Effect of nintedanib on airway inflammation and remodeling in a murine chronic asthma model.

INTRODUCTION: Nintedanib is a multi-tyrosine kinase receptor inhibitor recently approved for treatment of idiopathic pulmonary fibrosis. Although angiogenesis is a key process involved in airway structural changes in patients with bronchial asthma, the effect of nintedanib targeting the angiokinase pathway on airway inflammation and remodeling has not been evaluated. METHODS: We used a 3-month ovalbumin (OVA) challenge mouse model of airway remodeling. Nintedanib was orally administrated during the challenge period, and the effects were examined based on the percentage of airway inflammatory cells, airway hyper-reactivity (AHR), peribronchial goblet cell hyperplasia, total lung collagen and smooth muscle area. The expression of growth factor receptors was analyzed in mice lung tissues. RESULTS: The OVA challenged group showed a significant increase in airway eosinophilic inflammation, elevated Th2 cytokines, AHR, and airway remodeling compared to those in the control group. The airway remodeling process, as evaluated by goblet cell hyperplasia, total lung collagen level, and airway smooth muscle area, was suppressed by nintedanib compared to that by OVA. Nintedanib effectively suppressed the phosphorylation of vascular endothelial growth factor/ platelet derived growth factor subunit2/fibroblast growth factor3 receptors in the mice lung. CONCLUSIONS: Nintedanib effectively ameliorated airway inflammation and remodeling in an OVA-induced chronic asthma model. These results suggest that nintedanib could be a new treatment agent targeting airway remodeling in patients with severe asthma.

Effect of nilotinib on airway remodeling in a murine model of chronic asthma.

UNLABELLED: ABSTRACT Objective: The tyrosine kinase inhibitor nilotinib has potent inhibitory activity against the stem cell growth factor receptor c-Kit and platelet-derived growth factor receptor (PDGFR). The present study aimed to determine whether nilotinib suppresses airway remodeling and whether its effect is associated with the c-Kit and PDGFR pathways. We also aimed to compare the effect of nilotinib and imatinib on remodeling. METHODS: We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with nilotinib or imatinib during the OVA challenge. RESULTS: Compared with control mice, the mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, airway hyperresponsiveness (AHR), and exhibited features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of nilotinib significantly inhibited eosinophilic inflammation, AHR, and remodeling in mice chronically exposed to OVA. Nilotinib showed a trend of more potent effect than imatinib on attenuating remodeling in hydroxyproline assay and smooth muscle staining. Nilotinib treatment significantly reduced the expression of phosphorylated (p)-c-Kit, p-PDGFRß, and p-extracellular signal-regulated kinase 1/2. The expression levels of the genes encoding c-Kit and PDGFRß were also reduced by nilotinib treatment. Treatment with nilotinib did not affect significantly the level of OVA-specific IgE and IgG1 in serum. In vitro, nilotinib significantly inhibited cell proliferation of fibroblast. CONCLUSIONS: These results suggest that nilotinib administration can prevent airway inflammation, AHR, and airway remodeling associated with chronic allergen challenge.

Blockade of IL-33/ST2 ameliorates airway inflammation in a murine model of allergic asthma.

OBJECTIVE: Interleukin (IL)-33 is involved in the development of lung inflammation by inducing or amplifying Th2 type-mediated responses in various animal models of allergic asthma. The ST2 gene is a member of the IL-1 receptor family, producing a transmembrane form (ST2L) and a soluble secreted form (sST2). sST2 has been shown to block this IL-33/ST2 signaling pathway. This study aimed to investigate whether anti-IL-33 and sST2 reduced airway inflammation in a murine model of asthma. METHODS: BALB/c mice were sensitized and challenged with ovalbumin (OVA), and the effect of sST2 and anti-IL-33 antibody on airway inflammation and airway hyperresponsiveness (AHR) was evaluated. Furthermore, we measured changes in various cytokines in the bronchoalveolar lavage (BAL) fluid when treated with sST2 or anti-IL-33. RESULTS: We observed that anti-IL-33 antibody and sST2 exert a negative regulation on OVA-mediated allergic airway inflammation. Both treatments reduced total cell counts and eosinophil counts in BAL fluid and AHR to methacholine. The Th2 cytokines, such as IL-4, IL-5, and IL-13 in BAL fluid were also significantly decreased after both treatments. However, there were no changes in the level of TGF- ß1 and IL-10 after each treatment. CONCLUSIONS: These results suggest that anti-IL-33 as well as sST2 have therapeutic potential for allergic asthma through inhibition of Th2 cytokine production.

Effect of imatinib on airway smooth muscle thickening in a murine model of chronic asthma.

BACKGROUND: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and remodeling. The tyrosine kinase inhibitor imatinib mesylate was developed to inhibit BCR-ABL kinase activity; however, it also has potent inhibitory activity against the c-Kit and platelet-derived growth factor receptors. The present study aimed to determine whether imatinib suppresses airway smooth muscle (ASM) remodeling and whether its effect is associated with growth factors such as transforming growth factor (TGF)-ß1 and stem cell factor (SCF). METHODS: We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with imatinib during the OVA challenge. RESULTS: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and AHR compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of imatinib significantly inhibited the development of AHR, eosinophilic inflammation and, importantly, ASM remodeling in mice chronically exposed to OVA. Imatinib treatment significantly reduced the levels of interleukin-4, -5 and -13. In addition, TGF-ß1 and SCF were significantly reduced in the imatinib-treated animals. CONCLUSIONS: These results suggest that imatinib administration can prevent not only airway inflammation, but also airway remodeling associated with chronic allergen challenge. Imatinib may provide a clinically attractive therapy for chronic severe asthma.

Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice.

BACKGROUND: The tyrosine kinase inhibitor imatinib mesylate was developed as an inhibitor of the kinase activity of BCR-ABL. However, imatinib also has potent inhibitory activity against the platelet-derived growth factor receptor (PDGFR). Nilotinib is approved for treating patients with chronic myeloid leukemia showing resistance or intolerance to imatinib. Like imatinib, nilotinib selectively inhibits the tyrosine kinase activity of PDGFR. OBJECTIVES: We examined the effect of imatinib and nilotinib on acute lung injury and pulmonary fibrosis in a mouse model. METHODS: Mice were treated by intratracheal instillation of bleomycin. Imatinib or nilotinib were administered by oral gavage. To study the early inflammatory and late fibrotic phases of lung injury, mice were sacrificed on days 3, 7, 14 and 21 after bleomycin instillation. RESULTS: Histopathology showed that imatinib and nilotinib attenuated the extent of lung injury and fibrosis. The numbers of inflammatory cells and levels of IL-6, IL-1ß and tumor necrosis factor-α were decreased in the imatinib and nilotinib groups on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline on days 14 and 21, which was accompanied by decreased expression levels of transforming growth factor (TGF)-ß1 and PDGFR-ß. Imatinib and nilotinib also significantly reduced the expression levels of the genes for TGF-ß1 and platelet-derived growth factor (PDGF). Imatinib and nilotinib treatment also significantly inhibited the PDGF-induced proliferation of lung fibroblasts in vitro. When imatinib or nilotinib was given 7 days after the instillation of bleomycin, only nilotinib attenuated pulmonary fibrosis. CONCLUSIONS: Imatinib and nilotinib attenuated bleomycin-induced acute lung injury and pulmonary fibrosis in mice. In a therapeutic model, nilotinib showed more potent antifibrotic effects than imatinib.

Inhibitory effects of anti-immunoglobulin E antibodies on airway remodeling in a murine model of chronic asthma.

BACKGROUND: Airway remodeling is one of the cardinal features of asthma and is thought to play a pivotal role in refractory or persistent asthma. Immunoglobulin E (IgE) has a major effect on the pathogenesis of asthma. The aim of this study was to investigate the effects of anti-IgE antibody not only on airway inflammation and bronchial hyperresponsiveness, but also on airway remodeling in a murine model of chronic asthma. METHODS: The authors developed a mouse model of chronic asthma in which ovalbumin (OVA)-sensitized female BALB/c-mice were exposed to intranasal OVA administration twice a week for 3 months. Anti-IgE antibodies were administered intravenously starting on the 38th day and once a month thereafter for 3 months during the intranasal OVA challenge. RESULTS: Mice that were chronically exposed to OVA developed sustained eosinophilic airway inflammation and airway hyperresponsiveness (AHR) to methacholine and showed increased levels of collagen, hydroxyproline, and alpha-smooth muscle actin, as compared with control mice. Treatment with anti-IgE antibody inhibited the development of AHR, eosinophilic inflammation, and airway remodeling. Moreover, anti-IgE antibody treatment reduced the levels of interleukin (IL)-5 and IL-13 in the bronchoalveolar lavage fluids, although it did not affect the levels of IL-10, transforming growth factor-beta, and activin A. CONCLUSION: These results suggest that anti-IgE antibody treatment modulates the airway inflammation and remodeling associated with chronic allergen challenge. The inhibition of inflammation may be related to the regulation of Th2 cytokines. However, the mechanisms underlying the blocking of airway remodeling by anti-IgE antibody remain to be elucidated.

Effect of pravastatin on bleomycin-induced acute lung injury and pulmonary fibrosis.

1. Pravastatin is best known for its antilipidemic action. Recent studies have shown that statins have immunomodulatory and anti-inflammatory effects. The present study aimed to determine whether or not pravastatin can attenuate acute lung injury and fibrosis in a mouse model. 2. Bleomycin was given to C57BL6 mice through intratracheal instillation. Pravastatin was given through intraperitoneal injection. To study the effect of pravastatin on the early inflammatory phase and the late fibrotic phase, mice were killed on days 3, 7, 14 and 21. 3. Pravastatin attenuated the histopathological change of bleomycin-induced lung injury and fibrosis. The accumulation of neutrophils and increased production of tumor necrosis factor-α in bronchoalveolar lavage fluid were inhibited in the early inflammatory phase. Pravastatin effectively inhibited the increase of lung hydroxyproline content induced by bleomycin. Furthermore, pravastatin reduced the increased expression of transforming growth factor (TGF)-ß1, connective tissue growth factor (CTGF), RhoA and cyclin D1. The increased levels of TGF-ß1 and CTGF mRNA expression were also significantly inhibited by pravastatin. 4. Pravastatin effectively attenuated bleomycin-induced lung injury and pulmonary fibrosis in mice. Our results provide evidence for the therapeutic potential of pravastatin in the treatment of acute lung injury and pulmonary fibrosis.

Effect of peroxisome proliferator-activated receptor-gamma on airway smooth muscle thickening in a murine model of chronic asthma.

BACKGROUND: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and remodeling. Peroxisome proliferator-activated receptors (PPARs) were reported to regulate inflammatory responses in many cells. In this study we examined the effect of a PPAR-gamma agonist on the airway smooth muscle and the production of transforming growth factor (TGF)-beta1 and vascular endothelial growth factor (VEGF). METHODS: We developed a mouse model of airway remodeling including smooth muscle thickening in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated intranasally with ciglitazone during OVA challenge. RESULTS: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and AHR to methacholine compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of ciglitazone intranasally significantly inhibited the development of AHR, eosinophilic inflammation, and importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. However, intranasal ciglitazone treatment did not reduce the level of TGF-beta1 and VEGF in bronchoalveolar lavage fluid. CONCLUSIONS: These results suggest that intranasal administration of ciglitazone can prevent not only airway inflammation, but also airway remodeling associated with chronic allergen challenge. The mechanism might not be related to VEGF and TGF production. Further study is needed.

Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies.

INTRODUCTION: Neutropenia recovery may be associated with deterioration in oxygenation and exacerbation of pre-existing pulmonary disease. However, risk factors for acute respiratory distress syndrome (ARDS) during neutropenia recovery in patients with hematologic malignancies have not been studied. METHODS: We studied critically ill patients with hematologic malignancies with the dual objectives of describing patients with ARDS during neutropenia recovery and identifying risk factors for ARDS during neutropenia recovery. A cohort of consecutive neutropenic patients with hematologic malignancies who were admitted to the intensive care unit (ICU) was studied. During a 6-year period, 71 patients recovered from neutropenia, of whom 38 (53.5%) developed ARDS during recovery. RESULTS: Compared with non-ARDS patients, patients who experienced ARDS during neutropenia recovery were more likely to have pneumonia, be admitted to the ICU for respiratory failure, and receive mechanical ventilator therapy. The in-ICU mortality was significantly different between the two groups (86.8% versus 51.5%, respectively, for patients who developed ARDS during neutropenia recovery versus those who did not during neutropenia recovery). In multivariate analysis, only occurrence of pneumonia during the neutropenic episode was associated with a marked increase in the risk of ARDS (odds ratio, 4.76). CONCLUSIONS: Patients with hematologic malignancies complicated by pneumonia during neutropenia are at increased risk for ARDS during neutropenia recovery.

Inhibitory Effects of Resveratrol on Airway Remodeling by Transforming Growth Factor-ß/Smad Signaling Pathway in Chronic Asthma Model.

PURPOSE: Asthma is a chronic airway disease characterized by airway remodeling, leading to a progressive decline in lung function. Therapeutic agents that attenuate airway remodeling can complement the limited effects of traditional glucocorticoids. In this study, we investigated the effect of resveratrol on allergic airway inflammation and remodeling in a murine model of chronic bronchial asthma. METHODS: Peribronchial smooth muscle thickening that developed in mice challenged with a 3-month repeated exposure to ovalbumin (OVA) was used to study airway remodeling. Oral resveratrol was administered daily during the OVA challenge. The expression of TGF-ß1/Smad signaling proteins and downstream mesenchymal markers in the presence or absence of resveratrol was examined in bronchial epithelial cells. RESULTS: OVA sensitization and chronic challenge increased airway hyperresponsiveness, inflammation, goblet cell hyperplasia, α-smooth muscle actin (SMA), and collagen deposition. Resveratrol effectively suppressed OVA-induced airway inflammation and remodeling. The expression of TGF-ß1/phosphorylated Smad2/3 was increased in the lung tissues of OVA-challenged mice but effectively inhibited by resveratrol. In bronchial epithelial cells, the TGF-ß1-induced expression of the mesenchymal markers snail, slug, vimentin, and α-SMA was suppressed by resveratrol treatment. CONCLUSIONS: Resveratrol effectively ameliorated both airway inflammation and airway structural changes in a mouse model of bronchial asthma. These effects were mediated by decreased TGF-ß1 expression, in turn suppressing TGF-ß1/Smad signaling and the epithelial-mesenchymal transition process. Our results demonstrate the potential benefits of resveratrol for the treatment of airway remodeling associated with bronchial asthma.

Effect of intranasal rosiglitazone on airway inflammation and remodeling in a murine model of chronic asthma.

BACKGROUND/AIMS: Asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Peroxisome proliferator-activated receptors have been reported to regulate inflammatory responses in many cells. In this study, we examined the effects of intranasal rosiglitazone on airway remodeling in a chronic asthma model. METHODS: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated intranasally with rosiglitazone with or without an antagonist during OVA challenge. We determined airway inflammation and the degree of airway remodeling by smooth muscle actin area and collagen deposition. RESULTS: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, compared with control mice. Additionally, the mice developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of rosiglitazone intranasally inhibited the eosinophilic inflammation significantly, and, importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. Expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was increased in the OVA group and decreased in the rosiglitazone group. Co-treatment with GW9660 (a rosiglitazone antagonist) and rosiglitazone increased the expression of TLR-4 and NF-κB. CONCLUSIONS: These results suggest that intranasal administration of rosiglitazone can prevent not only air way inf lammation but also air way remodeling associated with chronic allergen challenge. This beneficial effect is mediated by inhibition of TLR-4 and NF-κB pathways.

Clinical characteristics of asthma combined with COPD feature.

PURPOSE: In clinical practice, some patients with asthma show incompletely reversible airflow obstruction, resembling chronic obstructive pulmonary disease (COPD). The aim of this study was to analyze this overlap phenotype of asthma with COPD feature. MATERIALS AND METHODS: A total of 256 patients, over the age of 40 years or more with a diagnosis of asthma, based on either 1) positive response to bronchodilator: >200 mL forced expiratory volume in 1 s (FEV1) and >12% baseline or 2) positive methacholine or mannitol provocation test, were enrolled. Among the asthma patients, we defined the overlap group with incompletely reversible airflow obstruction [postbronchodilator FEV1/forced vital capacity (FVC)<70] at the initial time of admission and continuing airflow obstruction after at least 3 months follow up. We evaluated clinical features, serum eosinophil counts, serum total immunoglobulin (Ig) E with allergy skin prick test, spirometry, methacholine or mannitol provocation challenges and bronchodilator responses, based on their retrospective medical record data. All of the tests mentioned above were performed within one week. RESULTS: The study population was divided into two groups: asthma only (62%, n=159, postbronchodilator FEV1/FVC≥70) and overlap group (38%, n=97, postbronchodilator FEV1/FVC<70). The overlap group was older, and contained more males and a higher percentage of current or ex-smokers than the asthma only group. Significantly lower FEV1 and higher total lung capacity, functional residual capacity, and residual volume were observed in the overlap group. Finally, significantly lower serum eosinophil count and higher IgE were seen in the overlap group. CONCLUSION: Our results showed that the overlap phenotype was older, male asthmatic patients who have a higher lifetime smoking intensity, more atopy and generally worse lung function.