two mouse models of COPD induced by cigarette smoke (CS) exposure alone or in combination with lipopolysaccharide (LPS). METHODS: One hundred eight wild-type C57BL/6 mice were equally divided into three groups: the (1) control group, (2) CS-exposed group (CS group), and (3) CS + LPS-exposed group (CS + LPS group). The body weight of the mice was recorded, and noninvasive lung function tests were performed monthly. Inflammation was evaluated by counting the number of inflammatory cells in bronchoalveolar lavage fluid and measuring the expression of the IL-6 mRNA in mouse lung tissue. Changes in pathology were assessed by performing hematoxylin and eosin and Masson staining of lung tissue sections. RESULTS: The two treatments induced emphysema and airway remodeling and decreased lung function. Emphysema was induced after 1 month of exposure to CS or CS + LPS, while airway remodeling was induced after 2 months of exposure to CS + LPS and 3 months of exposure to CS. Moreover, the mice in the CS + LPS group exhibited more severe inflammation and airway remodeling than the mice in the CS group, but the two treatments induced similar levels of emphysema. CONCLUSION: Compared with the single CS exposure method, the CS + LPS exposure method is a more suitable model of COPD in airway remodeling research. Conversely, the CS exposure method is a more suitable model of COPD for emphysema research due to its simple operation.

Assessment of hip involvement in patients with ankylosing spondylitis: reliability and validity of the Hip Inflammation MRI Scoring System.

BACKGROUND: This study aimed to test the reliability and validity of the Hip Inflammation MRI Scoring System (HIMRISS) in assessing hip involvement of AS patients with AS at different stages of the bath ankylosing spondylitis radiology index (BASRI-hip) scoring system. METHODS: Fifty-two outpatients with ankylosing spondylitis (AS) were included in this study. The subjects' data includes demographics, clinical characteristics, disease activity score, and functional index. Based on the Harris hip scoring (HHS) of involved hip and BASRI-hip score, we devided these patients into no hip involvement group((HHS ≥ 80 and BASRI ≤ 1) (Group A), mild hip involvement subgroup (BASRI = 2 or BASRI ≤ 1 and HHS ≤ 79) (Group B), and moderate to advanced hip involvement subgroup (BASRI ≥ 3) (Group C). Data was analyzed statistically by SPSS software. RESULTS: In total of 44 patients (88 hips), group A consisted of 21 hips, group B consisted of 42 hips and group C consisted of 25 hips. The test-retest intraclass correlation coefficients (ICCs) in four raters were 0.955 ~ 0.977 and interrater ICC was 0.993. HIMRISS correlated moderately with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (r = 0.540, p < 0.001), the Bath ankylosing spondylitis functional index (BASFI) (r = 0.540, p < 0.001), the Bath Ankylosing Spondylitis Functional Index (BASFI) (r = 0.581, p < 0.001), ASDAS-ESR (r = 0.604, p < 0.001), and Ankylosing Spondylitis Disease Activity Score (ASDAS)-C reactive protein (CRP) (r = 0.575, p < 0.001). HIMRISS in groups B and C was significantly higher than that in group A: 29.38 (17.00, 40.94) vs. 14.50 (11.38, 22.25), p = 0.009; 38 (31.13, 64.38) vs 14.50 (11.38, 22.25), p < 0.001. CONCLUSIONS: HIMRISS applied to patients with AS demonstrated a satisfactory reliability, meaning it is a reliable quantitive assessment tool for evaluating early hip involvement in patients with AS.

Does psychological distress influence postoperative satisfaction and outcomes in patients undergoing total knee arthroplasty? A prospective cohort study.

BACKGROUND: Preoperative psychological distress may be related to dissatisfaction and poorer outcomes after total knee arthroplasty (TKA). However, the kind of psychological distress that could influence postoperative satisfaction and outcomes remains controversial. Few studies have examined these issues in Chinese cohorts. Thus, this study aimed to examine (1) the prevalence of preoperative psychological distress in patients undergoing TKA and (2) whether preoperative psychological distress influences patient satisfaction, early postoperative outcomes, and improvement of knee function after TKA. METHODS: We prospectively included 210 patients undergoing unilateral primary TKA between March 2017 and September 2017 at our institution. Preoperatively, patients completed the Depression Anxiety and Stress Scales and new Knee Society Scores (KSS) questionnaires. At 3 months and 1 year postoperatively, patients' KSS and overall satisfaction were assessed. Stepwise multivariate linear regression models were used to assess the variables that influenced changes in each KSS item. RESULTS: Preoperatively, 89 (42.4%) patients experienced psychological distress. The satisfaction rate and postoperative KSS were not significantly different between patients with or without psychological distress; a higher preoperative score was shown to predict less KSS improvement. Patients with depression had fewer symptom score changes. CONCLUSIONS: The prevalence of preoperative psychological distress was relatively high; thus, surgeons should consider the patient's psychological state. Patients' satisfaction was not influenced by psychological factors. Patients with depression and higher preoperative scores had lower symptom scores and KSS improvement, respectively.

Melatonin modulates airway smooth muscle cell phenotype by targeting the STAT3/Akt/GSK-3ß pathway in experimental asthma.

Among the troika of clinicopathologic features of asthma, airway remodelling has gained sufficient attention for its contribution to progressive airway narrowing. Much effort has been directed at the management of airway smooth muscle cells (ASMCs), but few attempts have proven to prevent the progression of remodelling. Recently, accumulating data have shown the anti-inflammatory/anti-proliferative potency of melatonin (a crucial neurohormone involved in many physiological and pathological processes) in diverse cells. However, no evidence has confirmed its effect on ASMCs. The present study investigates the benefits of melatonin in asthma, with an emphasis on airway remodelling. The results indicated that melatonin significantly attenuated airway hyperresponsiveness (AHR), inflammation and remodelling in a house dust mite (HDM) model. Melatonin markedly alleviated goblet cell hyperplasia/metaplasia, collagen deposition and airway smooth muscle hyperplasia/hypertrophy, implying the achievement of remodelling remission. The data obtained in vitro further revealed that melatonin notably inhibited ASMCs proliferation, VEGF synthesis and cell migration induced by PDGF, which might depend on STAT3 signalling. Moreover, melatonin remarkably relieved ASMCs contraction and reversed ASMCs phenotype switching induced by TGF-ß, probably via the Akt/GSK-3ß pathway. Altogether, our findings illustrated for the first time that melatonin improves asthmatic airway remodelling by balancing the phenotypic proportions of ASMCs, thus highlighting a novel purpose for melatonin as a potent option for the management of asthma.

Model-Free Robust Optimal Feedback Mechanisms of Biological Motor Control.

Sensorimotor tasks that humans perform are often affected by different sources of uncertainty. Nevertheless, the central nervous system (CNS) can gracefully coordinate our movements. Most learning frameworks rely on the internal model principle, which requires a precise internal representation in the CNS to predict the outcomes of our motor commands. However, learning a perfect internal model in a complex environment over a short period of time is a nontrivial problem. Indeed, achieving proficient motor skills may require years of training for some difficult tasks. Internal models alone may not be adequate to explain the motor adaptation behavior during the early phase of learning. Recent studies investigating the active regulation of motor variability, the presence of suboptimal inference, and model-free learning have challenged some of the traditional viewpoints on the sensorimotor learning mechanism. As a result, it may be necessary to develop a computational framework that can account for these new phenomena. Here, we develop a novel theory of motor learning, based on model-free adaptive optimal control, which can bypass some of the difficulties in existing theories. This new theory is based on our recently developed adaptive dynamic programming (ADP) and robust ADP (RADP) methods and is especially useful for accounting for motor learning behavior when an internal model is inaccurate or unavailable. Our preliminary computational results are in line with experimental observations reported in the literature and can account for some phenomena that are inexplicable using existing models.

Cementless Total Hip Arthroplasty for Adult Patients With Sequelae From Childhood Hip Infection: A Medium-Term Follow-Up Study.

BACKGROUND: The aim of this study is to evaluate midterm clinical and radiographic results of total hip arthroplasties (THAs) with cementless implants for adult patients with sequelae from childhood hip infection. METHODS: Between 2002 and 2016, 165 patients (165 hips) who had a hip infection during childhood were treated with THAs with cementless implants. The average duration of follow-up was 93.5 months (range 26-206). Clinical results were evaluated via the Harris Hip Score and radiographic results were analyzed with postoperative serial X-rays. RESULTS: The average Harris Hip Score increased from 27 (range 8-53) before surgery to 91 (range 45-100) at the latest follow-up examination (P < .001). At the latest follow-up evaluation, 9 cementless acetabular components demonstrated partial, nonprogressive radiolucencies. No subsidence of more than 2 mm or evidence of a radiolucent line was observed around the femoral components. Intraoperative periprosthetic fractures occurred in 11 hips, including 3 acetabular fractures, 2 fractures of greater trochanter, 1 femoral shaft fracture, and 5 fractures of femoral calcar. Postoperative complications included 3 cases of periprosthetic infection, 1 episode of dislocation, 1 case of a femoral periprosthetic fracture, 5 cases of sciatic nerve injury, 1 case of femoral nerve injury, and 1 case of squeaking from a ceramic bearing surface. CONCLUSION: Cementless THA for adult patients with sequelae from childhood hip infection presents significant technical challenges and a relatively high complication rate. With meticulous surgical planning and anticipation for the key technical challenges frequently encountered, the medium-term clinical and radiographic results of THA in this setting were good with high implant survivorship and patient satisfaction.

Change in hepatitis B virus large surface antigen variant prevalence 13 years after implementation of a universal vaccination program in China.

A nationwide hepatitis B virus (HBV) vaccination program was implemented in China starting in 1992. To study the change in HBV variant prevalence with massive immunization, large HBV surface protein (LHBs) genes from HBV surface antigen (HBsAg)-positive sera were amplified and sequenced. The prevalences of LHBs mutants were compared between the 1992 and 2005 surveys in child and adult groups. The prevalence of "α" determinant mutants in the children increased from 6.5% in 1992 to 14.8% in 2005, where the G145R mutant occurred most frequently. In contrast, mutation frequencies showed little difference between 1992 (9.4%) and 2005 (9.9%) in adults. Moreover, compared to the 1992 survey, the child group surface (S) protein mutation frequency specifically increased (P = 0.005) in the 2005 survey, but the pre-S region mutation frequency did not show a significant difference (P > 0.05). However, the mutation frequency in the adult group increased in both the pre-S and S regions. Furthermore, the frequencies of the disease-related pre-S2 deletion and start codon mutations were significantly higher in the adult groups than in the child groups in both the 1992 and 2005 surveys (P < 0.01). Massive immunization enhances the HBV S protein mutation; the prevalence of LHBs mutants, particularly disease-related mutants, tends to increase with patient age.

Protective effects of astragaloside IV against ovalbumin-induced lung inflammation are regulated/mediated by T-bet/GATA-3.

Bronchial asthma is characterized by chronic lung inflammation, airway hyperresponsiveness, and airway remodelling. Astragaloside IV (3-O-ß-D-xylopyranosyl-6-O-ß-D-glucopyranosyl-cycloastragenol, AST), the primary pure saponin isolated from the root of Astragalus membranaceus, is an effective compound with distinct pharmacological effects including anti-inflammation, immunoregulation, and antifibrosis. However, the effect of AST on asthma remains unclear. In the present study, in the murine model of asthma, the airway hyperresponsiveness was relieved after treatment with AST, accompanied by a reduction of inflammatory cells. In addition, the levels of IL-4 and IL-5 decreased, while the IFN-γ level increased, in bronchoalveolar lavage fluid. The compound also significantly inhibited the synthesis of GATA-3-encoding mRNA and protein in addition to increasing the synthesis of T-bet-encoding mRNA and protein in both lung tissues and CD4+ T cells. Our findings indicate that AST treatment inhibits ovalbumin-induced airway inflammation by modulating the key master switches GATA-3 and T-bet, which results in committing T helper cells to a Th1 phenotype.

A miRNA-21-Mediated PTEN/Akt/NF-κB Axis Promotes Chronic Obstructive Pulmonary Disease Pathogenesis.

Background: This study sought to explore the underlying mechanism of miR-21 mediated apoptosis and inflammation in chronic obstructive pulmonary disease (COPD) induced by cigarette smoke (CS). Methods: We detected levels and PTEN/Akt/NF-κB axis protein levels in peripheral lung tissues of COPD patients and CS-exposed mice and HBE cells. Western blotting assay was used to determine the expression of cleaved caspase-3. IL-6 and IL-8 protein was detected in cell supernatant from cells by ELISA. HBE cells were transfected with a miR-21 inhibitor, and co-culture with A549. Results: Increased miR-21 expression, reduced PTEN expression and following activation of Akt in in peripheral lung tissues of COPD patients and CS-exposed mice and HBE cells. Inhibition of miR-21 showed enhanced PTEN levels and reduced the expression of phosphorylated form of Akt and NF-κB. Decreased expression of cleaved caspase-3, IL-6 and IL-8 in A549 cells co cultured with HBE cells transfected with miR-21 inhibitor compared with transfected with miR-21 control inhibitor. Conclusion: MiR-21 contributes to COPD pathogenesis by modulating apoptosis and inflammation through the PTEN/Akt/NF-κB pathway. Targeting miR-21 may increase PTEN expression and inhibit Akt/NF-κB pathway, offering potential diagnostic and therapeutic value in COPD management.

Association of radiological severity of hip involvement with clinical characteristics and sagittal spinopelvic balance in patients with ankylosing spondylitis.

INTRODUCTION: This is the first study to analyze the associations between the radiological severity of hip involvement with clinical characteristics and sagittal spinopelvic balance in patients with ankylosing spondylitis (AS). METHOD: We evaluated 182 patients with AS who were referred to outpatient clinics. Patient demographic data and clinical and radiographic parameters were collected. Patients were divided into three groups based on the Bath Ankylosing Spondylitis Radiology Hip Index. Clinical characteristics and spinopelvic parameters acquired by a low-dose biplanar imaging system were evaluated among these groups. RESULTS: Patients with more severe hip involvement were older and had longer disease duration and diagnostic delay, with lower Harris Hip Score (p < 0.001) and 12-item Short Form Health Survey Physical Component Score (p < 0.001) and higher Bath Ankylosing Spondylitis Disease Activity Index (p = 0.030) and Functional Index (p < 0.001). Patients with more severe hip involvement had significantly higher sacroiliac grade (p < 0.001) and higher modified Stoke Ankylosing Spondylitis Spinal Score (p < 0.001). Patients with moderate and severe hip involvement had similar lumbar lordosis and spino-sacral angle, whereas patients with severe hip involvement had lower pelvic tilt, pelvic femoral angle, higher sacral slope, and sagittal vertical axis. CONCLUSIONS: The severity of hip involvement is associated with physical function and is not consistent with the severity of spinal involvement. Severe hip involvement impairs the ability to retrovert the pelvis to accommodate the sagittal deformity, and spinopelvic parameters should be concretely evaluated in preoperative counseling of patients with AS waiting for total hip arthroplasty. Key Points • The severity of hip involvement in patients with AS is associated with physical function. • Severe hip involvement impairs the ability to retrovert the pelvis to accommodate the sagittal deformity.

circADAMTS6 via stabilizing CAMK2A is involved in smoking-induced emphysema through driving M2 macrophage polarization.

Cigarette smoke (CS), an indoor environmental pollutant, is a prominent risk factor for emphysema, which is a pathological feature of chronic obstructive pulmonary disease (COPD). Emerging function of circRNAs in immune responses and disease progression shed new light to explore the pathogenesis of emphysema. In this research, we demonstrated, by single-cell RNA sequencing (scRNAseq), that the ratio of M2 macrophages were increased in lung tissues of humans and mice with smoking-related emphysema. Further, our data showed that circADAMTS6 was associated with cigarette smoke extract (CSE)-induced M2 macrophage polarization. Mechanistically, in macrophages, circADAMTS6 stabilized CAMK2A mRNA via forming a circADAMTS6/IGF2BP2/CAMK2A RNA-protein ternary complex to activate CREB, which drives M2 macrophage polarization and leads to emphysema. In addition, in macrophages of mouse lung tissues, downregulation of circADAMTS6 reversed M2 macrophage polarization, the proteinase/anti-proteinase imbalance, and the elastin degradation, which protecting against CS-induced emphysema. Moreover, for macrophages and in a model with co-cultured lung organoids, the target of circADAMTS6 restored the growth of lung organoids compared to CSE-treated macrophages. Our results also demonstrated that, for smokers and COPD smokers, elevation of circADAMTS6 negatively correlated with lung function. Overall, this study reveals a novel mechanism for circADAMTS6-driven M2 macrophage polarization in smoking-related emphysema and postulates that circADAMTS6 could serve as a diagnostic and therapeutic marker for smoking-related emphysema.

CD146 deficiency aggravates chronic obstructive pulmonary disease via the increased production of S100A9 and MMP-9 in macrophages.

Chronic obstructive pulmonary disease (COPD) is a leading cause of global death. As a molecule beyond adhesion, CD146 is involved in COPD pathogenesis. However, the mechanisms of CD146 in COPD remain largely elusive. We hypothesized that CD146 regulates the production of matrix metalloproteinase-9 (MMP-9) in macrophages and thereby contributes to COPD. Here, we constructed a murine model of COPD using lipopolysaccharide (LPS) and porcine pancreatic elastase (PPE). In COPD-like mice, LPS and PPE decreased the pulmonary expression of CD146. MMP-9 expression and bioactivity were increased in CD146 knockout COPD-like mice. In vitro, LPS decreased CD146 expression in macrophages. With or without LPS challenge, CD146-defective macrophages produced more MMP-9. Transcriptome analysis based on next-generation sequencing (NGS) revealed that S100A9 regulated MMP-9 production in CD146-defective macrophages. Targeting S100A9 with paquinimod decreased lung inflammation and alleviated alveolar destruction in COPD-like mice. Collectively, our study suggests that CD146 negatively regulates MMP-9 production in macrophages via the S100A9 pathway in COPD.

Stenotrophomonas maltophilia contributes to smoking-related emphysema through IRF1-triggered PANoptosis of alveolar epithelial cells.

Cigarette smoke (CS), the main source of indoor air pollution and the primary risk factor for respiratory diseases, contains chemicals that can perturb microbiota through antibiotic effects. Although smoking induces a disturbance of microbiota in the lower respiratory tract, whether and how it contributes to initiation or promotion of emphysema are not well clarified. Here, we demonstrated an aberrant microbiome in lung tissue of patients with smoking-related COPD. We found that Stenotrophomonas maltophilia (S. maltophilia) was expanded in lung tissue of patients with smoking-related COPD. We revealed that S. maltophilia drives PANoptosis in alveolar epithelial cells and represses formation of alveolar organoids through IRF1 (interferon regulatory factor 1). Mechanistically, IRF1 accelerated transcription of ZBP1 (Z-DNA Binding Protein 1) in S. maltophilia-infected alveolar epithelial cells. Elevated ZBP1 served as a component of the PANoptosome, which triggered PANoptosis in these cells. By using of alveolar organoids infected by S. maltophilia, we found that targeting of IRF1 mitigated S. maltophilia-induced injury of these organoids. Moreover, the expansion of S. maltophilia and the expression of IRF1 negatively correlated with the progression of emphysema. Thus, the present study provides insights into the mechanism of lung dysbiosis in smoking-related COPD, and presents a potential target for mitigation of COPD progression.