Background: Pulmonary ischemia-reperfusion injury (PIRI) is a major cause of fatality post-lung transplantation. Though some long non-coding RNAs (lncRNAs) have been studied in acute lung injury (ALI), their effects on PIRI remain undefined. The present study aims to explore the underlying mechanism of small nucleolar RNA host gene 16 (SNHG16) in PIRI. Methods: PIR mouse and oxygen-glucose deprivation/reoxygenation (OGD/R) cell models were established. Exosomes were extracted from human pulmonary microvascular endothelial cells (HPMECs). Functional and rescue experiments were conducted in OGD/R-exposed HPMECs, OGD/R-exposed pulmonary alveolar epithelial type II cells (AECs), and I/R model mice. The relationships among SNHG16, miR-372-3p/miR-373-3p, and MTCH2 were also verified using dual luciferase reporter assay, RNA pull-down and RIP assay. Results: SNHG16 was downregulated in OGD/R-exposed HPMECs, and SNHG16 overexpression accelerated proliferation, angiogenesis, and ameliorated mitochondrial respiration in OGD/R-exposed HPMECs. HPMEC-derived exosomal SNHG16 suppressed OGD/R-induced type II AEC injury. SNHG16 ameliorated lung injury in PIR mice. Mechanistically, SNHG16 targeted and negatively regulated miR-372-3p and miR-373-3p expression, and MTCH2, a target gene of miR-372-3p/miR-373-3p. SNHG16 was found to upregulate MTCH2 expression not only in a miR-372-3p and miR-373-3p-dependent manner but also suppress ubiquitination induced MTCH2 degradation. Conclusions: Our findings revealed that SNHG16 overexpression suppressed OGD/R-induced HPMEC apoptosis by promoting Warburg effect, and HPMEC-derived exosomal SNHG16 alleviated PIRI through the miR-372-3p/miR-373-3p/MTCH2 axis, suggesting that SNHG16 as a therapeutic target for PIRI.

Pulmonary inflammatory myofibroblastic tumor (PIMT) is a rare, borderline mesenchymal neoplasm with unclear etiology. It carries recurrence risks but lacks robust data on surgical outcomes in adults. This study analyzes clinicopathological features and long-term results of surgically managed adult PIMT patients at a single center. A retrospective analysis of 14 adults (9 male, 5 female; mean age 47.6± 14.1 years) undergoing surgical resection for pathologically confirmed PIMT (2012-2023) at a single institution. All patients underwent video-assisted thoracoscopic surgery. Immunohistochemistry was systematically analyzed. The median follow-up for all patients was 53 months (range, 24-122 months). Common presenting symptoms included cough (35.7

During ischemia, succinate accumulates and leads to significant damage to the tissues. The specific role of succinate in lung ischemia-reperfusion injury (LIRI) remains unresolved. Differential metabolites in LIRI were identified through untargeted metabolomics using gas chromatography-mass spectrometry (GC-MS). Type II alveolar epithelial cells (AECs) were cultured and subjected to hypoxia/reoxygenation (H/R) in vitro, while an in vivo LIRI model was developed using C57BL/6 mice. Cytokine levels, lung oedema, histopathological alterations and lung functionality were evaluated. Protein levels were analysed through Western blotting. The mitochondrial membrane potential (Δψm) was measured using the JC-1 fluorescent dye, and mitochondrial morphology in Type II AECs following H/R damage was observed with a transmission electron microscope (TEM). Oxidative stress and apoptosis markers were detected in lung tissues and Type II AECs. Succinate was increased in the peripheral serum of LIRI patients and the C57BL/6 mices model. Succinate pre-treatment promotes Type II AEC cell apoptosis and oxidative stress, inhibits mitochondrial membrane potential and damages the alveolar epithelial cells' mitochondrial activity after H/R. Meanwhile, succinate may considerably reduce the amounts of acyl-CoA oxidase 1 (ACOX1) and isocitrate dehydrogenase 2 (IDH2) protein expression. Importantly, N-acetyl-L-cysteine (NAC) was observed to dramatically retard succinate-induced cell apoptosis, mitochondrial dysfunction and ROS levels in alveolar epithelial cells following H/R in vivo, with succinate-neutralising antibodies protecting LIRI in vitro. In conclusion, during ischemia, the build-up of succinate contributes to the advancement of LIRI by enhancing mitochondrial oxidative stress and promoting cell apoptosis, and blocking succinate may be a potential target for LIRI treatment.

Acute lung injury (ALI) is a severe form of sepsis that is associated with a high rate of morbidity and death in critically ill individuals. The emergence of ALI is the result of several factors at work. Case mortality rates might range from 40% to 70%. Researchers have discovered that epigenetic alterations are important in the pathophysiology of ALI and that using epigenetic inhibitors may help reduce symptoms. In embryonic development, circadian rhythm, the cell cycle, and cancer, methylation of m6A seems to be relevant all along the way. According to recent research, posttranscriptional methylation is a key player in the development of alveolar lymphoma. In this study, we clustered ALI based on m6A-related factors, analyzed different classes of immune cell enrichment and inflammatory cytokine expression, screened clustered differential genes for ALI to construct coexpression networks, screened key ALI genes potentially regulated by m6A modifications, and then typed the disease based on key genes to compare the consistency of different clustering results. Our findings have revealed a hitherto undiscovered prognostic sign and a therapeutic target for ALI therapy in m6A and immune invading cells, respectively.

Purpose:Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS.Methods:We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system.Results:In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats.Conclusion:Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.

Infectious diseases are the leading cause of death in both adults and children, with respiratory infections being the leading cause of death. A growing body of evidence suggests that bacterially released extracellular membrane vesicles play an important role in bacterial pathogenicity by targeting and (de)regulating host cells through the delivery of nucleic acids, proteins, lipids, and carbohydrates. Among the many factors contributing to bacterial pathogenicity are the outer membrane vesicles produced by the bacteria themselves. Bacterial membrane vesicles are being studied in more detail because of their potential role as deleterious mediators in bacterial infections. This review provides an overview of the most current information on the emerging role of bacterial membrane vesicles in the pathophysiology of pneumonia and its complications and their adoption as promising targets for future preventive and therapeutic approaches.

Background. Pulmonary ischemia reperfusion- (I/R-) induced dysfunction is a significant clinical problem after lung transplantation. In this study, we aim to explore the molecular mechanism of lung I/R injury (LIRI). Methods. Bioinformatic analysis of gene involved in oxidative stress. A HUVEC oxygen glucose deprivation/reoxygenation (OGD/R) model and I/R mouse model were first established via I/R. The cellular proliferation, migration, reactive oxygen species (ROS), and parameters of lung injury were assessed via CCK-8, EdU staining, Transwell, cellular ROS kit, and H&E staining. We also confirmed related gene expressions and protein levels and the interaction between the tissue factor pathway inhibitor (TFPI) promotor and ZNF354C. Results. Bioinformatic analysis results showed TFPI contributed to oxidative stress. OGD/R caused a reduction in cell viability and migration, hypermethylation of TFPI, increased ROS, and downregulation of ZNF354C, TFPI, and DNA methyltransferases (DNMTs) in HUVECs. Besides, ZNF354C could directly bind to the TFPI promoter, enhance proliferation and migration, and inhibit ROS in OGD/R-induced HUVECs by upregulating TFPI. More importantly, we discovered that 5-Aza could reduce TFPI methylation, upregulate TFPI, and enhance the binding of ZNF354C to the TFPI promoter in LIRI. Furthermore, DNMT1 silencing could induce proliferation and migration and prevent ROS in OGD/R-induced HUVECs by upregulating ZNF354C. Additionally, we verified that ZNF354C could alleviate LIRI by preventing DNA methylation in vivo. Conclusions. ZNF354C overexpression induced proliferation and migration, as well as suppressed ROS in OGD/R-induced HUVECs, and alleviated LIRI in mice by inhibiting TFPI promoter methylation to upregulate TFPI. Therefore, ZNF354C and TFPI methylation might be promising molecular markers for LIRI therapy.

Background Early lung cancer detection remains a clinical challenge for standard diagnostic biopsies due to insufficient tumor morphological evidence. As epigenetic alterations precede morphological changes, expression alterations of certain imprinted genes could serve as actionable diagnostic biomarkers for malignant lung lesions. Results Using the previously established quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) method, elevated aberrant allelic expression of imprinted genes GNAS , GRB10 , SNRPN and HM13 was observed in lung cancers over benign lesions and normal controls, which were pathologically confirmed among histologically stained normal, paracancerous and malignant tissue sections. Based on the differential imprinting signatures, a diagnostic grading model was built on 246 formalin-fixed and paraffin-embedded (FFPE) surgically resected lung tissue specimens, tested against 30 lung cytology and small biopsy specimens, and blindly validated in an independent cohort of 155 patients. The QCIGISH diagnostic model demonstrated 99.1% sensitivity (95% CI 97.5–100.0%) and 92.1% specificity (95% CI 83.5–100.0%) in the blinded validation set. Of particular importance, QCIGISH achieved 97.1% sensitivity (95% CI 91.6–100.0%) for carcinoma in situ to stage IB cancers with 100% sensitivity and 91.7% specificity (95% CI 76.0–100.0%) noted for pulmonary nodules with diameters ≤ 2 cm. Conclusions Our findings demonstrated the diagnostic value of epigenetic imprinting alterations as highly accurate translational biomarkers for a more definitive diagnosis of suspicious lung lesions.

目的 本研究旨在阐明内皮细胞特异性敲除TFPI对内毒素引起小鼠急性肺损伤的影响和可能机制.方法 采用气管内滴注内毒素建立急性肺损伤小鼠模型.与野生型小鼠比较,评价内皮细胞中的TFPI对急性肺损伤内皮细胞屏障功能和炎性反应的作用,评价内皮细胞敲除TFPI后对炎性信号通路NF-κB通路的影响.结果 内皮细胞敲除TFPI可以明显加重内毒素所引起急性肺损伤的肺部病理改变,增加肺泡灌洗液中蛋白含量及伊文思蓝的渗透,促进肺组织及肺泡灌洗液中炎性因子TNF-α、IL-1β和IL-6的分泌.内皮细胞敲除TFPI小鼠与野生型内毒素诱导的急性肺损伤小鼠比较,肺泡灌洗液及肺组织中炎性细胞浸润增加.研究发现内皮细胞TFPI敲除与野生型小鼠相比内毒素诱导后,其炎性信号通路NF-κB激活更加明显.以上研究结果证实内皮细胞TFPI敲除小鼠急性肺损伤后肺组织中的炎性反应和血管渗透性都明显增加.结论 特异性内皮细胞TFPI敲除小鼠,在内毒素诱导的急性肺损伤模型中,通过对NF-κB信号通路的激活来促进肺组织的炎性反应和血管内皮细胞的通透性.

目的 探究凝血因子Xα (FXα)抑制剂利伐沙班对内毒素诱导小鼠急性肺损伤的影响及相关机制.方法 将C57BL/6小鼠随机分为对照组(PBS组)、标准饲料组(N-LPS组)、0.2 mg/g利伐沙班组(L-LPS组)和0.4 mg/g利伐沙班组(H-LPS组).PBS组气管内滴入磷酸盐缓冲液(PBS)作为对照,标准饲料喂养;N-LPS组、L-LPS组和H-LPS组用气管内滴注内毒素方法建立小鼠急性肺损伤模型,造模前分别给予标准饲料或含有0.2 mg/g和0.4 mg/g利伐沙班的饲料喂养10d,测定血药浓度.通过检测肺组织学病理评分、小动物CT、肺水肿、炎症细胞浸润以及支气管肺泡灌洗液中炎症细胞因子激活等评价肺损伤程度.用Western blot及免疫组织化学方法检测髓过氧化物酶、蛋白酶激活受体-2 (PAR-2)和核转录因子-κB (NF-κB)表达情况.结果 应用含有利伐沙班药物饲料喂养的小鼠血浆中利伐沙班血药浓度增加,凝血酶原时间延长.利伐沙班干预可以减轻内毒素诱导小鼠急性肺损伤白细胞浸润和肺组织结构的病理改变(P＜0.05).药物干预组与急性肺损伤组相比,肺泡灌洗液中的肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β)、IL-6、总蛋白和伊文思蓝浓度降低.内毒素诱导的急性肺损伤肺组织中PAR-2和NF-κB蛋白表达增加,利伐沙班干预可以减轻急性肺损伤病理改变,降低PAR-2和促炎细胞因子表达,降低肺损伤伤后肺组织中P65蛋白的磷酸化水平.结论 利伐沙班可通过非凝血途径,经抑制PAR-2-NF-κB信号通路来缓解内毒素诱导急性肺损伤的炎症反应.

LncRNA HAND2-AS1 is characterized as a tumor suppressor involved in several types of malignancies, but its role in non-small cell lung cancer (NSCLC) is unknown. Our study was carried out to investigate the involvement of lncRNA HAND2-AS1 in NSCLC. In our study, we observed that levels of HAND2-AS1 were lower in tumor tissues than that in adjacent healthy tissues. Compared with healthy controls, plasma levels of HAND2-AS1 were lower, while levels of transforming growth factor β (TGF-β) were higher in NSCLC patients. A significant negative correlation between plasma levels of HAND2-AS1 and TGF-β1 was found in NSCLC patients but not in healthy controls. LncRNA HAND2-AS1 overexpression inhibits, while exogenous TGF-β1 treatment promotes cell migration and invasion ability and cancer cell stemness. Cancer cells with lncRNA HAND2-AS1 overexpression showed down-regulated TGF-β1, while TGF-β1 treatment showed no significant effects on lncRNA HAND2-AS1 expression. TGF-β1 attenuated the inhibitory effects of lncRNA HAND2-AS1 overexpression on cell migration, invasion and stemness. We concluded that lncRNA HAND2-AS1 may regulate the migration, invasion and stemness of NSCLC cells through interactions with TGF-β1.

OBJECTIVE To evaluate the effect and mechanism of rivaroxaban, an inhibitor of coagulation factor Xa (FXa), on endotoxin-induced injury to human umbilical vein endothelial cells (HUVEC). METHODS When cultured HUVEC grow to 80% fusion, they were divided into four groups according to the random number method: blank control group (DMEM medium), lipopolysaccharide (LPS) group (cells were challenged by 100 μg/L LPS for 16 hours), FXa+LPS group (cells were challenged by LPS for 16 hours after they were cultured with 100 nmol/L FXa for 24 hours), and FXa +RIV+LPS group (cells were challenged by LPS for 16 hours after they were cultured with 100 nmol/L FXa and 1 μmol/L rivaroxaban for 24 hours). After each group of cells were challenged with LPS, the cell activity was detected by the cell proliferation and toxicity kit (CCK-8); the cell migration ability was detected by cell scratch experiments; the abilities of cells migration were measured by scratch-wound-healing assay; the apoptosis of cells were evaluated using flow cytometry; the endothelial barrier of cells was assessed by Transwell and Evans blue; the levels of tumor necrosis factor-α (TNF-α), interleukin (IL-1β, IL-6) were detected by the enzyme linked immunosorbent assay (ELISA); the expressions of nuclear factor-ΚB (NF-ΚB) and mitogen activated protein kinase (MAPK) signaling pathway were detected by Western Blot. RESULTS Compared with blank control group, the cell viability in LPS group was significantly decreased, and the migration ability, number of apoptotic cells, and barrier permeability of endothelial cells was significantly increased, the levels of TNF-α, IL-1β and IL-6 were significantly increased, and the expressions of phosphorylation of c-Jun N-terminal kinase (p-JNK), phosphorylation of p38MAPK (p-p38MAPK), phosphorylation of transforming growth factor kinase 1 (p-TAK1) and phosphorylation of NF-ΚBp65 (p-NF-ΚBp65) were significantly increased. It indicated that LPS could stimulate the inflammatory response of vascular endothelial cells, and had a significant impact on cell activity, apoptosis and function. There was no significant difference in above indexes between FXa+LPS group and LPS group, except for the level of IL-6 being higher in FXa+LPS group. Compared with FXa+LPS group, in FXa+RIV+LPS group, the cell activity was significantly increased (A value: 0.42±0.02 vs. 0.33±0.02), and migration ability was significantly decreased (folds: 1.78±0.17 vs. 2.24±0.20), the number of apoptotic cells was significantly decreased [(11.30±0.70)% vs. (21.03±0.19)%], and permeability of monolayers endothelial cells was significantly decreased [(149±12)% vs. (253±15)%], the levels of inflammatory cytokines were significantly decreased [IL-1β (ng/L): 163.2±20.7 vs. 477.8±20.2, IL-6 (ng/L): 69.3±0.5 vs. 238.0±24.1, TNF-α (ng/L): 117.0±13.1 vs. 196.2±4.5], the expressions of p-TAK1 and p-NF-ΚBp65 were significantly decreased (p-TAK1/TAK1: 0.74±0.09 vs. 1.85±0.15, p-NF-ΚBp65/NF-ΚBp65: 1.15±0.17 vs. 2.36±0.20), with statistically significant differences (all P < 0.05). There was no significant difference in the p-JNK, p-p38MAPK expressions between FXa+RIV+LPS group and FXa+LPS group (p-JNK/JNK: 1.64±0.12 vs. 1.65±0.15, p-p38MAPK/p38MAPK: 2.31±0.32 vs. 2.35±0.20, both P > 0.05). CONCLUSIONS Rivaroxaban can effectively relieve the inflammatory response of HUVEC stimulated by LPS, which may be related to the inhibition of NF-ΚB signaling pathway activation rather than MAPK signaling pathway.

OBJECTIVES The aim of this study was to explore the predictors of the improvement in moderate ischaemic mitral regurgitation (IMR) after off-pump coronary artery bypass grafting (OPCAB) focusing on left ventricular (LV) dyssynchrony. METHODS A prospective study was performed among 135 patients (age at surgery, mean ± SD: 67.0 ± 8.2 years, 33.3% women) with prior myocardial infarction and moderate IMR undergoing OPCAB from 2008 to 2015. Preoperative and follow-up clinical and echocardiographic parameters were analysed, focusing on LV global/regional dyssynchrony. Patients were grouped by IMR at 1 year postoperatively: improved group with no or mild IMR (n = 61) and failure group with moderate or severe IMR (n = 67). Data were compared between groups to explore the predictors of IMR improvement after OPCAB. RESULTS Seven patients who died before the 1-year postoperative assessment were excluded. At the 1-year follow up, there were 61 patients in the improved group and 67 patients in the failure group. Preoperatively, the improved group had smaller LV global dyssynchrony, LV regional dyssynchrony (papillary muscle systolic dyssynchrony; improved group versus failure group: 48.5 ± 4.5 ms vs 57.1 ± 3.9 ms; P < 0.001) and greater LV ejection fraction (improved group versus failure group: 44.7 ± 5.0% vs 36.7 ± 6.7%; P < 0.001) than the failure group. Papillary muscle systolic dyssynchrony (odds ratio 1.556, 95% confidence interval 1.313-1.845; P < 0.001) and preoperative ejection fraction (odds ratio 0.799, 95% confidence interval 0.691-0.924; P = 0.002) were independent predictors of moderate IMR improvement after OPCAB. CONCLUSIONS In the selected patients, preoperative moderate IMR could be relieved by coronary artery bypass grafting. Greater ejection fraction and absence of LV regional dyssynchrony may predict the improvement in moderate IMR after coronary artery bypass grafting, suggesting that LV dyssynchrony especially regional dyssynchrony and preserved ventricular function would be important to the outcome of patients with moderate IMR.

OBJECTIVES The aim of this study was to explore the predictors of the improvement in moderate ischaemic mitral regurgitation (IMR) after off-pump coronary artery bypass grafting (OPCAB) focusing on left ventricular (LV) dyssynchrony. METHODS A prospective study was performed among 135 patients (age at surgery, mean ± SD: 67.0 ± 8.2 years, 33.3% women) with prior myocardial infarction and moderate IMR undergoing OPCAB from 2008 to 2015. Preoperative and follow-up clinical and echocardiographic parameters were analysed, focusing on LV global/regional dyssynchrony. Patients were grouped by IMR at 1 year postoperatively: improved group with no or mild IMR (n = 61) and failure group with moderate or severe IMR (n = 67). Data were compared between groups to explore the predictors of IMR improvement after OPCAB. RESULTS Seven patients who died before the 1-year postoperative assessment were excluded. At the 1-year follow up, there were 61 patients in the improved group and 67 patients in the failure group. Preoperatively, the improved group had smaller LV global dyssynchrony, LV regional dyssynchrony (papillary muscle systolic dyssynchrony; improved group versus failure group: 48.5 ± 4.5 ms vs 57.1 ± 3.9 ms; P < 0.001) and greater LV ejection fraction (improved group versus failure group: 44.7 ± 5.0% vs 36.7 ± 6.7%; P < 0.001) than the failure group. Papillary muscle systolic dyssynchrony (odds ratio 1.556, 95% confidence interval 1.313-1.845; P < 0.001) and preoperative ejection fraction (odds ratio 0.799, 95% confidence interval 0.691-0.924; P = 0.002) were independent predictors of moderate IMR improvement after OPCAB. CONCLUSIONS In the selected patients, preoperative moderate IMR could be relieved by coronary artery bypass grafting. Greater ejection fraction and absence of LV regional dyssynchrony may predict the improvement in moderate IMR after coronary artery bypass grafting, suggesting that LV dyssynchrony especially regional dyssynchrony and preserved ventricular function would be important to the outcome of patients with moderate IMR.

The role of coagulation in acute lung injury (ALI) remains unclear. As factor Xa-dependent protease-activated receptor 2 (PAR-2) is reported to be an important target in blood coagulation and other processes, an inhibitor of factor Xa, rivaroxaban, was tested in vivo in C57BL/6 mice with ALI induced by intratracheal injections of lipopolysaccharide (LPS) and in vitro in LPS-stimulated human umbilical vein endothelial cells. Plasma concentrations and coagulation indices were measured in mice fed normal chow or chow containing rivaroxaban (0.2 or 0.4 mg/g) for 10 days. The rivaroxaban-treated mice had significantly reduced neutrophil sequestration with preservation of the lung tissue architecture compared with that in the untreated controls. The levels of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6, as well as total protein and Evans blue concentrations, were all significantly reduced in bronchoalveolar lavage fluid from mice treated with rivaroxaban. Rivaroxaban treatment also ameliorated the LPS-induced PAR-2 increase and nuclear factor kappa B (NF-κB) activation. In vitro, cells treated with rivaroxaban had higher cell viability with an attenuation of LPS-induced increases in membrane permeability and proinflammatory cytokine levels, as well as reduced apoptosis. Furthermore, rivaroxaban inhibited the phosphorylation of TAK1 and p65. These data show that rivaroxaban attenuates ALI and inflammation by inhibiting the PAR-2/NF-κB signaling pathway.

Objective: Focusing on 3-dimensional mitral valve structure, this study investigated predictors for moderate ischemic mitral regurgitation (IMR) improvement after off-pump coronary artery bypass grafting (OPCAB). Methods: This study included 143 patients (age 67.6 +/- 7.6 years, 32.9% female) with previous myocardial infarction and moderate IMR undergoing OPCAB. Preoperative 3-dimensional echocardiographic data were analyzed, focusing on mitral annular geometry and leaflet tethering model. Patients were grouped according to IMR at 1-year postoperative follow-up into improved (n = 65), with no or mild IMR, and failure (n = 70), with moderate or severe IMR, groups. Groups were compared to identify predictors of IMR improvement after OPCAB. Results: Eight patients died within 1 year. At 1 postoperative year, improved group included 65 patients; failure group included 70. Improved group had less preoperative annular flattening (smaller nonplanar angle) and segmental leaflet tethering (smaller A3, P1, P2, and P3 tethering angles) than failure group. Nonplanar angle (P<.001) and P3 tethering angle (P<.001) were independent predictors of moderate IMR improvement after OPCAB. Receiver operator characteristic curves defined P3 tethering angle of 28.8 degrees (sensitivity of 78.6%, specificity of 84.6%) and nonplanar angle of 158.1 degrees (sensitivity, 64.3% and specificity of 86.2%) as the cutoff values. Conclusions: Preoperative moderate IMR can be improved by OPCAB in selected patients. Less annular flattening and P3 leaflet tethering may predict improvement of moderate IMR after OPCAB, suggesting that the annular nonplanar saddle shape and less leaflet tethering toward P3 segment are important for the prognosis of moderate IMR.

As activation of the coagulation system is both a consequence and contributor to acute lung injury (ALI), pulmonary coagulopathy has become a potential target for therapeutic intervention in ALI patients. We investigated the effects and possible mechanisms of endothelial cell (EC)-anchored tissue factor pathway inhibitor (TFPI) on lipopolysaccharide (LPS)-induced ALI in mice. To assess the effect of EC-anchored TFPI deletion on ALI indices, TFPI knockout (cKO) mice were generated. Mice were instilled by direct intratracheal injection LPS for the preparation of an ALI model. Evans blue dye (EBD) was injected intravenously 2 h prior to animal sacrifice (48 h post-LPS). Lungs were fixed for histopathology and the prepared tissue was homogenized or used to extract bronchoalveolar lavage fluid (BALF) or detect EBD concentration. TFPI knockdown mice with ALI were compared to wild-type (WT) mice with ALI to assess the effect of TFPI on endothelial barrier function and inflammation. TFPI deletion markedly exacerbated LPS histopathological changes in lung, and the LPS changes in protein, EBD extravasation, proinflammatory cytokines TNF-alpha, IL-1 beta, and IL-6 in BALF in lung. The number and infiltration of white blood cells (WBCs) from BALF and lung tissue of TFPI cKO mice with LPS-challenged ALI was increased compared to WT mice with LPS-challenged ALI. We also found further increased toll-like receptor 4 and nuclear factor kappa-light-chain-enhancer of activated B cells activation and additional expression of vascular cell adhesion molecule 1 and reduction of angiotensin converting enzyme 2 expression in TFPI cKOthornLPS mice compared with WTthornLPS mice. Endothelial-specific TFPI deficiency promoted LPS-induced pulmonary inflammation and endothelial barrier permeability possibly via toll-like receptor 4-mediated nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway activation.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Mesenchymal stem cells (MSCs) have been shown to improve ALI, and the imbalance of regulatory T cells (Tregs) and Th17 cells is associated with mortality in ALI/ARDS patients. However, whether administration of lung-resident MSC (LRMSC) improves lung injury and regulates the balance of Tregs and Th17 cells remains unknown. An ALI animal model was induced by LPS, and PBS or LRMSC were administered via tail vein after 4 h. LRMSC were subsequently detected in the lungs by a live imaging system (Berthold LB983, Germany). Lung morphology; lung wet-to-dry weight ratio; and total protein concentration, inflammatory cells, and cytokines in bronchoalveolar lavage fluid (BALF) and plasma were determined. The percentage of Tregs in lung and spleen, and of Th17 cells in lung and blood, were also evaluated. The results showed that LRMSC not only attenuated histopathological damage but also mediated the downregulation of lung wet-to-dry weight ratio and the reduction of total protein concentration and inflammatory cells in BALF. LRMSC also decreased inflammatory cytokines in both BALF and plasma and increased KGF-2 and surfactant protein C (SPC) expression in the lung. Flow cytometry revealed the upregulation of Tregs and the downregulation of Th17 cells, and the increase in the ratio of Tregs and Th17 cells. The live imaging system showed that LRMSC migrated to and were retained in the injured area. In conclusion, the results indicated that administration of LRMSC attenuates LPS-induced ALI via upregulating the balance of Tregs and Th17 cells.

Cardiac transplantation has been limited by the inability to long preserve donor hearts safely. Hydrogen sulfide (H2S) has been recognized as an important gasotransmitter exerting potent cardioprotection from ischemia/reperfusion injury (I/R). Herein we investigated the cardioprotective effects of a novel long-term and slow releasing H2S system, namely DATS-MSN, in heart preservation solution using a heart transplantation models. The release of H2S from DATS-MSN was slow and continuous in the University of Wisconsin solution (UW), correspondingly, DATS-MSN application demonstrated superior cardioprotective effects over the control and traditional H2S donors after 6 h heart preservation and 1 h reperfusion, associated with greater allograft performance including left ventricular developed pressure (LVDP) and dP/dt (max), reduced plasmic CK-MB and troponin I levels, inhibited myocardial inflammation, increased antioxidant enzyme activities, preserved mitochondria structure and function, and decreased cardiomyocyte apoptosis index. Also, DATS-MSN application presented significant superiority in long-term allografts survival and function after 8 weeks of transplantation. In the in vitro experiments, cardiomyocytes injury from hypoxia was found to be relived with the treatment of DATS-MSN by anti-inflammatory effects via TLR4/NLRP3 pathway. The present work provides a long-term releasing H2S donor compatibly applied in the donor heart preservation, and preliminary explores its underlying mechanisms.

BACKGROUND:Embryonic stem cells (ESCs) are pluripotent stem cells and can differentiate into cardiomyocytes when cultured in appropriate conditions. The function of hypoxia-inducible factors (HIFs) has been identified in directing the formation of cardiac lineages. The purpose of this study was to investigate the ability of HIF2α to induce differentiation of ESCs into cardiomyocytes and to explore the potential underlying molecular mechanisms.METHODS:Cardiac differentiation from mouse ESCs was analyzed using the "hanging drop" method, and success was determined by assaying the numbers of beating embryoid bodies and the expression level of cardiac markers. The expression of HIF2α was then manipulated during cardiac differentiation with piggyBac transposon and the lentivirus system. The underlying mechanism was finally examined via administering selective inhibitors of the Wnt/β-catenin signaling pathway.RESULTS:Overexpressing HIF2α can significantly drive mouse ESCs to form cardiomyocytes. Contrarily, knockdown of HIF2α inhibits the emergence of cardiac cells. In addition, the cardiomyogenesis-promoting effect of HIF2α occurred by increasing the protein level of β-catenin, an effector that contributes to cardiac differentiation at an early stage of ESC differentiation.CONCLUSION:HIF2α has a cardiomyogenesis-promoting effect in ESCs via enhancing the activation of the Wnt/β-catenin signaling pathway. Our results may be beneficial for generating and applying cardiomyocytes from ESCs safely and effectively in the future.