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

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 in vitro 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.

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

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.

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

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.

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

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.

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

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.

Endoplasmic Reticulum Stress and the Related Signaling Networks in Severe Asthma

The endoplasmic reticulum (ER) is a specialized organelle that plays a central role in biosynthesis, correct protein folding, and posttranslational modifications of secretory and membrane proteins. Loss of homeostasis in ER functions triggers the ER stress response, resulting in activation of unfolded protein response (UPR), a hallmark of many inflammatory diseases. These pathways have been reported as critical players in the pathogenesis of various pulmonary disorders, including pulmonary fibrosis, lung injury, and chronic airway disorders. More interestingly, ER stress and the related signaling networks are emerging as important modulators of inflammatory and immune responses in the development of allergen-induced bronchial asthma, especially severe asthma.

Cryoablation of a Small Pulmonary Nodule with Pure Ground-Glass Opacity: A Case Report

Treatments for pure ground-glass nodules (GGNs) include limited resection; however, surgery is not always possible in patients with limited pulmonary functional reserve. In such patients, cryoablation may be a suitable alternative to treat a pure GGN. Here, we report our initial experience with cryoablation of a pure GGN that remained after repeated surgical resection in a patient with multiple GGNs. A 5-mm-sized pure GGN in the left lower lobe was cryoablated successfully without recurrence at the 6-month follow-up.

Endobronchial Neurilemmoma Mimicking a Bronchial Polyp

Neurilemmomas are relatively uncommon, slowly growing tumors which originate from Schwann cells. Intrathoracic neurilemmomas often occur in the chest wall and posterior mediastinum, but endobronchial neurilemmomas are exceedingly rare. These tumors in trachea or bronchus are usually detected by radiologic examinations, mostly computed tomography scan of chest. An 88-year-old man was admitted for management of pneumonia in left lower lobe and parapneumonic effusion. On bronchoscopic examination, there was a small polypoid nodule less than 1 cm in diameter mimicking an endobronchial inflammatory polyp at the bifurcation of the right anterior segmental bronchus and lateral segmental bronchus and under auto-fluorescence imaging, the nodule showed reddish brown area with defined margin. The bronchoscopic biopsy revealed that the bronchial nodule was endobronchial neurilemmoma. This is an interesting case of endobronchial neurilemmoma mimicking a bronchial polyp that is detected incidentally via bronchoscopy.

Delayed Diagnosis of Small Cell Lung Cancer in a Patient with Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disorder induced by Aspergillus fumigatus that occurs generally in patients with underlying chronic airway disorders. However, the development of ABPA associated with lung malignancy remains unknown. An 80-year-old woman was admitted for evaluation of chronic cough. Her radiologic finding was a mass like opacity with mucoid impaction, showing finger-in-glove sign, one of the typical radiologic findings for ABPA. In addition, laboratory tests revealed that her data satisfied the diagnostic criteria for ABPA. Interestingly, final pathologic examination showed that the mass lesion was small cell lung cancer. Here, we describe a case of delayed diagnosis of small cell lung cancer with ABPA, suggesting that a possibility of accompanying lung malignancy such as small cell lung cancer should be considered in patients with ABPA. This case let us realize the importance of clinical suspicion that different entities of diseases can be occurred simultaneously for the correct diagnosis without delay.

Late Recurrence of Ovarian Cancer Mimicking a Primary Lung Malignancy after Curative Resection

The majority of patients with an advanced-stage ovarian cancer relapse within approximately 18 months after completion of the first-line therapy. Recurrent ovarian cancer commonly presents as peritoneal seeding, while other distant sites are anywhere including the pleura, liver, lung, central nervous system, spleen, skin, bone, and breast. As pulmonary metastases usually occur through hematogenous or lymphangitic routes, the pattern of the metastases of ovarian cancer is multiple and scattered diffusely. The solitary pulmonary metastasis of ovarian cancer is an extremely rare condition, thus it can be misdiagnosed as a primary lung cancer, unless physician has a clinical suspicion. Herein, we introduce a case of solitary pulmonary metastasis of ovarian cancer which occurred 9 years after the curative surgery and chemotherapy.

A Novel Synthetic Mycolic Acid Inhibits Bronchial Hyperresponsiveness and Allergic Inflammation in a Mouse Model of Asthma

PURPOSE: Recognition of microbes is important to trigger the innate immune system. Mycolic acid (MA) is a component of the cell walls of mycobacteria such as Mycobacterium bovis Bacillus Calmette-Guerin. MA has immunogenic properties, which may modulate the innate and adaptive immune response. This study aimed to investigate whether a novel synthetic MA (sMA) inhibits allergic inflammatory responses in a mouse model of asthma. METHODS: BALB/c mice were injected intraperitoneally with sMA followed by sensitization and challenge with ovalbumin (OVA). Mice were examined for bronchial hyperresponsiveness (BHR), the influx of inflammatory cells into the lung tissues, histopathological changes in the lungs and CD4+CD25+Foxp3+ T cells in the spleen, and examined the response after the depleting regulatory T cells (Tregs) with an anti-CD25mAb. RESULTS: Treatment of mice with sMA suppressed the asthmatic response, including BHR, bronchoalveolar inflammation, and pulmonary eosinophilic inflammation. Anti-CD25mAb treatment abrogated the suppressive effects of sMA in this mouse model of asthma and totally depleted CD4+CD25+Foxp3+ T cells in the spleen. CONCLUSIONS: sMA attenuated allergic inflammation in a mouse model of asthma, which might be related with CD4+CD25+Foxp3+ T cell.

Bacillus Calmette-Guerin Suppresses Asthmatic Responses via CD4+CD25+ Regulatory T Cells and Dendritic Cells

PURPOSE: Bacillus Calmette-Guerin (BCG) is known to suppress the asthmatic responses in a murine model of asthma and to induce dendritic cells (DCs) maturation. Mature DCs play a crucial role in the differentiation of regulatory T cells (Tregs), which are known to regulate allergic inflammatory responses. To investigate whether BCG regulates Tregs in a DCs-mediated manner, we analyzed in a murine model of asthma. METHODS: BALB/c mice were injected intraperitoneally with BCG or intravenously with BCG-stimulated DCs and then sensitized and challenged with ovalbumin (OVA). Mice were analysed for bronchial hyperresponsiveness (BHR), the influx of inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and histopathological changes in the lung. To identify the mechanisms, IgE, IgG1 and IgG2a in the serum were analysed and the CD25+ Tregs in the mice were depleted with anti-CD25 monoclonal antibody (mAb). RESULTS: BCG and the transfer of BCG-stimulated DCs both suppressed all aspects of the asthmatic responses, namely, BHR, the production of total IgE and OVA-specific IgE and IgGs, and pulmonary eosinophilic inflammation. Anti-CD25mAb treatment reversed these effects. CONCLUSIONS: BCG can attenuate the allergic inflammation in a mouse model of asthma by a Tregs-related mechanism that is mediated by DCs.

Macromineral intake in non-alcoholic beverages for children and adolescents: Using the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV, 2007-2009)

The aims of this study were to estimate daily intake of macrominerals from beverages, liquid teas, and liquid coffees and to evaluate their potential health risks for Korean children and adolescents (1-to 19 years old). Assessment of dietary intake was conducted using the actual level of sodium, calcium, phosphorus, potassium, and magnesium in non-alcoholic beverages and (207 beverages, 19 liquid teas, and 24 liquid coffees) the food consumption amount drawn from "The Fourth Korea National Health and Nutrition Examination Survey (2007-2009)". To estimate the dietary intake of non-alcoholic beverages, 6,082 children and adolescents (Scenario I) were compared with 1,704 non-alcoholic beverage consumption subjects among them (Scenario II). Calculation of the estimated daily intake of macrominerals was based on point estimates and probabilistic estimates. The values of probabilistic macromineral intake, which is a Monte-Carlo approach considering probabilistic density functions of variables, were presented using the probabilistic model. The level of safety for macrominerals was evaluated by comparison with population nutrient intake goal (Goal, 2.0 g/day) for sodium, tolerable upper intake level (UL) for calcium (2,500 mg/day) and phosphorus (3,000-3,500 mg/day) set by the Korean Nutrition Society (Dietary Reference Intakes for Koreans, KDRI). For total children and adolescents (Scenario I), mean daily intake of sodium, calcium, phosphorus, potassium, and magnesium estimated by probabilistic estimates using Monte Carlo simulation was, respectively, 7.93, 10.92, 6.73, 23.41, and 1.11, and 95th percentile daily intake of those was, respectively, 28.02, 44.86, 27.43, 98.14, and 3.87 mg/day. For consumers-only (Scenario II), mean daily intake of sodium, calcium, phosphorus, potassium, and magnesium estimated by probabilistic estimates using Monte Carlo simulation was, respectively, 19.10, 25.77, 15.83, 56.56, and 2.86 mg/day, and 95th percentile daily intake of those was, respectively, 62.67, 101.95, 62.09, 227.92, and 8.67 mg/day. For Scenarios I.II, sodium, calcium, and phosphorus did not have a mean an 95th percentile intake that met or exceeded the 5% of Goal and UL.

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

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 / 결핵및호흡기질환

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.

A Multicenter Study of Pertussis Infection in Adults with Coughing in Korea: PCR-Based Study / 결핵및호흡기질환

BACKGROUND: Limited data on the incidence and clinical characteristics of adult pertussis infections are available in Korea. METHODS: Thirty-one hospitals and the Korean Centers for Disease Control and Prevention collaborated to investigate the incidence and clinical characteristics of pertussis infections among adults with a bothersome cough in non-outbreak, ordinary outpatient settings. Nasopharyngeal aspirates or nasopharyngeal swabs were collected for polymerase chain reaction (PCR) and culture tests. RESULTS: The study enrolled 934 patients between September 2009 and April 2011. Five patients were diagnosed as confirmed cases, satisfying both clinical and laboratory criteria (five positive PCR and one concurrent positive culture). Among 607 patients with cough duration of at least 2 weeks, 504 satisfied the clinical criteria of the US Centers for Disease Control and Prevention (i.e., probable case). The clinical pertussis cases (i.e., both probable and confirmed cases) had a wide age distribution (45.7+/-15.5 years) and cough duration (median, 30 days; interquartile range, 18.0~50.0 days). In addition, sputum, rhinorrhea, and myalgia were less common and dyspnea was more common in the clinical cases, compared to the others (p=0.037, p=0.006, p=0.005, and p=0.030, respectively). CONCLUSION: The positive rate of pertussis infection may be low in non-outbreak, ordinary clinical settings if a PCR-based method is used. However, further prospective, well-designed, multicenter studies are needed.

Effects of Add-On Therapy with NDC-052, an Extract from Magnoliae Flos, in Adult Asthmatic Patients Receiving Inhaled Corticosteroids

BACKGROUND/AIMS: There is a need for new anti-asthmatic medications with fewer side effects. NDC-052, an extract of the medicinal herb Magnoliae flos, which has a long history of clinical use, was recently found to have anti-inflammatory effects. Herein, we evaluated the effects of NDC-052 as an add-on therapy in patients with mild to moderate asthma using inhaled corticosteroids (ICS). METHODS: In a non-comparative, multi-center trial, 148 patients taking ICS received NDC-052 for eight weeks. We evaluated their forced expiratory volume in one second (FEV1), morning and evening peak expiratory flow rate (AM and PM PEFR), AM/PM asthma symptom scores, visual analogue symptom (VAS) scores, night-time wakening, frequency of short-acting beta2-agonist usage, and adverse events. RESULTS: After eight weeks, both AM and PM PEFRs were significantly improved. Asthma symptom scores, VAS scores, the frequency of nights without awakening, and the frequency of beta2-agonist use were also reduced. Most of the adverse drug reactions were mild and resolved spontaneously. CONCLUSIONS: The addition of NDC-052 to ICS had a beneficial effect on asthma control in patients with mild to moderate asthma, with good tolerability and fewer side effects. Further studies are necessary to evaluate the effects of NDC-052 in patients with severe and/or refractory asthma.

Assessment of Therapeutic Response of Ablated Lesion after Radiofrequency Ablation in Patients with Unresectable Lung Malignancies by Multiphase Contrast-enhanced MRI

PURPOSE: We evaluated which phase was important to recognize local progression of an ablated zone after RFA on multiphase contrast-enhanced MRI (CE-MRI) in patients with unresectable lung malignancy. MATERIALS AND METHODS: Twenty patients who had unresectable lung malignancy underwent multiphase CE-MRI examinations immediately after RFA. We evaluated the enhancement patterns of the ablated zone on multiphase CE-MRI: type I, no enhancement of the ablated zone; type II, enhancement of the ablated margin; type III, heterogeneous enhancement of the ablated zone. We evaluated the association enhancement type with local progression of the ablated zone on the follow up CT using Spearman's ranked test. RESULTS: In complete ablation, the enhancement pattern was types I (11.1%) or II (88.9%). In unsuccessfully treated, type II (57.1%) or III (42.9%) pattern observed in the arterial phase. However, types II (21.4%) and III (78.6%) observed in the venous, and types II (7.1%) and III (92.9%) observed equilibrium phases. Local progression of the ablated zone was associated with the enhancement pattern in equilibrium phases (r=0.8, p < .05). CONCLUSION: Equilibrium phases on multiphase CE-MRI might play a more important role in evaluating an ablated zone for predicting local recurrence after RFA.

Vancomycin-Resistant Enterococcus faecium Meningitis Treated with Linezolid: A Case Report and Review of the Literature

Vancomycin-resistant enterococci (VRE) infection is a serious problem because optimal therapy has not been established. Different agents in various combinations, including teicoplanin, chloramphenicol, and quinupristin/dalfopristin, have been used to treat patients with VRE meningitis, but the efficacy of these agents is not satisfactory because of their limited ability to penetrate into the cerebrospinal fluid. We report a case of nosocomial vancomycin-resistant Enterococcus faecium meningitis in a patient with ventriculoperitoneal shunt that was successfully treated with linezolid. We will also review previously reported cases of vancomycin-resistant E. faecium meningitis treated by linezolid.

Differential diagnosis and treatment of chronic cough / 대한내과학회지

No abstract available.