Combination of TWEAK and TGF-ß1 induces the production of TSLP, RANTES, and TARC in BEAS-2B human bronchial epithelial cells during epithelial-mesenchymal transition.

AIM OF THE STUDY: In patients with asthma, chronic inflammatory processes and the subsequent remodeling of the airways contribute to the symptoms and the pathophysiological changes. Epithelial-mesenchymal transition (EMT) is thought to play an important role in tissue remodeling. Previous reports show that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a cytokine of the TNF superfamily, exerts pro-inflammatory effects, and enhances transforming growth factor (TGF)-ß-induced EMT in bronchial epithelial cells. In this study, we investigated the TWEAK-induced cytokine and chemokine production in the human bronchial epithelial cell line BEAS-2B during EMT. MATERIALS AND METHODS: Quantitative real-time RT-PCR, enzyme-linked immunosorbent assays, western blotting, and immunohistochemistry were used to define the production of cytokines and chemokines. RESULTS: We found that TWEAK increases mRNA and protein levels of thymic stromal lymphopoietin (TSLP), monocyte chemoattractant protein -1 (MCP-1), regulated upon activation normal T cell express sequence (RANTES), and IL-8 in BEAS-2B bronchial epithelial cells. Moreover, co-treatment with TWEAK and TGF-ß1 induces not only features of EMT but also enhances the production of TSLP and RANTES. Thymus- and activation-regulated chemokines (TARC) production is induced by the co-treatment of TWEAK and TGF-ß1 but not by TWEAK or TGF-ß1 stimulation alone. Furthermore, the increased mRNA expression of TSLP and RANTES after co-treatment with TWEAK and TGF-ß1 is prevented by inhibitors of Smad-independent signaling pathways. CONCLUSIONS: In the present study, we have revealed a novel mechanism for the production of asthma-related cytokines and chemokines in EMT driven by the co-stimulation with TWEAK and TGF-ß1. We conclude that cellular EMT processes caused by TWEAK and TGF-ß1 may contribute to chronic airway inflammation and remodeling.

Evaluation of switching low-dose inhaled corticosteroid to pranlukast for step-down therapy in well-controlled patients with mild persistent asthma.

OBJECTIVE: Treatment guidelines for asthma recommend step-down therapy for well-controlled asthma patients. However, the precise strategy for step-down therapy has not been well defined. We investigated whether well-controlled patients with mild persistent asthma can tolerate a step-down therapy of either a reduced dose of inhaled corticosteroid (ICS) or a switch to a leukotriene receptor antagonist (LTRA), pranlukast hydrate. METHODS: We recruited 40 adult patients with mild persistent asthma who were well-controlled for at least 3 months with a low-dose ICS therapy. The patients were randomly assigned to either an ICS dose reduction or a switch to pranlukast for 6 months. RESULTS: FeNO levels in the pranlukast group were significantly increased over that in the ICS group. There were no significant differences between the two groups for lung function, FOT, at the endpoint. The percentage of patients with controlled asthma was 72.2% in the pranlukast group and 90% in the ICS group. No statistically significant difference between the two groups in the percentages of patients with treatment failure was observed. CONCLUSIONS: Patients with mild persistent asthma that is well-controlled by a low dose of ICS can be switched to pranlukast safely for at least 6 months. However, 27.8% of the pranlukast group failed to maintain well-control, and FeNO levels increased with the switch to pranlukast at 6 months. This study was been limited by the small sample size and should therefore be considered preliminary. Further studies are needed to investigate the therapeutic efficacy of LTRA monotherapy as a step-down therapy.

TWEAK enhances TGF-ß-induced epithelial-mesenchymal transition in human bronchial epithelial cells.

BACKGROUND: Chronic airway inflammatory disorders, such as asthma, are characterized by airway inflammation and remodeling. Chronic inflammation and damage to the airway epithelium cause airway remodeling, which is associated with improper epithelial repair, and is characterized by elevated expression of transforming growth factor-ß (TGF-ß). Epithelial-mesenchymal transition (EMT) is an important mechanism during embryonic development and tissue remodeling whereby epithelial cells gain the capacity to increase motility by down-regulation of epithelial markers and up-regulation of mesenchymal markers. TGF-ß is a central inducer of EMT, and TGF-ß-induced EMT is enhanced by pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß. We investigated whether the pro-inflammatory cytokine TWEAK (TNF-like weak inducer of apoptosis) enhanced TGF-ß1-induced EMT in the human bronchial epithelial cell line BEAS-2B. METHODS: Quantitative RT-PCR and western blotting were used to define alterations in epithelial and mesenchymal marker expression in BEAS-2B cells. The cells were assessed for 48 h after stimulation with TGF-ß1 alone or in combination with TWEAK. RESULTS: TGF-ß1 induced spindle-like morphology and loss of cell contact, and reduced the expression of epithelial marker E-cadherin and increased the expression of mesenchymal markers N-cadherin and vimentin. Our data, for the first time, show that TWEAK reduced the expression of E-cadherin, and that co-treatment with TGF-ß1 and TWEAK enhanced the TGF-ß1-induced features of EMT. Moreover, hyaluronan synthase 2 expression was up-regulated by a combination with TGF-ß1 and TWEAK, but not TNF-α. We also demonstrated that the Smad, p38 MAPK, and NF-κB signaling pathways, and the transcriptional repressor ZEB2 might mediate N-cadherin up-regulation by TGF-ß1 in combination with TWEAK. CONCLUSIONS: These findings suggest that the pro-inflammatory cytokine TWEAK and TGF-ß1 have synergistic effects in EMT and may contribute to chronic airway changes and remodeling.

Severe gastritis due to pembrolizumab treatment in a lung cancer patient.

Immune checkpoint inhibitors (ICIs) are known to induce gastrointestinal adverse events. Colitis occurs most frequently, and gastritis is less common. A few case reports of gastritis induced by ICIs have indicated that colitis induced by cytotoxic T-lymphocyte antigen-4 (CTLA-4) resembles inflammatory bowel disease (IBD) and that programmed death-1/programmed death ligand-1 (PD-1/PD-L1) inhibitor can also induce the same type of colitis. We herein encountered a case of gastritis arising after 25 cycles of pembrolizumab administration in which the pathological and endoscopic findings resembled those of IBD. ICIs may induce gastritis in a manner similar to the pathogenesis of IBD.

Characterization of tenascin-C as a novel biomarker for asthma: utility of tenascin-C in combination with periostin or immunoglobulin E.

BACKGROUND: Extracellular matrix proteins tenascin-C (TNC) and periostin, which were identified as T-helper cell type 2 cytokine-induced genes in human bronchial epithelial cells, accumulate in the airway basement membrane of asthmatic patients. Although serum periostin has been accepted as a type 2 biomarker, serum TNC has not been evaluated as a systemic biomarker in asthma. Therefore, the objective of this study was to evaluate whether serum TNC can serve as a novel biomarker for asthma. METHODS: We evaluated 126 adult patients with mild to severe asthma. Serum TNC, periostin, and total IgE concentrations were quantified using enzyme-linked immunosorbent assays. RESULTS: Serum TNC levels were significantly higher in patients with severe asthma and high serum total IgE levels. Patients with both high serum TNC (> 37.16 ng/mL) and high serum periostin (> 95 ng/mL) levels (n = 20) or patients with both high serum TNC and high serum total IgE (> 100 IU/mL) levels (n = 36) presented higher disease severity and more severe airflow limitation than patients in other subpopulations. CONCLUSIONS: To our knowledge, this is the first study to show that serum TNC levels in asthmatic patients are associated with clinical features of asthma and that the combination of serum TNC and periostin levels or combination of serum TNC and total IgE levels were more useful for asthma than each single marker, suggesting that serum TNC can serve as a novel biomarker for asthma.

Antioxidant nutrients in plasma of Japanese patients with chronic obstructive pulmonary disease, asthma-COPD overlap syndrome and bronchial asthma.

BACKGROUND: Few studies to date have investigated the antioxidant nutrients such as vitamin C (ascorbic acid), vitamin E (α-tocopherol), retinol and carotenoids in plasma from patients with pulmonary disease in Japan. To clarify the role of antioxidant nutrients such as vitamin C, vitamin E, retinol and various carotenoids in plasma of Japanese patients with chronic obstructive lung diseases (COPD), asthma-COPD overlap syndrome (ACOS) and/or bronchial asthma (BA), we compared to healthy elderly controls. METHODS: Ascorbic acid (AA), carotenoids (lutein, zeaxanthin, ß-cryptoxanthin, α-carotene, ß-carotene and lycopene), retinol and α-tocopherol levels in plasma were determined by using a high performance liquid chromatography. Reduced glutathione (GSH), oxidised glutathione (GSSG) in whole blood and urinary 8-OHdG were also determined. RESULTS: Plasma AA level of COPD subjects was significantly lower than that of healthy elderly people. Conversely, ACOS and BA subjects showed no significant difference from healthy elderly people. Moreover, plasma lycopene and total carotenoid levels and GSH content in blood were significantly lower in COPD subjects than these in healthy elderly people. However, other redox markers such as GSSG, GSH/GSSG ratio and urinary 8-OHdG found no significant differences between COPD, ACOS and BA compared to healthy elderly people. CONCLUSIONS: These results suggested that COPD of Japanese patients may develop partly because of oxidative stress derived from a shortage of antioxidant nutrients, especially of AA and lycopene, as well as GSH while this may not be the case in both ACOS and BA.

Factors influencing weaning from mechanical ventilation in elderly patients with severe pneumonia.

AIMS: The purpose of this study was to determine the factors that adversely affect the weaning of elderly patients with community-acquired pneumonia from mechanical ventilation. METHODS: This study retrospectively investigated the medical records of 71 elderly patients (65 years or older) who were admitted to the hospital because of community-acquired pneumonia and required mechanical ventilation between January 2003 and December 2007. The patients were divided into two groups: group A, which included 33 patients who were successfully weaned from mechanical ventilation, and group B, which included 38 patients who could not be weaned from mechanical ventilation. The study compared the patients' background, vital signs, and laboratory and bacteriological examinations at the beginning of mechanical ventilation. A multiple logistic regression analysis was performed to identify the factors associated with difficulties in weaning patients from mechanical ventilation. RESULTS: In group B, there were significantly more smokers (P < 0.05) and more patients with emphysematous changes on thoracic CT (P < 0.05). In group A, the concentrations of total serum protein (P < 0.05) and albumin (P < 0.05) were significantly higher. A multiple logistic regression analysis revealed that patients with community-acquired pneumonia who showed emphysematous changes on thoracic CT (OR = 4.92, 95%CI 1.08-22.46) and/or a low concentration of serum albumin <3.0 g/dL (OR = 4.25, 95%CI 1.17-15.45) had difficulty being weaned from mechanical ventilation. CONCLUSION: Our study suggests that elderly patients with community-acquired pneumonia with emphysematous changes on thoracic CT and/or a low concentration of serum albumin level have difficulty being weaned from mechanical ventilation.