[Show abstract][Hide abstract] ABSTRACT: Reactive oxygen species (ROS) play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, L-2-oxothiazolidine-4-carboxylic acid (OTC) or α-lipoic acid (LA) on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA) increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-β1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), hypoxia-inducible factor (HIF)-1α, and HIF-2α was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-κB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling.
International Journal of Molecular Sciences 12/2012; 13(7):7915-37. · 2.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although some therapeutics provide an opportunity for cure, recurrence is a major obstacle to achieve a complete remission for lung cancers. Therefore, precise assessment of lung cancers has been a task with challenge. In recent years, integration of positron emission tomography and computed tomography (PET-CT) and whole-body magnetic resonance imaging (WB-MRI) have been introduced as an alternative to standard multimodality imaging strategies and are now increasingly applied to various malignancies. However, there is little information on the surveillance capability of WB-MRI in patients with lung cancers. We aimed to investigate the clinical potential of WB-MRI as a novel surveillance modality after curative treatments for lung cancers, comparing it with PET-CT. Sixty two consecutive patients with lung malignancy who underwent both WB-MRI and PET-CT were selected to assess the recurrent malignant lesions. The clinical data including radiologic and pathologic findings were collected and analyzed retrospectively. On each lymph node station, the ability of WB-MRI to detect malignant lesions significantly correlated with that of PET-CT (γ=0.86; P<.01). The correlation coefficient ranged from 0.999 to 1 for assessing distant metastases from lung cancers by two modalities (P<.01). Based on the pathologic confirmation, both modalities showed an equivalent diagnostic accuracy (PET-CT: sensitivity 85.71%, specificity 47.27% versus WB-MRI: sensitivity 85.71%, specificity 56.25%). This study demonstrates the clinical potential of WB-MRI, together with PET-CT, as a novel surveillance modality for lung cancers after curative treatments.
Magnetic Resonance Imaging 07/2012; · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Occupational asthma is characterized by airway inflammation and hyperresponsiveness associated with increased vascular permeability. AMP-activated protein kinase (AMPK) has been suggested to be a novel signaling molecule modulating inflammatory responses.
We sought to evaluate the involvement of AMPK in pathogenesis of occupational asthma and more specifically investigate the effect and molecular mechanisms of AMPK activation in regulating vascular permeability.
The mechanisms of action and therapeutic potential of an AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) were tested in a murine model of toluene diisocyanate (TDI)-induced asthma.
AICAR attenuated airway inflammation and hyperresponsiveness increased by TDI inhalation. Moreover, TDI-induced increases in levels of hypoxia-inducible factor (HIF)-1α, HIF-2α, vascular endothelial growth factor A (VEGFA), and plasma exudation were substantially decreased by treatment with AICAR. Our results also showed that VEGFA expression was remarkably reduced by inhibition of HIF-1α and HIF-2α with 2-methoxyestradiol (2ME2) and that an inhibitor of VEGFA activity, CBO-P11 as well as 2ME2 significantly suppressed vascular permeability, airway infiltration of inflammatory cells, and airway hyperresponsiveness induced by TDI. In addition, AICAR reduced reactive oxygen species (ROS) generation and levels of malondialdehyde and T-helper type 2 cytokines (IL-4, IL-5, and IL-13), while this agent enhanced expression of an anti-inflammatory cytokine, IL-10.
These results suggest that AMPK activation ameliorates airway inflammatory responses by reducing vascular permeability via HIF/VEGFA pathway as well as by inhibiting ROS production and thus may be a possible therapeutic strategy for TDI-induced asthma and other airway inflammatory diseases.
Agents and Actions 06/2012; 61(10):1069-83. · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was aimed to determine the effects of quercetin on the interleukin-1β (IL-1β)-induced proliferation of rheumatoid synovial fibroblasts (RASFs) and production of matrix metalloproteinases (MMPs), cyclooxygenase (COX), and prostaglandin E2 (PGE2) by RASFs. The proliferation and apoptosis of RASFs was evaluated with CCK-8 reagent and flow cytometry in the presence of IL-1with CCK-8 reagquercetin. The expression of MMPs, IL-1β enhanced the expression of MMP-1, MMP-3, tissue inhibitor of metalloproteinase (TIMP)-1, COXs, PGE2, and intracellular mitogen-activated protein kinase (MAPK) signalings including phosphorylated extracellular signal-regulated kinase (p-ERK), p-p38, phosphorylated c-Jun N-terminal kinase (p-JNK), and nuclear factor kB (NF-kB) were examined by immunoblotting or semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) in conditions as described above. Quercetin inhibits unstimulated and IL-1β-induced proliferation of RASFs and MMP-1, 3, COX-2 messenger ribonucleic acid and protein expression, PGE2 production induced with IL-1β. Quercetin also inhibits the phosphorylation of ERK-1/2, p38, JNK and activation of NF-kB by IL-1ed. These results indicate that quercetin inhibits synovial fibroblasts proliferation and MMPs, COX-2, and PGE2 production, which involved joint destruction in rheumatoid arthritis (RA), and suggest that it might be a new therapeutic agent for management of RA.
[Show abstract][Hide abstract] ABSTRACT: Background: The aim of this study was to evaluate the prevalence, risk factors, and survival of lung cancer in patients with idiopathic pulmonary fibrosis (IPF).Methods: IPF with lung cancer from tertiary hospitals consisted of 1685 patients who had been diagnosed between 2003 and 2007. We reviewed their medical records retrospectively to evaluate the prevalence, risk factors and prognosis of lung cancer in IPF patients.Results: Among all patients with IPF, 114 cases (6.8%) had lung cancer with IPF. The incidence of lung cancer in patients with IPF was 1.03 persons per 100 person-year (25 patients/2408 years). Most cases of lung cancer (73/114, 68.9%) were located in IPF-associated areas; the lung cancer typically developed in peripheral and lower lobe areas. The study revealed that forced vital capacity (% predicted) at the initial diagnosis and development of lung cancer were independent prognostic factors in patients with IPF.Conclusions: Lung cancer in patients with IPF was significantly related with the IPF prognosis. An active evaluation should be performed in patients with IPF to detect lung cancer early.
[Show abstract][Hide abstract] ABSTRACT: The p38 mitogen-activated protein kinase (MAPK) appears to play an important role in various pathophysiological responses and has been suggested to be involved in many processes considered critical to the inflammatory response and tissue remodeling. Bronchial asthma is a chronic inflammatory disorder of the airway accompanied by increased vascular permeability. Vascular endothelial growth factor (VEGF) is a potent stimulator of bronchial inflammation, airway remodeling, and physiologic dysregulation that augments antigen sensitization and T-helper type 2 cell (Th2)-mediated inflammation in allergic airway diseases. However, there are little data on the relationship between p38 MAPK signaling and VEGF expression in allergic airway disease.
This study aimed to investigate the role of p38 MAPK on the pathogenesis of allergic airway disease, more specifically in VEGF expression.
Using ovalbumin (OVA)-inhaled mice and a selective p38 MAPK inhibitor, SB 239063, the involvement of p38 MAPK in allergen-induced VEGF expression in the airway was evaluated.
The increases of phosphorylation of p38 MAPK, VEGF protein expression, and vascular permeability in the lung after OVA inhalation were decreased substantially by the administration of SB 239063. In addition, SB 239063 significantly reduced the increase of Th2 cytokines and OVA-specific IgE. The inhibition of p38 MAPK or VEGF signaling prevented and also decreased the increases in the number of inflammatory cells and airway hyperresponsiveness in OVA-induced allergic airway disease.
These results indicate that inhibition of p38 MAPK may attenuate allergen-induced airway inflammation and vascular leakage through modulation of VEGF expression in mice.
Journal of Clinical Immunology 02/2012; 32(3):574-86. · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute lung injury (ALI) is a devastating disorder of the lung by various causes and its cardinal features are tissue inflammation, pulmonary edema, low lung compliance, and widespread capillary leakage. Among phosphoinositide 3-kinases (PI3Ks), PI3K-γ isoform has been shown to play an important role in a number of immune/inflammatory responses.
We investigated the role of PI3K-γ and its molecular basis in lipopolysaccharide (LPS)-induced ALI using a selective inhibitor for PI3K-γ, AS 605240, and LPS-treated C57BL/6 mice.
Treatment of mice with LPS showed an increase of lung inflammation and vascular leakage. Production of reactive oxygen species (ROS), interleukin (IL)-1β, tumor necrosis factor-α, and IL-4, adhesion molecule, and vascular endothelial growth factor (VEGF) was also increased. Administration of AS 605240 to LPS-treated mice markedly reduced the pathophysiological features of ALI and the increased production of ROS, cytokines, adhesion molecule, and VEGF in the lung. Our results also showed that treatment of mice with LPS activates nuclear factor-κB (NF-κB) and degradation of inhibitory κBα (IκBα) through PI3K-γ. Additionally, infiltration of dendritic cells (DCs) and expression of toll-like receptor 4 (TLR4) were significantly increased in the lung of LPS-treated mice, and inhibition of PI3K-γ reduced the infiltration of DCs and TLR4 expression in the lung.
These results indicate that PI3K-γ is critically involved in LPS-induced ALI by regulating IκBα/NF-κB pathway and innate immune responses. Based on our data, we suggest that PI3K-γ isoform is a promising target for the treatment of ALI.
Journal of Clinical Immunology 12/2011; 32(2):340-51. · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the effects of adrenomedullin (AM) on interleukin (IL)-1β-induced proliferation of rheumatoid synovial fibroblasts (RASFs) and production of matrix metalloproteinases (MMPs), cyclooxygenase (COX) and prostaglandin E2 (PGE2) by RASFs. The RASFs proliferation was evaluated with CCK-8 reagent in the presence of IL-1β with/without AM (1-52) and AM inhibitor (AM (22-52)). MMPs, tissue inhibitor of metalloproteinase (TIMP-1), COXs, PGE2 and intracellular mitogen-activated protein kinase (MAPK) signalings, including p-ERK, p-p38, p-JNK were examined by immunoblotting or semiquantitative RT-PCR and ELISA. AM (1-52) inhibited IL-1β-induced RASFs proliferation and inhibited MMP-1, 3, COX-2 and PGE2 production. AM (1-52) also inhibited IL-1β-induced phosphorylation of ERK-1/2, p38, JNK. AM 22-52 inhibited the effects of AM (1-52) on proliferation of RASFs and production of MMP-1, 3, COX-2 via MAPKs. These results suggest that AM might involved joint destruction in rheumatoid arthritis and indicate that it might be a new therapeutic modality for management of this disease.
[Show abstract][Hide abstract] ABSTRACT: Inflammatory myofibroblastic tumor (IMT) is a rare tumorous lesion that presents as a solitary nodule. Complete surgical resection is the standard treatment. However, due to its rarity, the optimal therapeutic strategy for multiple IMTs has not been defined. A 32-year-old man was referred to our hospital for evaluation of multiple pulmonary nodules. On computed tomography (CT) scan of the chest, there were a 3.0 × 1.7 cm mass with heterogeneous enhancement in the left upper lobe and multiple small nodules bilaterally. We performed wedge resection of the mass, and histopathology revealed IMT. He was treated with oral corticosteroids. The clinical and radiologic responses were so excellent that a CT scan showed complete resolution 1 month after the initiation of corticosteroid therapy. These observations suggest that corticosteroids may be the way to treat bilateral multiple IMT of the lung.
Beiträge zur Klinik der Tuberkulose 08/2011; 189(5):433-5. · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary cryptococcosis is occasionally detected on routine imaging studies in healthy hosts with no or mild symptoms. Isolated pulmonary cryptococcosis may be observed without specific therapy in asymptomatic immunocompetent hosts. However, considering that dissemination from a pulmonary infection can occur in patients with no immunologic defects, treatment of asymptomatic pulmonary cryptococcosis in immunocompetent hosts remains controversial. The aim of this study was to determine the role of fluconazole therapy in the management of isolated pulmonary cryptococcosis in asymptomatic healthy hosts.
We retrospectively analyzed the medical records and radiographic findings of 10 healthy subjects with isolated pulmonary cryptococcosis diagnosed incidentally and treated with oral fluconazole.
All patients had no respiratory or constitutional symptoms. The most common radiological findings were pulmonary nodules, and the number of nodules in each patient was from 1 to 9. After histological confirmation, all patients were treated with oral fluconazole at a dosage of 400 mg per day for a median period of 6.4 months. No patient developed an adverse reaction to fluconazole. The mean interval between the initiation of antifungal therapy and final radiological response was 8.3 months. Seven of the 10 patients showed complete resolution, and the other 3 patients were assessed as having partial resolution. During the average follow-up period of 11.9 months, all patients showed a favourable outcome with no relapse. The overall cure rate was 70%.
These results suggest that fluconazole may be an attractive therapeutic option for asymptomatic pulmonary cryptococcosis in immunocompetent hosts.