Seung Yong Park

Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-κB/HIF-1α signaling pathway

Lipopolysaccharide (LPS) is involved in a variety of inflammatory disorders. Under stress conditions, endoplasmic reticulum (ER) loses the homeostasis in its functions, which is defined as ER stress. Little is known how ER stress is implicated in LPS-induced lung inflammation. In this study, effects of inhibition of ER stress on LPS-induced lung inflammation and transcriptional regulation were examined. An ER stress regulator, 4-phenylbutyrate (PBA) reduced LPS-induced increases of various ER stress markers in the lung. Furthermore, inhibition of ER stress reduced the LPS-induced lung inflammation. Moreover, LPS-induced increases of NF-κB and HIF-1α activity were lowered by inhibition of ER stress. These results suggest that inhibition of ER stress ameliorates LPS-induced lung inflammation through modulation of NF-κB/IκB and HIF-1α signaling pathway.

Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation

BACKGROUND Despite many studies on endoplasmic reticulum (ER) stress in patients with various inflammatory diseases, there is scarce information on ER stress in patients with bronchial asthma. OBJECTIVE In this study we aimed to elucidate the role of ER stress in the pathogenesis of bronchial asthma. METHODS Using mice sensitized with ovalbumin (OVA) and LPS and challenged with OVA (OVA(LPS)-OVA mice), as well as mice sensitized and challenged with OVA (OVA-OVA mice), we investigated whether ER stress is involved in the pathogenesis of bronchial asthma. Moreover, we also determined the levels of ER stress markers in blood and bronchoalveolar lavage fluid from asthmatic patients. RESULTS The OVA(LPS)-OVA mice showed that the expression of ER stress markers and the protein levels of unfolded protein response-related markers in lung tissue were significantly increased after OVA challenge. Moreover, we found that ER stress markers in PBMCs and bronchoalveolar lavage fluid from human asthmatic patients were dramatically increased compared with those from healthy control subjects. In OVA(LPS)-OVA mice 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced the increases in ER stress, nuclear translocation of nuclear factor κB, inflammatory cytokine levels, dendritic cell infiltration, Toll-like receptor 4 expression, airway inflammation, and bronchial hyperresponsiveness, whereas it further enhanced the increase in IL-10 levels. Additionally, the established asthmatic features of OVA-OVA mice were substantially attenuated by 4-PBA administered after completion of OVA challenge. CONCLUSION These results indicate that ER stress might be implicated in the pathogenesis of bronchial asthma at least in part through modulation of nuclear factor κB activation.

Mast Cells Can Mediate Vascular Permeability through Regulation of the PI3K–HIF-1α–VEGF Axis

RATIONALE Bronchial inflammation is usually accompanied by increased vascular permeability. Mast cells release a number of mediators that act directly on the vasculature, resulting in vasodilatation, increased permeability, and subsequent plasma protein extravasation. Vascular endothelial growth factor (VEGF) has been implicated to contribute to asthmatic tissue edema through its effect on vascular permeability. However, the effects of mast cells on VEGF-mediated signaling in allergic airway disease are not clearly understood. OBJECTIVES An aim of the present study was to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease. METHODS We used genetically mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-v) (W/W(v)) mice and the congenic normal WBB6F(1)(+/+) mouse model for allergic airway disease to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease, more specifically in vascular permeability. MEASUREMENTS AND MAIN RESULTS Our present study, with ovalbumin (OVA)-sensitized without adjuvant and OVA-challenged mice, revealed the following typical pathophysiologic features of allergic airway diseases: increased inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of VEGF. However, levels of VEGF and plasma exudation in W/W(v) mice after OVA inhalation were significantly lower than levels in WBB6F(1)(+/+) mice. Moreover, mast cell-reconstituted W/W(v) mice restored vascular permeability and VEGF levels similar to those of the WBB6F(1)(+/+) mice. Our data also showed that VEGF expression was regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) activation through the phosphatidylinositol 3-kinase (PI3K)-HIF-1alpha pathway in allergic airway disease. CONCLUSIONS These results suggest that mast cells modulate vascular permeability by the regulation of the PI3K-HIF-1alpha-VEGF axis.

Change of connexin 37 in allergen-induced airway inflammation.

Gap junction channels formed with connexins directly link to the cytoplasm of adjacent cells and have been implicated in intercellular signaling. Connexin 37 (Cx37) is expressed in the gas-exchange region of the lung. Recently, Cx37 has been reported to be involved in the pathogenesis of inflammatory disease. However, no data are available on the role of Cx37 in allergic airway inflammatory disease. In the present study, we used a murine model of ovalbumin (OVA)-induced allergic airway disease and primary murine epithelial cells to examine the change of Cx37 in allergic airway disease. These mice develop the following typical pathophysiological features of asthma: airway hyperresponsiveness, airway inflammation, and increased IL-4, IL-5, IL-13, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, eotaxin, and RANTES levels in lungs. Cx37 protein and mRNA expression were decreased in OVA-induced allergic airway disease. Immunoreactive Cx37 localized in epithelial layers around the bronchioles in control mice, which dramatically disappeared in allergen-induced asthmatic lungs. Moreover, the levels of Cx37 protein in lung tissues showed significantly negative correlations with airway inflammation, airway responsiveness, and levels of Th2 cytokines in lungs. These findings indicate that change of Cx37 may be associated with the asthma phenotype.

l-2-Oxothiazolidine-4-Carboxylic Acid or α-Lipoic Acid Attenuates Airway Remodeling: Involvement of Nuclear Factor-κB (NF-κB), Nuclear Factor Erythroid 2p45-Related Factor-2 (Nrf2), and Hypoxia-Inducible Factor (HIF)

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.

Extra-Axial Chordoma Presenting as a Lung Mass

Chordomas are slow-growing, malignant tumors of bone that are thought to be derived from the primitive notochord and occur almost exclusively in the axial skeleton. The so-called extra-axial chordoma has been shown to demonstrate identical features to the classic chordoma, except that it is found outside the axial skeleton. Only six cases of extra-axial chordoma have been reported in the literature to date. In this report, we present another case of extra-axial chordoma for the first time originating from the lung parenchyma. A 79-year-old man presented a 7.3-cm-sized cavitary lung mass. Pathologic examination, including immunohistochemical studies, revealed that the mass was a chordoma. We report an extra-axial chordoma for the first time presenting as a lung mass.

Acute necrotizing pneumonia combined with parapneumonic effusion caused by Mycobacterium lentiflavum: a case report

BackgroundMycobacterium lentiflavum (M. lentiflavum), a slow growing nontuberculous mycobacterium (NTM), has recently been described as an emerging human pathogen regardless of the immune status of the host. Previous reports have demonstrated that cervical lymphadenitis of children is the most frequent pathology of M. lentiflavum. However, there are little reports regarding pulmonary diseases by M. lentiflavum specifically in immunocompetent patients.Case presentationA 60-year-old man having prolonged productive cough and dyspnea with fever was initially diagnosed as pneumonia with parapneumonic effusion. Imaging studies showed that the radiologic abnormality was acute bronchopneumonic infiltration with abscess formation in the left lower lobe and parapneumonic pleural effusion. M. lentiflavum was identified in the cultured pleural tissues. On the basis of these findings, he was diagnosed as pulmonary infection and pleurisy caused by M. lentiflavum, which was treated with a combination of antibiotics covering NTM. His clinical manifestations were dramatically improved by the treatment targeting NTM, while those were refractory to empirical antibiotic therapy.ConclusionIn this report, we introduce the isolation of M. lentiflavum from pleural tissues associated with acute necrotizing pneumonia combined with parapneumonic effusion in an immunocompetent host, suggesting that the M. lentiflavum can be a human pathogen invovled in pulmonary infectious diseases and pleurisy with poor response to empirical antibiotic treatment.

Tonsillar metastasis of small cell lung cancer in a patient with idiopathic pulmonary fibrosis: a case report.

AbstractSmall cell lung cancer (SCLC) metastasizes widely, but palatine tonsil is an extremely unusual site for metastasis. Idiopathic pulmonary fibrosis (IPF) is associated with increased risk of lung cancer. However, the most common histological findings among patients of lung cancer with IPF are known as non-SCLC such as adenocarcinoma and squamous cell carcinoma. In addition, the majority of them are located in IPF-associated fibrotic peripheral lesions.A 77-year-old man visited for 1-month persistent cough and dyspnea, with inspiratory dry crackles on both lower lung fields and a large oval mass in his throat. Chest computed tomography revealed 2 masses in the left lower lobe, 1 mass in the right upper lobe, and multiple enlarged mediastinal lymph nodes of the lung accompanying with IPF, which were diagnosed as SCLC pathologically. Very interestingly, the tonsillar mass was also confirmed as the metastatic lesion of SCLC. Chemotherapy for SCLC and medical treatment for IPF were applied. However, in following-up, he expired due to respiratory failure by an acute exacerbation of IPF 3 months after the diagnosis.In this current report, we describe, for the first time, a case of tonsillar metastasis of SCLC with IPF detected simultaneously in a 77-year-old man.

Application of whole-body MRI to detect the recurrence of lung cancer

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.

A Case of Primary Pulmonary Lymphoepithelioma-like Carcinoma Misdiagnosed as Adenocarcinoma.

Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is rare, with a more favorable prognosis compared with that of other types of non-small cell lung cancers. Herein, we describe an interesting case of primary pulmonary LELC confirmed postoperatively, which had been initially diagnosed as poorly differentiated adenocarcinoma. We suggest that despite the rarity of pulmonary LELC, it should be included as one of the differential diagnoses for lung malignancies. Physicians should consider taking a larger biopsy, especially when histologic examination shows undifferentiated nature.