Abstract Background: Pyroptosis was implicated in acute lung injury (ALI). Disulfiram is reported as an effective pyroptosis inhibitor by inhibiting gasdermin D(GSDMD). However, the function of pyroptosis executor GSDMD and treatment of disulfiramon on ALI, especially whether it was involved in ALI-associated intestinal mucosal barrier impairment remains unclear. This study aims to explore the role of pyroptosis and disulfiram’ treatment on ALI and related intestinal mucosal barrier impairment. Methods: First, we established lipopolysaccharide (LPS)-induced ALI models in wild-type and Gsdmd knockout ( Gsdmd −/− ), to detect the effect of pyroptosis on ALI-related intestinal mucosal barrier impairment. Furthermore, we used wild-type mice treated with disulfiram to investigate the treatment of disulfiram on ALI and related intestinal mucosal barrier impairment. Results: The data showed that GSDMD-mediated pyroptosis was activated in both lung and intestinal mucosa tissues in LPS-induced ALI, and deficiency of Gsdmd ameliorated LPS-induced ALI and related intestinal mucosal barrier damage. We also disclosed that disulfiram inhibited the pyroptosis level, and alleviated ALI and related intestinal mucosal barrier impairment induced by LPS. Conclusions: These findings suggested the role of GSDMD-mediated pyroptosis and the potential application treatment of disulfiram in ALI and related intestinal mucosal barrier damage.
This study aimed to identify the role and regulation of thymic stromal lymphopoietin (TSLP) in asthmatic airway remodelling. To identify the expression of TSLP, α smooth muscle actin (α-SMA) and collagen I in bronchial tissues, bronchial biopsy specimens were collected from patients with asthma and healthy controls and stained with specific antibodies, respectively. To characterize the signalling pathways regulated by TSLP, we silenced or overexpressed TSLP in human lung fibroblast (HLF-1) cells by shRNA approaches or transfection and detected the expression of TSLP receptor (TSLPR) by enzyme-linked immunosorbent assay and Western blot analysis. In TSLP signalling pathway, the protein expression of total signal transducer and activator of transcription 3 (STAT3), STAT5, the phosphorylation of STAT3 (pSTAT3) and STAT5 (pSTAT5), TSLP, α-SMA and collagen I were also detected by Western blotting. In addition, the α-SMA, collagen I and mRNA expression were determined by real-time reverse-transcription. To further confirm the TSLP-STAT3 signalling pathway in HLF-1 cells, we inhibited STAT3 activity by targeted small molecules and then detected TSLP-induced expression of α-SMA and collagen I in both mRNA and protein levels by quantitative real-time reverse-transcription and Western blotting, respectively. First, overexpression of TSLP, α-SMA and collagen I was detected in epithelium collected from patients with asthma. Second, STAT3 activity and the expression of α-SMA and collagen I were controlled, regulated by TSLP. Specifically, the pSTAT3, α-SMA and collagen I were induced by the introduction of TSLP in HLF-1 cells, and the repression of α-SMA and collagen I was detected after TSLP silencing. Third, no changes of pSTAT5 were found in the presence of the STAT3 inhibitor, and TSLP-induced α-SMA and collagen I upregulation is in a STAT3 dependent manner. If we inhibit STAT3 activity by STAT3 targeted small molecules, TSLP-induced α-SMA and collagen I upregulation cannot be detected. The functions of TSLP in asthmatic airway remodelling were performed through STAT3 signalling pathway.
Purpose: Infected nonunion after open reduction internal fixation (ORIF) is a serious complication. The aim of this study was to evaluate the usefulness of serum D-dimer for preoperative diagnosis of infected nonunion. Patients and methods: Patients undergoing debridement and external fixation for infected nonunion (n=32) and replacement of internal fixation due to aseptic failure (n=34) were enrolled and compared in this retrospective study. The optimum cutoff value of D-dimer for identification of infected nonunion was determined by calculating the Youden J statistic. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of four preoperative laboratory parameters—serum D-dimer level, white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)—for diagnosis of infected nonunion were compared. Results: Serum D-dimer level was significantly higher in patients with infected nonunion than in patients with aseptic nonunion: 2.62 mg/mL (range, 0.13–11.90 mg/mL) vs 0.35 mg/mL (range, 0.07–6.46 mg/mL; p <0.001). WBC count, CRP, and ESR demonstrated sensitivity of 12.5% (95% CI: 4.08–29.93), 40.6% (95% CI: 24.22–59.21), and 56.3% (95% CI: 37.88–73.16), respectively, and specificity of 94.1% (95% CI: 78.94–98.97), 88.2% (95% CI: 71.61–96.16), and 85.3% (95% CI: 68.17–94.46), respectively. Using the Youden index, 1.70 mg/mL was determined as the optimal threshold value for serum D-dimer for the diagnosis of infected nonunion. The sensitivity and specificity of serum D-dimer (>1.70 mg/mL) were 75.0% (95% CI: 56.25–87.87) and 91.2% (95% CI: 75.19–97.69). Conclusions: Serum D-dimer level may be useful for preoperative prediction of infected nonunion in patients after ORIF. Keywords: fracture-related infection, laboratory test, preoperative prediction, nonunion
Aim of this study: Airway remodeling, which encompasses structural changes in airway is a main feature of asthma. Interleukin-33 (IL-33) has been reported to be a vital cytokine in airway remodeling in asthma, but the underlying mechanisms are not clear yet. This study focused on discussing the role of IL-33 in airway remodeling in asthma. Material and methods: Female BALB/c mice were divided into a control group, an OVA induced allergic airway disease group and an anti-ST2 antibody intervention group. Immunohistochemistry and western blot were performed to detect IL-33, ST2 expression in addition to airway remodeling markers a-smooth muscle actin (a-SMA) and type 1 collagen in OVA-induced mice model. Levels of p-JNK and p-STAT3 activation in mice were detected by western blot. Human lung fibroblast (HLF) were stimulated with rhIL-33, anti-ST2 antibody and JNK inhibitor sp600125 and levels of JNK and STAT3 activation were determined via western blot and immunofluorescence staining. Results: Anti-ST2 treatment inhibited JNK/STAT3 phosphorylation and airway remodeling in OVA-induced mouse model. IL-33 induced a-SMA and collagen 1 expression was inhibited by anti-ST2 antibody and sp600125 treatment via decreased JNK/STAT3 phosphorylation in human lung fibroblast. Conclusions: IL-33 promoted airway remodeling by interacting with ST2 to activate the JNK/STAT3 signaling pathway in asthma.
Abstract Background Cigarette smoke (CS) is a major risk factor for COPD. Follistatin-like protein 1(FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulaton, airway inflammation and remodeling. Methods Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1 +/- mice and FSTL1 flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA) ,an inhibitor of autophagy, were applied in CS exposed WT mice. The lung tissue and serum from patients and murine models were tested for FSTL1 and autophagy associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed by Electron Microscope Technology(EMT). LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined by ELISA. Airway remodeling and lung function were also assessed. Results Both FSTL1 and autophagy biomarkers increased in COPD patients and CS exposed WT mice. Autophagy activation was upregulated in CS exposed mice accompanied by airway remodeling and airway inflammation. FSTL1 +/- mice showed a lower level of CS-induced autophagy compared with control mice. FSTL1 +/- mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS exposed WT mice with 3-MA pretreatment have a similar manifestation with CS exposed FSTL1 +/- mice. Conclusions FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke induced COPD.
The invasive techniques can be direct and objective to assess small airway function, but they have significant risks and inconveniences for patients and cannot be repeated often. Some sophisticated techniques such as fractional exhaled nitric oxide (FeNO) and impulse oscillometry (IOS) may surmount such restrictions. Therefore, we investigated the relation among FeNO, IOS, and small airway function in asthmatic patients.We recruited 140 asthmatic patients including 69 patients with small airway normal function and 71 patients with small airway dysfunction. FeNO, eosinophil（EOS）count and total immunoglobulin E (IgE) in peripheral blood, pulmonary function, as well as IOS were measured.The levels of FeNO, the reactance area (AX), the resonant frequency Fres and EOS were significantly increased in small airway dysfunction group compared with small airway normal function group (P < 0.01 respectively). A multiple regression model showed that FeNO, AX and Fres were correlative factors of mid forced expiratory flow of percentages of predicted values [FEF25-75 (%pred)] (P < 0.01, respectively). A receiver operating characteristic (ROC) analysis showed that the combination of FeNO, AX and Fres had a greater area under the ROC curve (AUC) than each of them (AUC: 0.881, P < .001, 95％CI: 0.815-0.929).FeNO and IOS are helpful in diagnosis of small airway dysfunction with high sensitivity and specificity, and FeNO combined with IOS can better evaluate the small airway function in asthmatic patients.
Cyclosprin A (CsA) has been widely used clinically to treat the patients who have undergone organ transplantation or acquired autoimmune disease. The purpose of this study is to determine the effects of three different doses of CsA (1.5, 7.5, 15 mg/kg body weight) on the skeletal biomechanical proprieties at different anatomic sites in rats.Fifty-six male 3-month-old Wistar rats were divided into five groups. Eight rats were randomly chosen as the basal group, while the others were randomly distributed into four groups of 12 animals each. One group was used as controls and received daily subcutaneous injection of 1 ml of saline solution; another three experimental groups were injected subcutaneously with CsA in a daily dose of 1.5, 7.5, and 15 mg/kg body weight respectively for 60 days. The bone biomechanical proprieties, the bone mineral density, as well as the trabecular bone architecture were measured at different anatomic sites, i.e. the lumbar vertebra, the middle femur shaft, and the proximal femur.CsA therapy at 7.5 and 1.5 mg/kg can significantly reduce the ultimate force, the ultimate stress and the energy absorption per unit of bone volume of the lumbar vertebra, with no effect on the middle femur. CsA therapy at 7.5 mg/kg can significantly reduce the ultimate force, the ultimate stress and the Young's modulus of the femoral neck, but not CsA at 1.5 mg/kg. Furthermore, CsA therapy at 7.5 and 1.5 mg/kg can significantly reduce the bone mineral density of the lumber vertebra and the proximal femur, but have no effect on the middle femur. CsA therapy at 7.5 and 1.5 mg/kg can also significantly reduce the bone volume fraction of the proximal tibia and the lumber vertebra, but has no effect on the cortical thickness of the middle femoral shaft. In the 15 mg/kg CsA group only one rat survived, and the kidney and liver histology of the survived rat showed extensive tissue necrosis.Long-term use of CsA can weaken the biomechanical properties and thus increase the fracture rate of the lumbar vertebra and the proximal femur. However, CsA therapy has less effect on the middle femur shaft. The effects of CsA on skeleton are site-specific.
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