Hee Moon

Peroxisome Proliferator-Activated Receptor γ Agonist Down-Regulates IL-17 Expression in a Murine Model of Allergic Airway Inflammation

Peroxisome proliferator-activated receptor γ (PPARγ) plays a critical role in the control of airway inflammation. Recently, IL-17 has been found to be implicated in many immune and inflammatory responses, including airway inflammation. However, no data are available concerning the effect of PPARγ on IL-17 production in airway inflammatory diseases. In this study, we used a mouse model of asthma to evaluate the effect of two PPARγ agonists, rosiglitazone or pioglitazone, on IL-17 expression in allergic airway disease. After OVA inhalation, mice developed the typical pathophysiological features of asthma, and the expression of IL-17 protein and mRNA in the lungs was increased. Administration of rosiglitazone or pioglitazone reduced the pathophysiological features of asthma and decreased the increased IL-17 protein and mRNA expression after OVA inhalation. In addition, the attenuating effect of PPARγ agonist on allergic airway inflammation and bronchial hyperresponsiveness is abrogated by coadministration of rIL-17. This study also showed that the inhibition of IL-17 activity with anti-IL-17 Ab remarkably reduced the increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, and the increased levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and OVA-specific IgE in serum. In addition, we found that administration of rosiglitazone or pioglitazone decreased the increased NF-κB activity and that a NF-κB inhibitor, BAY 11-7085, substantially reduced the increased IL-17 protein levels in the lung tissues after OVA inhalation. These findings suggest that the therapeutic effect of PPARγ in asthma is partly mediated by regulation of IL-17 expression via NF-κB pathway.

Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease

BACKGROUND Bronchial asthma is a chronic inflammatory disorder of the airways characterized by increased expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases is associated with increased gene transcription, whereas hypoacetylation induced by histone deacetylases is associated with suppression of gene expression. Sirtuin 1 (SIRT1) is a member of the silent information regulator 2 family that belongs to class III histone deacetylase. OBJECTIVE This study aimed to investigate the role of SIRT1 and the related molecular mechanisms in the pathogenesis of allergic airway disease. METHODS By using a murine model of ovalbumin (OVA)-induced allergic airway disease and murine tracheal epithelial cells, this study investigated the involvement of SIRT1 and its signaling networks in allergic airway inflammation and hyperresponsiveness. RESULTS In this study with mice after inhalation of OVA, the increased levels of SIRT1, hypoxia-inducible factor 1alpha (HIF-1alpha), and vascular endothelial growth factor protein in the lungs after OVA inhalation were decreased substantially by the administration of a SIRT1 inhibitor, sirtinol. We also showed that the administration of sirtinol reduced significantly the increased numbers of inflammatory cells of the airways; airway hyperresponsiveness; increased levels of IL-4, IL-5, and IL-13; and increased vascular permeability in the lungs after OVA inhalation. In addition, we have found that inhibition of SIRT1 reduced OVA-induced upregulation of HIF-1alpha in airway epithelial cells. CONCLUSIONS These results indicate that inhibition of SIRT1 might attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular endothelial growth factor expression mediated by HIF-1alpha in mice.

HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium.

Hypoxia‐inducible factor‐1α (HIF‐1α) plays a critical role in immune and inflammatory responses. One of the HIF‐1α target genes is vascular endothelial growth factor (VEGF), which is a potent stimulator of inflammation, airway remodeling, and physiologic dysregulation in allergic airway diseases. Using OVA‐treated mice and murine tracheal epithelial cells, the signaling networks involved in HIF‐1α activation and the role of HIF‐1α in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF‐1α siRNA suppressed VEGF expression. In addition, the increased levels of HIF‐1α and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF‐1α inhibitor, 2‐methoxyestradiol. Our data also show that the increased numbers of inflammatory cells, increased airway hyperresponsiveness, levels of IL‐4, IL‐5, IL‐13, and vascular permeability in the lungs after OVA inhalation were significantly reduced by 2‐methoxyestradiol or a VEGF inhibitor, CBO‐P11. Moreover, we found that inhibition of the PI3K p110δ isoform (PI3K‐δ) or HIF‐1α reduced OVA‐induced HIF‐1α activation in airway epithelial cells. These findings indicate that HIF‐1α inhibition may attenuate antigen‐induced airway inflammation and hyperresponsiveness through the modulation of vascular leakage mediated by VEGF, and that PI3K‐δ signaling may be involved in the allergen‐induced HIF‐1α activation.

Phosphoinositide 3-kinase δ inhibitor suppresses interleukin-17 expression in a murine asthma model

Phosphoinositide 3-kinases (PI3Ks) contribute to the pathogenesis of asthma by regulating the activation of inflammatory mediators, inflammatory cell recruitment and immune cell function. Recent findings have indicated that PI3Ks also regulate the expression of interleukin (IL)-17, which has been recognised as an important cytokine involved in airway inflammation. In the present study, we investigated a role of PI3K&dgr; in the regulation of IL-17 expression in allergic airway disease using a murine model of asthma. After ovalbumin inhalation, administration of a selective p110&dgr; inhibitor, IC87114, significantly attenuated airway infiltration of total cells, lymphocytes, neutrophils and eosinophils, as well as airway hyperresponsiveness, and attenuated the increase in IL-17 protein and mRNA expression. Moreover, IC87114 reduced levels of IL-4, -5 and -13, expression of keratinocyte chemoattractant protein and mRNA, and nuclear factor (NF)-&kgr;B activity. In addition, a NF-&kgr;B inhibitor, BAY 11-7085 substantially reduced the increase in IL-17 protein levels. Our results also showed that inhibition of IL-17 activity with an anti-IL-17 antibody remarkably reduced airway inflammation and hyperresponsiveness. These findings suggest that inhibition of the p110&dgr; signalling pathway suppresses IL-17 expression through regulation of NF-&kgr;B activity and, thus, has therapeutic potential in asthma.

Pulmonary Benign Metastasizing Leiomyoma in a Postmenopausal Woman

Pulmonary benign metastasizing leiomyoma (BML) is a rare disease occurring predominantly in women of reproductive age and usually develops several years after the resection of a uterine leiomyoma. A 52-year-old postmenopausal woman was admitted to our hospital because of a right-sided empyema. Contrast-enhanced computed tomography showed a multiloculated pleural effusion on the right side and multiple small nodules in the left lung. A wedge biopsy revealed the pulmonary nodule consisting of branching glandular structures surrounded by abundant smooth muscle cells with no atypia. We performed a gynecologic examination to identify the primary origin of the pulmonary smooth muscle tumors. A uterine leiomyoma was found, and the patient underwent a total hysterectomy. Both pulmonary nodules and uterine leiomyoma were positive for estrogen and progesterone receptors. Therefore, we diagnosed the pulmonary lesions as BMLs. This is an interesting case of pulmonary BML identified simultaneously with uterine myoma in a postmenopausal woman. BML should be considered in women with multiple pulmonary nodules, even though it is rare.

Pulmonary cryptococcosis in asymptomatic immunocompetent hosts

Pulmonary cryptococcosis tends to occur commonly in immunocompromized patients. However, as more individuals are undergoing regular medical examinations, the number of cases of pulmonary cryptococcosis detected incidentally in immunocompetent individuals is increasing. The aim of the present study was to evaluate the radiologic manifestations of pulmonary cryptococcosis in immunocompetent patients with no significant symptoms. The clinical records and radiographic findings of 7 immunocompetent subjects with isolated pulmonary cryptococcosis who were diagnosed by pathological examinations, were reviewed. The mean age of patients was 68.4 y (range 58–80 y), and 6 of them were female. The radiographic manifestations in all patients were 1 or more nodules. Computed tomography (CT) demonstrated 22 pulmonary nodules with diameter from 3 mm to 22 mm, and multiple nodules were more frequent than solitary nodules (5 cases versus 2 cases). Axial analysis of patients showed that an involvement of the upper lobe was observed in all patients. Most nodules were well defined and smoothly marginated (21 nodules) and cavitations were infrequent findings (2 nodules). Lymphadenopathies were found in 2 patients. The most common imaging finding of pulmonary cryptococcosis in asymptomatic immunocompetent hosts was the presence of multiple nodules marginated smoothly with upper lobe predominance.

Pulmonary Crystal-Storing Histiocytoma in a Patient Without a Lymphoproliferative Disorder

Pulmonary crystal-storing histiocytoma is a very rare disorder and is characterized by infiltration of histiocytes with intracytoplasmic accumulation of crystallized immunoglobulins. It is usually associated with lymphoproliferative diseases or plasma cell dyscrasia. Here, we report a case of pulmonary crystal-storing histiocytoma in a 64-year-old man, presenting as a chronic pulmonary consolidation in the lung exposed to asbestos. Video-assisted thoracoscopic surgical biopsy displayed sheets of large, epithelioid histiocytes filled with a large number of needle-like crystals, showing the accumulation of crystallized polyclonal immunoglobulins. This lesion was consistent with crystal-storing histiocytosis or crystal-storing histiocytoma. With extensive clinical work-up, the current case was not associated with lymphoproliferative diseases. Herein, we present this extremely rare entity of pulmonary pathology, a pulmonary crystal-storing histiocytoma arising in the lung exposed to asbestos, and demonstrate the clinical, radiologic, and pathologic features of the tumor.

Chylothorax and chylopericardium as the initial clinical manifestation of Behcet’s disease

Behcet’s disease (BD) is a chronic relapsing systemic vasculitic disorder affecting the arteries, veins, and vessels of any size. Large vein thrombosis in BD is not commonly developed and most commonly observed in the veins in the lower extremities and inferior or superior vena cava. In this report, a 18-year-old male patient with large vein thrombosis involving superior vena cava was presented. He was treated due to chylothorax and chylopericardium with SVC syndrome before diagnosis of BD. SVC thrombosis complicated by chylothorax and chyolpericardium can be a rare presenting initial symptom of BD.

Benign intercostal schwannoma mimicking a solitary metastasis from lung cancer

A 61-year-old woman who had suffered from cough and sputum was referred for the evaluation of chronic consolidation on the left lower lung (LLL). Before she visited our hospital, she had been taking antibiotics, having received a diagnoss of pneumonia. However, her symptoms and radiological consolidation on the LLL had not improved. Chest radiography showed a dense consolidation on the LLL. Chest CT scan revealed a diffused consolidation combined with ground glass opacity on the LLL and a 2×1.5 cm heterogeneously enhanced mass with a smooth margin on the left seventh intercostal space (figure 1A,B). A percutaneous needle biopsy of the consolidative lesion on the LLL was performed. Histological examination revealed malignant cells along the alveolar septa (figure 2A,B), and this finding was interpreted as bronchioloalveolar carcinoma. Figure 1 (A, B) CT scan of the chest showed …