Jae Seok Jeong

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.

Blockade of Interplay between IL-17A and Endoplasmic Reticulum Stress Attenuates LPS-Induced Lung Injury.

IL-17 is a cytokine mainly from IL-17-producing T cells, which are one of subsets of CD4+ T cells and play a role in adaptive immune system. Recent studies have demonstrated that IL-17A can act rapidly as an innate immune responder during infection before the onset of its classic adaptive immune response. This role of IL-17A in innate immune response is implicated in lipopolysaccharide (LPS)-induced lung inflammation. Very recently, we have reported that endoplasmic reticulum (ER) stress is involved in LPS-induced lung inflammation in vivo and in vitro. This study aimed to elucidate the role of IL-17A in LPS-induced lung injury, focusing on the link with ER stress. We treated a murine model of LPS-induced lung injury with IL-17A neutralizing antibody and 4-phenylbutyrate (4-PBA), a representative ER stress inhibitor. In addition, we evaluated the effects of IL-17A on ER stress in LPS-stimulated bronchial epithelial cells. Our results showed that inhibition of IL-17A decreased LPS-induced pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-κB (NF-κB), infiltration of dendritic cells, increased expression of Toll-like receptor 4 (TLR4), activation of NLRP3 inflammasome, and increased ER stress in the lung. 4-PBA or TAK-242, a TLR4 inhibitor attenuated expression of IL-17A thereby improving LPS-induced lung inflammation. Intriguingly, we observed that stimulation with LPS increased expression of IL-17A in airway epithelial cells and co-stimulation with IL-17A further increased ER stress and NF-κB activation. This study indicates that the interrelationship between IL-17A and ER stress plays an important role in LPS-induced injury showing a positive feedback in airway epithelial cells and suggests that targeting their interaction can be a potential therapeutic approach to overcome one of severe refractory pulmonary disorders.

PI3Kγ activation is required for LPS-induced reactive oxygen species generation in respiratory epithelial cells

ObjectiveIn this study, we investigated the molecular basis of reactive oxygen species (ROS) generation induced by lipopolysaccharide (LPS) in A549 cells—an alveolar epithelial cell line.Experimental designA549 cells or normal human bronchial epithelial (NHBE) cells were stimulated with LPS. ROS generation was measured in A549 cells or NHBE cells pre-treated with a selective inhibitor of phosphatidylinositol 3-kinase γ (PI3Kγ), AS 605240, PI3Kγ siRNA, or a ROS scavenger, pyridoxamine (PM).ResultsTreatment of A549 cells or NHBE cells with LPS caused a significant increase in intracellular ROS generation. Pretreatment with the PI3Kγ inhibitor, AS 605240 decreased the LPS-induced increase of ROS generation, phosphorylation of Akt, and production of phosphatidyl 3,4,5-trisphosphate in A549 cells. In addition, interference with siRNA for PI3Kγ significantly reduced LPS-induced ROS generation in A549 cells. Treatment of A549 cells with LPS or hydrogen peroxide increased the nuclear factor-κB (NF-κB) in the nucleus, accompanying an increase in phosphorylation of inhibitory κB-α, degradation of the protein, and reduction of cytosolic NF-κB. Pretreatment with AS 605240 reduced these LPS-induced changes. In addition, pretreatment with PM or N-acetyl cysteine resulted in inhibition of nuclear NF-κB activation.ConclusionThese results suggest that PI3Kγ plays a key role in LPS-induced ROS generation in alveolar epithelial cells, thereby activating NF-κB.

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.

A Fatal Case of Acute Respiratory Failure Caused by Mycobacterium massiliense

Few recent reports have indicated that Mycobacterium massiliense causes various infections including respiratory infection. However, there is scarce information on the clinical significance, natural history of the infection, and therapeutic strategy. This report describes a case of an immunocompetent old man infected by M. massiliense that causes acute respiratory failure. In light of the general courses of non-tuberculous mycobacterium infections, rapid progression and fatality are very rare and odd. In addition, we discuss the biological and pathological properties of M. massiliense with the review of cases reported previously including our fatal one.

Pulmonary metastatic chordoma improved by platinum-based chemotherapy

Chordomas are rare, low-grade, primary malignant bone tumors that are locally invasive and frequently recur. Despite the provision of radical excision as a primary treatment, local recurrences ultimately develop in most patients with chordoma. For these reasons, postoperative therapy such as radiation therapy is often required. However, the chemotherapy, as the treatment of chordoma relapse, has not only limited experiences but also considerable controversy on its effectiveness. In addition, in the case of pulmonary nodules, it is difficult to diagnose or suspect pulmonary metastatic chordoma initially due to its rarity and similar histologic features to other malignancies. Herein, we present an interesting case of metastatic chordoma in a 52-year old woman, which has been well controlled by platinum-based chemotherapy.

Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response

Background Respiratory fungal exposure is known to be associated with severe allergic lung inflammation. Airway epithelium is an essential controller of allergic inflammation. An innate immune recognition receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome, and phosphoinositide 3 kinase (PI3K)-δ in airway epithelium are involved in various inflammatory processes. Objectives We investigated the role of NLRP3 inflammasome in fungi-induced allergic lung inflammation and examined the regulatory mechanism of NLRP3 inflammasome, focusing on PI3K-δ in airway epithelium. Methods We used two in vivo models induced by exposure to Aspergillus fumigatus (Af) and Alternaria alternata (Aa), as well as an Af-exposed in vitro system. We also checked NLRP3 expression in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA). Results Assembly/activation of NLRP3 inflammasome was increased in the lung of Af-exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in Af-stimulated murine and human epithelial cells. Similarly, pulmonary expression of NLRP3 in patients with ABPA was increased. Importantly, neutralisation of NLRP3 inflammasome derived IL-1β alleviated pathophysiological features of Af-induced allergic inflammation. Furthermore, PI3K-δ blockade improved Af-induced allergic inflammation through modulation of NLRP3 inflammasome, especially in epithelial cells. This modulatory role of PI3K-δ was mediated through the regulation of mitochondrial reactive oxygen species (mtROS) generation. NLRP3 inflammasome was also implicated in Aa-induced eosinophilic allergic inflammation, which was improved by PI3K-δ blockade. Conclusion These findings demonstrate that fungi-induced assembly/activation of NLRP3 inflammasome in airway epithelium may be modulated by PI3K-δ, which is mediated partly through the regulation of mtROS generation. Inhibition of PI3K-δ may have potential for treating fungi-induced severe allergic lung inflammation.

Endoplasmic Reticulum Stress and Allergic Diseases

Purpose of ReviewIn this review, we will integrate recent knowledge on endoplasmic reticulum (ER) stress and allergy, thereby highlighting the therapeutic potential of ER stress in the context of precision medicine for allergic diseases.Recent FindingsEmerging evidence suggests that allergic diseases are very heterogeneous having numerous endotypes. This leads to the new era of modern medicine, which assumes that a particular endotype-driven therapy, called precision medicine, would be more efficacious in a specific group of patients rather than in all patients. Currently, a dichotomy involving type 2/non-type 2 immune response underlies most of the studies on inflammatory and immunologic mechanisms of allergic disorders. Whereas there are several approved or investigational endotype-driven therapeutic agents targeting type 2 immune responses, investigation of mechanisms and endotype-driven interventions regarding non-type 2 immune response lags far behind.SummaryConsidering that non-type 2 immune response may represent a significant proportion of allergic disease, particularly corticosteroid-resistant severe disease, defining a novel concept of endotype-driven approach may be essential. Recently, stress responses originate from the endoplasmic reticulum (ER) and the associated inflammatory molecular platform has been suggested as a crucial player of immune and inflammatory responses. This implies that ER stress-related pathways may represent a new endotype-driven therapeutic strategy in the treatment of allergic diseases.

A Case Report of Mass-Forming Aspergillus Tracheobronchitis Successfully Treated with Voriconazole.

AbstractAspergillus tracheobronchitis (ATB) represents a rare disease entity accounting for 3.5% to 5.0% of cases of invasive aspergillosis. Particularly, mass-forming ATB is extremely rare, and clinical reports are limited. Given that the patency of the trachea and bronchi are essential for maintaining sufficient airflow, a central airway mass originating from an Aspergillus infection is likely to be associated with severe clinical manifestations and fatal outcomes. Although several therapeutic options for ATB have been suggested, including medication and airway interventions, the optimal choice of treatment in diverse clinical conditions remains under discussion.We report a case of ATB that initially manifested as severe dyspnea and total atelectasis of the left lung in a patient with newly detected diabetes.Radiographic study, bronchoscopy, and pathologic findings of the lesion revealed mass-forming type of ATB.Interestingly, our patients symptoms dramatically resolved with voriconazole without further invasive intervention.This clinical experience highlights the beneficial role of voriconazole in the treatment of rare and potentially fatal cases of ATB.