Publications by authors named "Yong Chul Lee"

165 Publications

Septal deviation could be associated with the development of bronchial asthma: a nationwide cohort study.

J Allergy Clin Immunol Pract 2021 Nov 12. Epub 2021 Nov 12.

Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea; Department of Internal Medicine, Research Center for Pulmonary Disorders, Jeonbuk National University Medical School, Jeonju, South Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2021.11.002DOI Listing
November 2021

Sequential afatinib and osimertinib in patients with EGFR mutation-positive NSCLC and acquired T790M: A global non-interventional study (UpSwinG).

Lung Cancer 2021 Sep 21;162:9-15. Epub 2021 Sep 21.

Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan. Electronic address:

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance.

Methods: In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR).

Results: At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.

Conclusion: Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.009DOI Listing
September 2021

COPD is a risk factor for COVID-19, but does not confer increased severity of the disease.

Respir Med 2021 Oct 5;189:106640. Epub 2021 Oct 5.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Jeonbuk National University Medical School, Jeonju, South Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea. Electronic address:

Epidemiologic studies suggest that COPD is associated with an increased risk of poor outcome in patients with COVID-19, although they failed to demonstrate COPD as a risk factor for acquiring COVID-19. However, most data have come from a limited global population. In this nationwide cohort study based on the Korean national health insurance claims-based database, COPD is associated with increased risk for COVID-19 and having COPD does not seem to confer substantial risk for severe COVID-19 and mortality. These findings indicate that heterogeneity in the populations across many countries may complicate the net effects of COPD on the COVID-19-related outcomes.
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http://dx.doi.org/10.1016/j.rmed.2021.106640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492002PMC
October 2021

An Unusual Manifestation of Rapidly Progressing Granulomatosis with Polyangiitis Involving Uterine Adnexa and Lung.

Am J Respir Crit Care Med 2021 06;203(11):1431-1432

Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Research Center for Pulmonary Disorders, and.

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http://dx.doi.org/10.1164/rccm.202001-0118IMDOI Listing
June 2021

A Mediastinal Cyst With Mullerian Differentiation in a Patient With an Ovarian Cyst.

Ann Thorac Surg 2020 11 12;110(5):e457. Epub 2020 Jun 12.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, South Korea. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2020.04.099DOI Listing
November 2020

Roles of PI3K pan-inhibitors and PI3K-δ inhibitors in allergic lung inflammation: a systematic review and meta-analysis.

Sci Rep 2020 05 6;10(1):7608. Epub 2020 May 6.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea.

Meta-analysis can be applied to study the effectiveness of the summary estimates for experimental papers, producing objective and unbiased results. We investigated the effects of phosphoinositide-3-kinase (PI3K) on the inflammatory profile in allergic mouse models, which are currently under development in signal transduction materials. PubMed, EMBASE and Web of Science databases were searched for relevant literature using the search terms " PI3K inhibitor" and "allergy" or "asthma". Cochrane Review Manager and R were used for handling continuous variables. The primary outcomes of the inflammatory profile were divided into cell counts and inflammatory cytokines. We used a random effects model to draw a forest plot. Through the database search and subsequent selection, 17 articles were identified. Regarding the cell counts, both the PI3K pan-inhibitors and PI3K-δ inhibitors effectively reduced the total cell counts, eosinophils, neutrophils and lymphocytes. In contrast to PI3K-δ inhibitors, PI3K pan-inhibitors effectively reduced macrophages. Regarding the inflammatory cytokines, PI3K pan-inhibitors and PI3K-δ inhibitors effectively reduced total IgE, IL-4, IL-5, IL-13, TNF-α, IL-1β, VEGF and had no effect on IL-6. Compared to the PI3K pan-inhibitors, which block all pathways, selective PI3K-δ inhibitors are expected to be relatively less toxic. Regarding the efficacy, PI3K-δ inhibitors have at least the same or better efficacy than PI3K pan-inhibitors in effector cells and inflammatory mediators.
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http://dx.doi.org/10.1038/s41598-020-64594-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203230PMC
May 2020

Epithelial PI3K-δ Promotes House Dust Mite-Induced Allergic Asthma in NLRP3 Inflammasome-Dependent and -Independent Manners.

Allergy Asthma Immunol Res 2020 03;12(2):338-358

Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea.

Purpose: Phosphoinositide 3-kinase (PI3K)-δ-dependent Akt activation is known to play critical roles in various immune responses of white blood cells in which PI3K-δ isoform is mostly expressed in contrast to the classes IA PI3Ks p110α and p110β. However, the immunological role of PI3K-δ isoform is still controversial in airway epithelium under house dust mite (HDM)-induced allergic response. This study aimed to evaluate the role of PI3K-δ isoform in HDM-induced allergic responses, focusing on NLRP3 inflammasome activation in airway epithelium.

Methods: We used wild-type mice and PI3K-δ knock-out (KO) mice for HDM-induced asthma animal model and also performed experiments using primary cultured murine tracheal epithelial cells and human airway epithelial cells.

Results: PI3K-δ activated HDM-induced NLRP3 inflammasome and epithelial cell-derived cytokines in the lung including airway epithelial cells. PI3K-δ KO mice or knock-down of PI3K-δ using siRNA exhibited the significant reduction in allergic asthmatic features and the suppression of NLRP3 inflammasome assembly as well as epithelial cell-derived cytokines. Interestingly, significantly increased expression of PI3K-δ isoform was observed in stimulated airway epithelial cells and the increases in epithelial cell-derived cytokines were markedly suppressed by blocking PI3K-δ, while these cytokine levels were independent of NLRP3 inflammasome activation.

Conclusions: The results of this study suggest that PI3K-δ-isoform can promote HDM-induced allergic airway inflammation via NLRP3 inflammasome-dependent response as well as via NLRP3 inflammasome-independent epithelial cell activation.
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http://dx.doi.org/10.4168/aair.2020.12.2.338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997282PMC
March 2020

Phosphatidylinositol 3-kinase-δ controls endoplasmic reticulum membrane fluidity and permeability in fungus-induced allergic inflammation in mice.

Br J Pharmacol 2020 04 27;177(7):1556-1567. Epub 2020 Jan 27.

Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School, Jeonju, Republic of Korea.

Background And Purpose: Phosphatidylinositol 3-kinase (PI3K), especially PI3K-δ, and endoplasmic reticulum (ER) stress play important roles in refractory asthma induced by the fungus Aspergillus fumigatus through mechanisms that are not well understood. Here we have investigated these mechanisms, using BEAS-2B human bronchial epithelial cells and a mouse model of A. fumigatus-induced allergic lung inflammation.

Experimental Approach: A selective PI3K-δ inhibitor, IC87114, and an ER folding chaperone, 4-phenylbutyric acid (4-PBA), were applied to a model of A. fumigatus-induced asthma in female C57BL/6 mice. The therapeutic potential of IC87114 and 4-PBA was assessed in relevant primary cell, tissue, and disease models, using immunohistochemistry, western blotting and assessment of ER redox state and membrane fluidity.

Key Results: Treatment with IC87114 or 4-PBA alleviated pulmonary inflammation and airway remodelling and reduced ER stress and inflammation-associated intra-ER hyperoxidation, disrupting protein disulfide isomerase (PDI) chaperone activity. IC87114 and 4-PBA also reversed changes in ER membrane fluidity and permeability and the resultant mitochondrial hyperactivation (i.e., Ca accumulation) under hyperoxidation, thereby restoring the physiological state of the ER and mitochondria. These compounds also abolished mitochondria-associated ER membrane (MAM) formation caused by the physical contact between these subcellular organelles.

Conclusion And Implications: PI3K-δ and ER stress mediate A. fumigatus-induced allergic lung inflammation by altering the ER redox state, PDI chaperone function, and ER membrane fluidity and permeability and by amplifying ER signalling to mitochondria through MAM formation. Thus, therapeutic strategies that target the PI3K-δ-ER stress axis could be an effective treatment for allergic asthma caused by fungi.
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http://dx.doi.org/10.1111/bph.14917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060358PMC
April 2020

Defining Bronchial Asthma with Phosphoinositide 3-Kinase Delta Activation: Towards Endotype-Driven Management.

Int J Mol Sci 2019 Jul 18;20(14). Epub 2019 Jul 18.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju 54907, Korea.

Phosphoinositide 3-kinase (PI3K) pathways play a critical role in orchestrating the chronic inflammation and the structural changes of the airways in patients with asthma. Recently, a great deal of progress has been made in developing selective and effective PI3K-targeted therapies on the basis of a vast amount of studies on the roles of specific PI3K isoforms and fine-tuned modulators of PI3Ks in a particular disease context. In particular, the pivotal roles of delta isoform of class I PI3Ks (PI3K-δ) in CD4-positive type 2 helper T cells-dominant disorders such as asthma have been consistently reported since the early investigations. Furthermore, there has been great advancement in our knowledge of the implications of PI3K-δ in various facets of allergic inflammation. This has involved the airway epithelial interface, adaptive T and B cells, potent effector cells (eosinophils and neutrophils), and, more recently, subcellular organelles (endoplasmic reticulum and mitochondria) and cytoplasmic innate immune receptors such as NLRP3 inflammasome, all of which make this PI3K isoform an important druggable target for treating asthma. Defining subpopulations of asthma patients with PI3K-δ activation, namely PI3K-δ-driven asthma endotype, may therefore provide us with a novel framework for the treatment of the disease, particularly for corticosteroid-resistant severe form, an important unresolved aspect of the current asthma management. In this review, we specifically summarize the recent advancement of our knowledge on the critical roles of PI3K-δ in the pathogenesis of bronchial asthma.
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http://dx.doi.org/10.3390/ijms20143525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679152PMC
July 2019

Association between Expression of 8-OHdG and Cigarette Smoking in Non-small Cell Lung Cancer.

J Pathol Transl Med 2019 Jul 11;53(4):217-224. Epub 2019 Mar 11.

Department of Pathology, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital, Research Institute for Endocrine Sciences, Chonbuk National University Medical School, Jeonju, Korea.

Background: Exposure to cigarette smoking (CS) is a major risk factor for the development of lung cancer. CS is known to cause oxidative DNA damage and mutation of tumor-related genes, and these factors are involved in carcinogenesis. 8-Hydroxydeoxyguanosine (8-OHdG) is considered to be a reliable biomarker for oxidative DNA damage. Increased levels of 8-OHdG are associated with a number of pathological conditions, including cancer. There are no reports on the expression of 8-OHdG by immunohistochemistry in non-small cell lung cancer (NSCLC).

Methods: We investigated the expression of 8-OHdG and p53 in 203 NSCLC tissues using immunohistochemistry and correlated it with clinicopathological features including smoking.

Results: The expression of 8-OHdG was observed in 83.3% of NSCLC. It was significantly correlated with a low T category, negative lymph node status, never-smoker, and longer overall survival (p < .05) by univariate analysis. But multivariate analysis revealed that 8-OHdG was not an independent prognostic factor for overall survival in NSCLC patients. The aberrant expression of p53 significantly correlated with smoking, male, squamous cell carcinoma, and Ki-67 positivity (p < .05).

Conclusions: The expression of 8-OHdG was associated with good prognostic factors. It was positively correlated with never-smokers in NSCLC, suggesting that oxidative damage of DNA cannot be explained by smoking alone and may depend on complex control mechanisms.
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http://dx.doi.org/10.4132/jptm.2019.02.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639704PMC
July 2019

A Novel Insight on Endotyping Heterogeneous Severe Asthma Based on Endoplasmic Reticulum Stress: Beyond the "Type 2/Non-Type 2 Dichotomy".

Int J Mol Sci 2019 Feb 7;20(3). Epub 2019 Feb 7.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju 54907, Korea.

Severe asthma is an extremely heterogeneous clinical syndrome in which diverse cellular and molecular pathobiologic mechanisms exist, namely endotypes. The current system for endotyping severe asthma is largely based on inflammatory cellular profiles and related pathways, namely the dichotomy of type 2 response (resulting in eosinophilic inflammation) and non-type 2 response (reinforcing non-eosinophilic inflammation involving neutrophils or less inflammatory cells), forming the basis of a development strategy for novel therapies. Although specific subgroups of type 2 severe asthma patients may derive benefit from modern precision medicine targeting type 2 cytokines, there is no approved and effective therapeutic agent for non-type 2 severe asthma, which comprises nearly 50% of all asthma patients. Importantly, the critical implication of endoplasmic reticulum (ER) stress and unfolded protein response-in close relation with several pivotal cellular immune/inflammatory platforms including mitochondria, NLRP3 inflammasome, and phosphoinositide 3-kinase-δ-in the generation of corticosteroid resistance is now being increasingly demonstrated in numerous experimental settings of severe asthma. Consistent with these findings, recent clinical data from a large European severe asthma cohort, in which molecular phenotyping as well as diverse clinical and physiological parameters from severe asthmatic patients were incorporated, suggest a brand new framework for endotyping severe asthma in relation to ER-associated mitochondria and inflammasome pathways. These findings highlight the view that ER stress-associated molecular pathways may serve as a unique endotype of severe asthma, and thus present a novel insight into the current knowledge and future development of treatment to overcome corticosteroid resistance in heterogeneous severe asthma.
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http://dx.doi.org/10.3390/ijms20030713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386842PMC
February 2019

Phosphoinositide 3-kinase-delta could be a biomarker for eosinophilic nasal polyps.

Sci Rep 2018 10 30;8(1):15990. Epub 2018 Oct 30.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea.

Nasal polyps (NP) cause diverse clinical symptoms of chronic rhinosinusitis (CRS). Chronic inflammation of sinonasal mucosa is known to be crucial in NP formation. We aimed to define the implications of phosphoinositide 3-kinase (PI3K)-δ in nasal inflammation associated with NP by analyzing NP tissue obtained from CRS patients. Results showed that expression of p110δ, a regulatory subunit of PI3K-δ, in NP tissue was increased compared to control tissue. Increased p110δ expression was closely correlated with more severe CRS features. Interestingly, p110δ expression was increased in eosinophilic NP, which are closely related to more complicated clinical courses of the disease. Furthermore, CRS patients possessing NP with higher p110δ expression displayed more eosinophils in NP tissue and blood, higher levels of IL-5 in NP tissue, and more severe features of the disease. Therefore, PI3K-δ may contribute to the formation of NP, especially eosinophilic NP associated with more severe clinical presentations and radiological features.
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http://dx.doi.org/10.1038/s41598-018-34345-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207677PMC
October 2018

Combined expression of protein disulfide isomerase and endoplasmic reticulum oxidoreductin 1-α is a poor prognostic marker for non-small cell lung cancer.

Oncol Lett 2018 Nov 21;16(5):5753-5760. Epub 2018 Aug 21.

Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine and Research Institute for Endocrine Sciences of Chonbuk National University, Jeonju, Jeonbuk 54907, Republic of Korea.

Protein disulfide isomerase (PDI) is one of the most abundant proteins in the endoplasmic reticulum (ER) and is known as a primary ER resident target of cigarette smoke-induced oxidation. PDI dysfunction triggers unfolded protein response and ER stress. Endoplasmic reticulum oxidoreductin 1-α (ERO1A) is a major regulator of PDI, and recent evidence implicates PDI and ERO1A as tumor prognostic factors. However, the associated role of PDI and ERO1A and their prognostic impact in non-small cell lung cancers (NSCLCs) remains unknown. The present study investigated the expression of PDI and ERO1A using immunohistochemistry and examined its association with smoking status and their prognostic impact in 198 NSCLCs. PDI and ERO1A expression were observed in 71.2 and 69.2% of NSCLCs, respectively, and their expressions were significantly associated with each other (P<0.001). Individual PDI (P=0.001) and ERO1A (P=0.005) expression were significantly associated with shorter overall survival (OS) in univariate analysis. PDI expression was significantly associated with never smoking (P=0.003). PDI expression (P<0.001) and the co-expression of PDI and ERO1A (P<0.001) were independent poor prognostic factors for OS in patients with NSCLC in multivariate analysis. Individual expression and co-expression of PDI and ERO1A may be used as novel prognostic indicators of NSCLC outcome.
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http://dx.doi.org/10.3892/ol.2018.9339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176373PMC
November 2018

Endobronchial Mucormycosis Successfully Treated with Flexible Bronchoscopic Cryotherapy.

Am J Respir Crit Care Med 2018 08;198(3):387-389

Division of Respiratory Medicine and Allergy, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, South Korea; and.

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http://dx.doi.org/10.1164/rccm.201708-1581IMDOI Listing
August 2018

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

Thorax 2018 08 5;73(8):758-768. Epub 2018 Apr 5.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea.

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 () and (), as well as an -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 -exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in -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 -induced allergic inflammation. Furthermore, PI3K-δ blockade improved -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 -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.
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http://dx.doi.org/10.1136/thoraxjnl-2017-210326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204980PMC
August 2018

PI3Kδ contributes to ER stress-associated asthma through ER-redox disturbances: the involvement of the RIDD-RIG-I-NF-κB axis.

Exp Mol Med 2018 02 16;50(2):e444. Epub 2018 Feb 16.

Department of Pharmacology and Institute of New Drug Development, School of Medicine, Chonbuk National University, Jeonju, Republic of Korea.

Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3Kδ inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model. In OVA/LPS-induced asthmatic mice, the activity of PI3K, downstream phosphorylation of AKT and activation of nuclear factor-κB (NF-κB) were all significantly elevated; these effects were reversed by IC87114. IC87114 treatment also reduced the OVA/LPS-induced ER stress response by enhancing the intra-ER oxidative folding status through suppression of protein disulfide isomerase activity, ER-associated reactive oxygen species (ROS) accumulation and NOX4 activity. Furthermore, inositol-requiring enzyme-1α (IRE1α)-dependent degradation (RIDD) of IRE1α was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kδ may induce severe airway inflammation and hyperresponsiveness by activating NF-κB signaling through ER-associated ROS and RIDD-RIG-I activation. The PI3Kδ inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma.
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http://dx.doi.org/10.1038/emm.2017.270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903822PMC
February 2018

Can Controlling Endoplasmic Reticulum Dysfunction Treat Allergic Inflammation in Severe Asthma With Fungal Sensitization?

Allergy Asthma Immunol Res 2018 Mar;10(2):106-120

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea.

Severe asthma is a heterogeneous disease entity to which diverse cellular components and pathogenetic mechanisms contribute. Current asthma therapies, including new biologic agents, are mainly targeting T helper type 2 cell-dominant inflammation, so that they are often unsatisfactory in the treatment of severe asthma. Respiratory fungal exposure has long been regarded as a precipitating factor for severe asthma phenotype. Moreover, as seen in clinical definitions of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS), fungal allergy-associated severe asthma phenotype is increasingly thought to have distinct pathobiologic mechanisms requiring different therapeutic approaches other than conventional treatment. However, there are still many unanswered questions on the direct causality of fungal sensitization in inducing severe allergic inflammation in SAFS. Recently, growing evidence suggests that stress response from the largest organelle, endoplasmic reticulum (ER), is closely interconnected to diverse cellular immune/inflammatory platforms, thereby being implicated in severe allergic lung inflammation. Interestingly, a recent study on this issue has suggested that ER stress responses and several associated molecular platforms, including phosphoinositide 3-kinase-δ and mitochondria, may be crucial players in the development of severe allergic inflammation in the SAFS. Defining emerging roles of ER and associated cellular platforms in SAFS may offer promising therapeutic options in the near future.
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http://dx.doi.org/10.4168/aair.2018.10.2.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809759PMC
March 2018

Endobronchial epithelial-myoepithelial carcinoma of the lung.

Thorax 2018 06 1;73(6):593-594. Epub 2017 Dec 1.

Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, Korea.

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http://dx.doi.org/10.1136/thoraxjnl-2017-211155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969340PMC
June 2018

Endoplasmic Reticulum Stress and Allergic Diseases.

Curr Allergy Asthma Rep 2017 Nov 8;17(12):82. Epub 2017 Nov 8.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, san 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea.

Purpose Of Review: In 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 Findings: Emerging 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. Considering 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.
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http://dx.doi.org/10.1007/s11882-017-0751-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683051PMC
November 2017

Benign metastasizing leiomyoma presenting as multiple cystic pulmonary nodules: a case report.

BMC Womens Health 2017 Sep 12;17(1):81. Epub 2017 Sep 12.

Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, Jeonbuk, 561-180, South Korea.

Background: Benign metastatic leiomyoma (BML) is an extremely rare disease. Although uterine leiomyomas are benign histologically, they can metastasize to distant sites. While the incidence is very low, the lung is the organ most frequently affected by BML. Pulmonary BML usually presents as numerous well-defined nodules of various sizes, while the cavitary or cystic features in the nodules are rarely observed on radiologic images.

Case Presentation: A 52-year-old woman complained of cough and dyspnea for one month. She had been previously diagnosed with uterine leiomyoma and had undergone total hysterectomy about 14 years prior. High-resolution computed tomography (CT) images showed that there were multiple cystic nodules of various sizes in both lungs. Pathologic examination revealed that the pulmonary nodule had complex branching glandular structures lined by a single layer of simple cuboidal to columnar epithelium that was surrounded by abundant spindle cells. Additional immunohistochemistry data suggested that pulmonary nodule diagnosis was BML-associated uterine leiomyoma.

Conclusion: In this report, we introduce an interesting case of pulmonary BML that presented as a combination of various kinds of nodules including simple round nodules, simple cysts, and cysts with a solid portion, which are very rare radiologic features of BML in lung. In addition, when the patient is a woman of reproductive age, physicians should meticulously review the gynecological history and suspect BML when there are various cystic pulmonary lesions.
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http://dx.doi.org/10.1186/s12905-017-0435-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596933PMC
September 2017

Current Epidemiological Data on Asthma Management in South Korea from Qualitative Assessment of Asthma Management by Health Insurance Review and Assessment Service (HIRA).

Tuberc Respir Dis (Seoul) 2017 Jul 3;80(3):221-225. Epub 2017 Jul 3.

Health Insurance Review & Assessment Service, Wonju, Korea.

Since 2015, the Health Insurance Review and Assessment Service (HIRA) has performed annual qualitative assessments of asthma management provided by all medical institutions that care for asthma patients in Korea. According to the third report of qualitative assessment of asthma management in 2017, the assessment appears to have contributed to improving the quality of asthma care provided by medical institutions, especially primary clinics. However, there is still a gap between the ideal goals of asthma management and actual health care policies/regulations in real clinical settings, which leads to the state of standstill with respect to the quality of asthma management despite considerable efforts such as the qualitative assessment of asthma management by national agencies such as the HIRA. At this point, a harmonized approach is needed to raise the level of asthma management among several components including medical policies, efforts of academic associations such as education and distribution of the guideline for management, and reliable financial support by the government.
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http://dx.doi.org/10.4046/trd.2017.80.3.221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526947PMC
July 2017

Curcumin and Curcuma longa L. extract ameliorate lipid accumulation through the regulation of the endoplasmic reticulum redox and ER stress.

Sci Rep 2017 07 26;7(1):6513. Epub 2017 Jul 26.

Department of Pharmacology and New Drug Development Institute, Chonbuk National University Medical School, Jeonju, Chonbuk, 561-180, Republic of Korea.

For this study, we examined the effects of curcumin against acute and chronic stress, paying specific attention to ROS. We also aimed to clarify the differences between acute and chronic stress conditions. We investigated the effects of curcumin against acute stress (once/1 day CCl treatment) and chronic-stress (every other day/4week CCl treatment). Compared with acute stress, in which the antioxidant system functioned properly and aspartate transaminase (AST) and ROS production increased, chronic stress increased AST, alanine aminotransferase (ALT), hepatic enzymes, and ROS more significantly, and the antioxidant system became impaired. We also found that ER-originated ROS accumulated in the chronic model, another difference between the two conditions. ER stress was induced consistently, and oxidative intra-ER protein folding status, representatively PDI, was impaired, especially in chronic stress. The PDI-associated client protein hepatic apoB accumulated with the PDI-binding status in chronic stress, and curcumin recovered the altered ER folding status, regulating ER stress and the resultant hepatic dyslipidemia. Throughout this study, curcumin and curcumin-rich Curcuma longa L. extract promoted recovery from CCl-induced hepatic toxicity in both stress conditions. For both stress-associated hepatic dyslipidemia, curcumin and Curcuma longa L. extract might be recommendable to recover liver activity.
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http://dx.doi.org/10.1038/s41598-017-06872-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529367PMC
July 2017

Coexistence of Mediastinal Castleman Disease with Spindle Cell Carcinoma of the Lung.

Am J Respir Crit Care Med 2017 09;196(5):652-654

1 Department of Internal Medicine and Research Center for Pulmonary Disorders and.

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http://dx.doi.org/10.1164/rccm.201701-0202IMDOI Listing
September 2017

Inhaled indacaterol for the treatment of COPD patients with destroyed lung by tuberculosis and moderate-to-severe airflow limitation: results from the randomized INFINITY study.

Int J Chron Obstruct Pulmon Dis 2017 29;12:1589-1596. Epub 2017 May 29.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background And Objective: Pulmonary tuberculosis (TB) is a risk factor for chronic obstructive pulmonary disease (COPD); however, few clinical studies have investigated treatment effectiveness in COPD patients with destroyed lung by TB. The Indacaterol effectiveness in COPD patients with Tuberculosis history (INFINITY) study assessed the efficacy and safety of once-daily inhaled indacaterol 150 µg for the treatment of Korean COPD patients with destroyed lung by TB and moderate-to-severe airflow limitation.

Methods: This was a multicenter, double-blind, parallel-group study, in which eligible patients were randomized (1:1) to receive either once-daily indacaterol 150 µg or placebo for 8 weeks. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s at Week 8; the secondary endpoints included changes in transition dyspnea index score and St George's Respiratory Questionnaire for COPD score at Week 8. Safety was evaluated over 8 weeks.

Results: Of the 136 patients randomized, 119 (87.5%) completed the study treatment. At Week 8, indacaterol significantly improved trough forced expiratory volume in 1 s versus placebo (treatment difference [TD] 140 mL, <0.001). Statistically significant improvement in transition dyspnea index score (TD =0.78, <0.05) and numerical improvement in St George's Respiratory Questionnaire for COPD score (TD =-2.36, =0.3563) were observed with indacaterol versus placebo at Week 8. Incidence of adverse events was comparable between the treatment groups.

Conclusion: Indacaterol provided significantly superior bronchodilation, significant improvement in breathlessness and improved health status with comparable safety versus placebo in Korean COPD patients with destroyed lung by TB and moderate-to-severe airflow limitation.
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http://dx.doi.org/10.2147/COPD.S128750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459963PMC
April 2018

Differentiating Smoking-Related Interstitial Fibrosis (SRIF) from Usual Interstitial Pneumonia (UIP) with Emphysema Using CT Features Based on Pathologically Proven Cases.

PLoS One 2016 9;11(9):e0162231. Epub 2016 Sep 9.

Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine, Jeonju, Jeonbuk, South Korea.

Objective: To differentiate smoking-related interstitial fibrosis (SRIF) from usual interstitial pneumonia (UIP) with emphysema on CT in combined pulmonary fibrosis and emphysema (CPFE) patients.

Materials And Methods: This study was approved by the institutional review board and informed consent was waived. We included 65 patients who underwent lung biopsy under the suspicion of UIP pattern on HRCT, and after radiologic-pathologic correlation, they were divided into three groups: UIP without emphysema (n = 30), UIP with emphysema (n = 26), and SRIF (n = 9). The quantitative extent of emphysema in the entire lung was visually assessed and fibrotic patterns were qualitatively analyzed based on six characteristics (asymmetry, juxta-subpleural sparing, emphysema beside the honeycombing area, absence of ground grass attenuation/reticulation in honeycombing area, inhomogeneous honeycombing, and absence of honeycombing in the upper lobes). Kaplan-Meier analysis was used for survival analysis, and logistic regression with a receiver operating characteristic curve was used to predict the possibility of SRIF.

Results: In qualitative analysis of fibrotic patterns, SRIF tended to exhibit more than three of six fibrotic features, whereas UIP with emphysema demonstrated about two of these characteristics (p = 0.035). In addition, SRIF had a higher extent of emphysema than UIP with emphysema when they have same amount of fibrosis (p = 0.014). In patients with SRIF, 5-year survival rate was 85.7%, while it was 40.7% in UIP with emphysema patients (p = 0.035).

Conclusion: Fibrotic CT patterns and survival rate differed between SRIF and UIP with emphysema among CPFE patients, which explains the variable prognosis of CPFE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162231PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017577PMC
August 2017

Small cell carcinoma of the pyriform sinus successfully treated with concurrent chemo-radiotherapy: A case report.

Medicine (Baltimore) 2016 Sep;95(36):e4759

Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Geumam-dong, Deokjin-gu, Jeonju, South Korea.

Background: Primary small cell carcinomas (SCCs) are uncommon in extrapulmonary sites and account for only 2.5% to 5.0% of all SCCs. SCCs in the pyriform sinus are rare and there is little information regarding this disease, especially on therapeutics. Herein, we present a case of successfully treated SCC in the right pyriform sinus that occurred in a patient with small cell lung carcinoma (SCLC) that completely resolved 4 years prior.

Methods: A 1.5 × 1.5-cm mass in the right pyriform sinus was detected on imaging studies in a 71-year-old male at a regular check-up visit after being in remission from SCLC.

Results: Based on histologic examination and immunohistochemistry, the tumor in the right pyriform sinus was diagnosed as an extrapulmonary SCC. Chemo-radiotherapy was applied to the SCC of the pyriform sinus with a regimen of etoposide and cisplatin. The patient exhibited complete response to treatment and has been disease free for 11 months.

Conclusion: This interesting case shows that chemotherapy with concurrent radiation may be an effective therapeutic modality for localized extrapulmonary SCC similar to localized SCLC, which is treated with concurrent chemo-radiotherapy as the standard therapeutic option.
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http://dx.doi.org/10.1097/MD.0000000000004759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023898PMC
September 2016

Pulmonary malignant melanoma with distant metastasis assessed by positron emission tomography-computed tomography.

Thorac Cancer 2016 07 25;7(4):503-7. Epub 2016 Feb 25.

Department of Internal Medicine, Research Center for Pulmonary Disorders Chonbuk National University Medical School Jeonju South Korea; Research Institute of Clinical Medicine-Biomedical Research Institute Chonbuk National University Hospital Jeonju South Korea.

Melanoma is a cutaneous malignant neoplasm of melanocytes. Primary malignant melanoma (MM) of the lung is very rare. Although previous reports have described the radiologic features of pulmonary MM, its rarity means that many factors are unknown. Thus, radiologic diagnosis is very difficult. Furthermore, there is little information regarding diagnostic application and/or the usefulness of [(18)F]-fluorine-2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (FDG-PET-CT) for primary pulmonary MM. A 69-year-old patient with a productive cough lasting three weeks was admitted to our hospital. Chest CT showed a large single mass with a multi-lobulated margin and homogeneous enhancement in the right upper lobe, which was subsequently diagnosed as a primary pulmonary MM with multiple metastases. On PET-CT images, the pulmonary mass and multiple bone lesions showed very increased uptakes of FDG. Considering that pulmonary metastasis from a mucocutaneous melanoma is the main differential diagnosis of primary pulmonary MM, systemic assessment of the whole body is more important than for other types of lung malignancies. This report introduces PET-CT as a useful diagnostic modality for pulmonary MM, especially in cases of distant multiple metastases.
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http://dx.doi.org/10.1111/1759-7714.12339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930973PMC
July 2016

Mediastinal Desmoid Tumor With Remarkably Rapid Growth: A Case Report.

Medicine (Baltimore) 2015 Dec;94(52):e2370

From the Department of Internal Medicine and Research Center for Pulmonary Disorders (JHL, JSJ, SRK, YCL); Department of Radiology (GYJ); Department of Pathology (MJC); and Department of Thoracic & Cardiovascular Surgery (JHK), Chonbuk National University Medical School, Jeonju, South Korea.

Desmoid tumors (DTs) are a group of rare and benign soft tissue tumors that result from monoclonal proliferation of well-differentiated fibroblasts. Since DTs tend to infiltrate and compress adjacent structures, the location of DTs is one of the most crucial factors for determining the severity of the disease. Furthermore, DTs can further complicate the clinical course of patients when the growth is remarkably rapid, especially for DTs occurring in anatomically critical compartments, including the thoracic cavity.The authors report a case of a 71-year-old man with a known mediastinal mass incidentally detected 4 months ago, presenting dyspnea with right-sided atelectasis and massive pleural effusion. Imaging studies revealed a 16.4 × 9.4-cm fibrous mass with high glucose metabolism in the anterior mediastinum. The mass infiltrated into the chest wall and also displaced the mediastinum contralaterally. Interestingly, the tumor had an extremely rapid doubling time of 31.3 days.En bloc resection of the tumor was performed as a curative as well as a diagnostic measure. Histopathologic examination showed spindle cells with low cellularity and high collagen deposition in the stroma. Immunohistochemical staining was positive for nuclear β-catenin. Based on these pathologic findings, the mass was diagnosed as DT. After surgery, there has been no evidence of recurrence of disease in the patient.This patient presents a mediastinal DT with extremely rapid growth. Notably, the doubling time of DT in our case was the shortest among reported cases of DT. Our experience also highlights the benefits of early interventional strategy, especially for rapidly growing DTs in the thoracic cavity.
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http://dx.doi.org/10.1097/MD.0000000000002370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291622PMC
December 2015

Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma.

Sci Rep 2015 Dec 2;5:17784. Epub 2015 Dec 2.

LG Life Sciences R&D Park, Daejeon, 305-380, Republic of Korea.

In recent decades, global pharmaceutical companies have suffered from an R&D innovation gap between the increased cost of a new drug's development and the decreased number of approvals. Drug repositioning offers another opportunity to fill the gap because the approved drugs have a known safety profile for human use, allowing for a reduction of the overall cost of drug development by eliminating rigorous safety assessment. In this study, we compared the transcriptional profile of LC28-0126, an investigational drug for acute myocardial infarction (MI) at clinical trial, obtained from healthy male subjects with molecular activity profiles in the Connectivity Map. We identified dyphilline, an FDA-approved drug for bronchial asthma, as a top ranked connection with LC28-0126. Subsequently, we demonstrated that LC28-0126 effectively ameliorates the pathophysiology of neutrophilic bronchial asthma in OVALPS-OVA mice accompanied with a reduction of inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), inhibition of the release of proinflammatory cytokines, relief of airway hyperactivity, and improvement of histopathological changes in the lung. Taken together, we suggest that LC28-0126 could be a potential therapeutic for bronchial asthma. In addition, this study demonstrated the potential general utility of computational drug repositioning using clinical profiles of the investigational drug.
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http://dx.doi.org/10.1038/srep17784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667219PMC
December 2015

Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress.

Thorax 2016 Jan 5;71(1):52-63. Epub 2015 Nov 5.

Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.

Background: Sensitisation with Aspergillus fumigatus (Af) is known to be associated with severe allergic lung inflammation, but the mechanism remains to be clarified. Phosphoinositide 3-kinase (PI3K)-δ and endoplasmic reticulum (ER) stress are suggested to be involved in steroid-resistant lung inflammation. We aimed to elucidate the role of PI3K-δ and its relationship with ER stress in fungus-induced allergic lung inflammation.

Methods: Using Af-exposed in vivo and in vitro experimental systems, we examined whether PI3K-δ regulates ER stress, thereby contributing to steroid resistance in fungus-induced allergic lung inflammation. Moreover, we checked expression of an ER stress marker in lung tissues isolated from patients with allergic bronchopulmonary aspergillosis.

Results: Af-exposed mice showed that ER stress markers, unfolded protein response (UPR)-related proteins, phosphorylated Akt, generation of mitochondrial reactive oxygen species (mtROS), eosinophilic allergic inflammation, and airway hyperresponsiveness (AHR) were increased in the lung. Similarly, glucose-regulated protein 78 was increased in lung tissues of patients with ABPA. A PI3K-δ inhibitor reduced Af-induced increases in ER stress markers, UPR-related proteins, allergic inflammation and AHR in mice. However, dexamethasone failed to reduce Af-induced allergic inflammation, AHR and elevation of ER stress. Administration of an ER stress inhibitor or a mtROS scavenger improved Af-induced allergic inflammation. The PI3K-δ inhibitor reduced Af-induced mtROS generation and the mtROS scavenger ameliorated ER stress. In primary cultured tracheal epithelial cells, Af-induced ER stress was inhibited by blockade of PI3K-δ.

Conclusions: These findings suggest that PI3K-δ regulates Af-induced steroid-resistant eosinophilic allergic lung inflammation through ER stress.
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http://dx.doi.org/10.1136/thoraxjnl-2015-207096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717427PMC
January 2016
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