Airway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma.To examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo.Cellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated β-galactosidase (SA-β-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3-targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma.Activation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance.TSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling.
Thymic stromal lymphopoietin (TSLP) acts as a critical cytokine involved in asthmatic airway remodeling. Our study aimed to characterize the crosstalk between airway epithelial cells and fibroblasts regulated by TSLP through the signaling pathways of Mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3).Human biopsy specimens and lung tissues from mice were stained with hematoxylin and eosin (H&E) and immunohistochemistry. Human lung fibroblasts were stimulated with human recombinant TSLP. The protein expression of phosphorylation of STAT3 (p-STAT3) and phosphorylation of MAPK as well as the expression of collagen I and alpha-smooth muscle actin (α-SMA) were detected by Western blotting and immunofluorescence. Co-culture was performed to detect the influence of TSLP secreted by airway epithelial cells on fibroblasts. An ovalbumin (OVA)-induced asthmatic murine model was established with or without intraperitoneal injection of SB203580 (inhibitor of p-38). Protein expression in lung tissue was detected by immunohistochemistry and western blotting.TSLP could activate MAPK in HLF-1. SB203580 could inhibit the activation of p38, attenuate phosphorylation of STAT3, and decrease the expression of collagen I and α-SMA consequently in human fibroblasts. Co-culture demonstrated that TSLP secreted by epithelial cells could promote the expression of collagen I and α-SMA and aggravates airway remodeling in fibroblasts. In vivo, expression of TSLP, collagen I, α-SMA, p-p38 and p-STAT3 was upregulated in airway tissue of OVA-challenged mice and downregulated in mice which were treated by SB203580. The tissue staining showed that airway structure change was attenuated by SB203580 compared with OVA challenged mice as well.TSLP might promote asthmatic airway remodeling via p38 MAPK-STAT3 axis activation and the crosstalk between airway epithelial cells and fibroblasts could aggravate remodeling. Blockade of p38 could alleviate airway remodeling which might provide a new therapeutic target for asthma.
The current limited approaches to calculating hillslope erosion rate hamper the study of the relationships among the rates of hillslope erosion, river incision, and tectonic uplift and hence the discussion of steady-state landscape evolution. In this paper, we use remote sensing and geochronological methods to calculate the upper and lower bounding hillslope erosion rates in the Qilian Shan range, Tibet. Our analysis focuses on five convex landslide sediment units derived from the weathered hillslopes at Qingyang Mountain on the tectonically active northeastern Tibetan Plateau. These sediment units range in thickness from 5.5 to 12.8 m and in volume from 119 × 103 to 260 × 103 m3. Based on field observations, measurements extracted from high-resolution DEMs, and optical stimulated luminescence (OSL) ages on fluvial terraces, we obtain lower and upper bounding rates of 0.13 ± 0.03 and 0.21 ± 0.04 mm/yr, respectively. Finally, we calculate incision rates, ranging from 0.21 ± 0.02 to 0.39 ± 0.01 mm/yr, from heights of a dated fluvial terrace above the present river and the time of abandonment of the associated bedrock strath estimated from OSL ages. The rates of hillslope erosion and river incision at Qingyang Mountain and the tectonic uplift of the Qilian Mountains are estimated to be within a factor of two over the past 117 ka, suggesting that a state of dynamic equilibrium has likely existed on this timescale.
Abstract Neovascularization, increased basal membrane thickness and increased airway smooth muscle ( ASM ) bulk are hallmarks of airway remodelling in asthma. In this study, we examined connective tissue growth factor ( CTGF ) dysregulation in human lung tissue and animal models of allergic airway disease. Immunohistochemistry revealed that ASM cells from patients with severe asthma (A) exhibited high expression of CTGF , compared to mild and non‐asthmatic ( NA ) tissues. This finding was replicated in a sheep model of allergic airways disease. In vitro, transforming growth factor ( TGF )‐β increased CTGF expression both in NA ‐ and A‐ ASM cells but the expression was higher in A‐ ASM at both the mRNA and protein level as assessed by PCR and Western blot. Transfection of CTGF promoter‐luciferase reporter constructs into NA ‐ and A‐ ASM cells indicated that no region of the CTGF promoter (−1500 to +200 bp) displayed enhanced activity in the presence of TGF ‐β. However, in silico analysis of the CTGF promoter suggested that distant transcription factor binding sites may influence CTGF promoter activation by TGF ‐β in ASM cells. The discord between promoter activity and mRNA expression was also explained, in part, by differential post‐transcriptional regulation in A‐ ASM cells due to enhanced mRNA stability for CTGF . In patients, higher CTGF gene expression in bronchial biopsies was correlated with increased basement membrane thickness indicating that the enhanced CTGF expression in A‐ ASM may contribute to airway remodelling in asthma.
The aim of this study was to evaluate the effects of quorum sensing (QS) systems in Pseudomonas aeruginosa ( P. aeruginosa ) on the expression of ampC gene induced by antibiotics. An in vitro dynamic model of P. aeruginosa biofilms was established in a silicon tube in once‐flowthrough system at 37 °C. Biofilm generation was identified by argentation. Biofilm morphology of standard P. aeruginosa strain (PAO‐1) and QS systems deficient strains (PDO100, rhlI deficient strain; PAO‐JP1, lasI deficient strain; and PAO‐MW1, rhlI and lasI deficient strain) were observed by optical microscope. The expression of ampC in PAO1, PAO1 with QS inhibitor (furanone C‐30) and the QS deficient strains before and after induced by antibiotics were quantified by real‐time quantitative PCR. The biofilms of PAO‐1 and PDO100 were much thicker and denser than that of PAO‐JP1 and PAO‐MW1. Being induced by antibiotics, the expression of ampC in PAO1 and PDO100 was significantly higher than that in PAO‐MW1 and PAO‐JP1. With the effect of furanone C‐30, the expression of ampC in PAO1 induced by antibiotics was reduced in a dose‐dependent manner. QS system, especially the las system, plays an important role in both biofilm formation and antimicrobials induced ampC expression and furanone C‐30 is a potent inhibitor for P. aeruginosa QS system.
Objective Treatment of distal femoral fracture in post‐polio patients is difficult because the bone is usually osteopenic, small and deformed. This retrospective study aimed to investigate the outcomes of distal femoral fracture in post‐polio patients treated by locking compression plates ( LCP ). Methods The medical records of 19 post‐polio patients (mean age 49 years at time of surgery) were reviewed and intraoperative data retrieved. Fracture union and callus formation were evaluated on radiographs taken at each postoperative visit. Functional outcome assessments included range of motion and H ospital for S pecial S urgery ( HSS ) score of the ipsilateral knee joint. Results Sixteen femoral fractures occurred in the poliomyelitis‐affected limbs. The mean duration of operation was 86 min and mean blood loss 120 mL. All fractures healed (mean, four months) but union was delayed in one. At the final follow‐up 2 yrs after surgery, the mean range of knee flexion was 105° (range, 90°–130°), and mean HSS score 76 points (range, 60–93). There were no cases of nonunion, implant cutout, or other complications. Conclusions LCP provides stable fixation of distal femoral fractures in post‐polio patients. Bony union and good functional outcomes are achieved, but delayed union and minimal callus may occur.
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