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.

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.

Transfusion Related Acute Lung Injury after Cesarean Section in a Patient with HELLP Syndrome / 가정의학회지

Transfusion-related acute lung injury (TRALI) is a serious adverse reaction of transfusion, and presents as hypoxemia and non-cardiogenic pulmonary edema within 6 hours of transfusion. A 14-year-old primigravida woman at 34 weeks of gestation presented with upper abdominal pain without dyspnea. Because she showed the syndrome of HELLP (hemolysis, elevated liver enzymes, and low platelet count), an emergency cesarean section delivery was performed, and blood was transfused. In the case of such patients, clinicians should closely observe the patient's condition at least during the 6 hours while the patient receives blood transfusion, and should suspect TRALI if the patient complains of respiratory symptoms such as dyspnea. Furthermore, echocardiography should be performed to distinguish between the different types of transfusion-related adverse reactions.

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.

Four Cases of Carbapenem-Resistant Enterobacteriaceae Infection from January to March in 2014 / 가정의학회지

Infection with carbapenem-resistant Enterobacteriaceae (CRE) and other multidrug resistant bacteria has increased rapidly in Korea. The Korea Centers for Disease Control and Prevention reported 1,609 cases of CRE infection in the country in 2013. The risk factors for CRE infection include history of treatment with antibiotics such as cephalosporins or carbapenem, trauma, diabetes, cancer, and history of ventilator support. Herein, we report four cases of CRE infection seen during a 3-month period in our hospital in 2014. CRE infection is associated with a high mortality rate of 30% to 50%, even with combination antibiotic therapy. Prevention of CRE infection in hospital settings is fundamental to controlling its transmission. Key preventive measures include, contact precautions, hand hygiene, education of healthcare personnel, screening for CRE when indicated, and exercising discretion in prescribing carbapenem or cephalosporins.

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 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.

Fine Needle Aspiration Cytology of Metastatic Adenocarcinoma of the Gingiva from the Lung: A Case Report

Metastases of malignant tumors to the oral region from distant sites are uncommon. A 45-year-old man with painless gingival swelling was diagnosed with adenocarcinoma of the lung. On cytology, clusters of tumor cells on mucous background revealed enlarged nuclei, indistinct cell borders, and irregular nuclear membranes. Some cells showed nuclear inclusions, nuclear grooves and small nucleoli. These findings are indicative of metastatic adenocarcinoma. We present a case of gingival metastasis from a lung adenocarcinoma.

Overlap Between Asthma and COPD: Where the Two Diseases Converge

Asthma and chronic obstructive pulmonary disease (COPD) are traditionally recognized as distinct diseases, with some clearly separate characteristic. Asthma originates in childhood, is associated with allergies and eosinophils, and is best treated by targeting inflammation, whereas COPD occurs in adults who smoke, involves neutrophils, and is best treated with bronchodilators and the removal of risk factors. However, the distinction between the two is not always clear. Patients with severe asthma may present with fixed airway obstruction, and patients with COPD may have hyperresponsiveness and eosinophilia. Recognizing and understanding these overlapping features may offer new insight into the mechanisms and treatment of chronic airway inflammatory diseases.

Comparison for the Effects of Triple Therapy with Salmeterol/Fluticasone Propionate and Tiotropium Bromide versus Individual Components in Patients of Severe COPD Combined with Bronchial Hyperresponsiveness / 결핵및호흡기질환

BACKGROUND: A combination of salmeterol and fluticasone propionate (SFC) and tiotropium bromide (TIO) is commonly prescribed for COPD patients but there is little data on their effectiveness, particularly in COPD patients with bronchial hyperresponsiveness. This study compared the spirometric improvement based on the change in FEV1, FEV1/FVC, and IC as well as the clinical outcomes of the therapeutic strategies with SFC and TIO versus the individual components in patients with severe COPD and bronchial hyperresponsiveness. METHODS: This study examined the spirometric data and clinical outcomes of 214 patients with COPD and hyperresponsiveness, who were divided into three groups according to the therapeutic regimen (TIO only, SFC only, and a triple therapy regimen). RESULTS: All regimen groups showed early improvement in the FEV1 and IC (at 3- and 6 months after treatment). However, long-term beneficial effects were observed only in the SFC group (at 24 months after treatment). However, these beneficial effects decreased after a 36-month follow up. In all spirometric results, the 12-, 24-, and 36-months data showed a similar degree of improvement in the three groups. The triple therapy group showed higher St. George's Respiratory Questionnaire scores and lower acute exacerbations and hospitalization. CONCLUSION: SFC can be a more important component in the pharmacological treatment of severe COPD patients with hyperresponsiveness than TIO, particularly in the spirometric and clinical outcomes.

Elevated C-reactive Protein Levels are a Sign of Pulmonary Arterial Hypertension in AECOPD / 결핵및호흡기질환

BACKGROUND: In chronic obstructive pulmonary disease (COPD) patients, the serum levels of C-reactive protein (CRP) are elevated and an increase of CRP is more exaggerated in the acute exacerbation form of COPD (AECOPD) than in stable COPD. Pulmonary arterial hypertension is a common complication of COPD. An increased level of CRP is known to be associated with the risk of systemic cardio-vascular disorders. However, few findings are available on the potential role of CRP in pulmonary arterial hypertension due to COPD. METHODS: This study was performed prospectively and the study population was composed of 72 patients that were hospitalized due to AECOPD. After receiving acute management for AECOPD, serum CRP levels were evaluated, arterial oxygen pressure (PaO2), was measured, and the existence of pulmonary arterial hypertension under room air inhalation was determined in the patients. RESULTS: The number of patients with pulmonary arterial hypertension was 47 (65.3%)., There was an increased prevalence of pulmonary arterial hypertension and an increase of serum CRP levels in patients with the higher stages of COPD (e.g., patients with stage 3 and stage 4 disease; P<0.05). The mean serum CRP levels of patients with pulmonary arterial hypertension and without pulmonary arterial hypertension were 37.6+/-7.4 mg/L and 19.9 +/-6.6 mg/L, respectively (P<0.05). However, there was no significant difference of the mean values of PaO2 between patients with pulmonary arterial hypertension and without pulmonary arterial hypertension statistically (77.8+/-3.6 mmHg versus 87.2+/-6.0 mmHg). CONCLUSION: We conclude that higher serum levels of CRP can be a sign for pulmonary arterial hypertension in AECOPD patients.

The clinical characteristics of non-resolving or slow-resolving pneumonia associated with the pathology of an organizing pneumonia / 대한내과학회지

BACKGROUND/AIMS: Non-resolving or slow-resolving pneumonia refers to the persistence of pulmonary infiltrates for >30 days after an initial pneumonia-like illness. Organizing pneumonia (OP) can be found on a lung biopsy in association with a number of diseases. The object of this study was to elucidate the clinical characteristics of the non-resolving pneumonia with the pathology of an OP and suggest the proper diagnostic and therapeutic approaches for the reduction of unnecessary procedures. METHODS: We retrospectively analyzed 70 patients diagnosed with an OP by percutaneous transthoracic needle biopsy and that met the inclusion criteria. Their pulmonary lesions were reviewed for disease resolution. Patients were divided into either a radiologically benign group (group I, n=57) or a malignancy group (group II, n=13) based on the computed tomography (CT) findings. RESULTS: All patients in group I and 8 patients in group II improved and had a complete resolution by 81.70+/-45.36 days. The microbiology findings showed that many infectious pathogens can lead to an OP despite antibiotic therapy. Three cases in group II were ultimately diagnosed as malignancies. CONCLUSIONS: Our data suggest that non-resolving or slow-resolving lesions were strongly suspicious for a malignancy on the CT scans, despite appearing to be benign OP pathologically; such cases should be considered for re-biopsy. In cased with pathology consistent with OP and benign CT findings, careful observation for 3 months is recommended to allow for the complete radiological resolution of the benign OP associated with infection.

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

Reactive oxygen species (ROS) play a crucial role in acute lung injury. Tissue inflammation, the increased vascular permeability, and plasma exudation are cardinal features of acute lung injury. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage and also has beneficial effects in several inflammatory disorders. Recently developed COMP-Ang1 is more potent than native Ang1 in phosphorylating tyrosine kinase with immunoglobulin and EGF homology domain 2 receptor in endothelial cells. However, there are no data on effects and related molecular mechanisms of COMP- Ang1 on ROS-induced acute lung injury. We used hydrogen peroxide (H2O2)-inhaled mice to evaluate the effect of COMP-Ang1 on pulmonary inflammation, bronchial hyper-responsiveness, and vascular leakage in acute lung injury. The results have revealed that VEGF expression, the levels of IL-4, TNF-alpha, IL-1 beta, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in lungs, the levels of hypoxia-inducible factor-1alpha (HIF-1 alpha) and NF-kappa B in nuclear protein extracts, phosphorylation of Akt, and vascular permeability were increased after inhalation of H2O2 and that the administration of COMP-Ang1 markedly reduced airway hyper-responsiveness, pulmonary inflammation, plasma extravasation, and the increases of cytokines, adhesion molecules, and VEGF in lungs treated with H2O2. We have also found that the activation of HIF-1a and NF-kappa B and the increase of phosphoinositide 3-kinase activity in lung tissues after H2O2 inhalation were decreased by the administration of COMP-Ang1. These results suggest that COMP-Ang1 ameliorates ROS-induced acute lung injury through attenuating vascular leakage and modulating inflammatory mediators.

Clear Cell "Sugar" Tumor of the Lung: A Well-Enhanced Mass with an Early Washout Pattern on Dynamic Contrast-Enhanced Computed Tomography

Clear cell tumor of the lung is a rare and very unusual benign pulmonary tumor. As clear cell tumor of the lung contains abundant cytoplasmic glycogen, this tumor is called "sugar tumor". We report a case of sugar tumor in a 64-yr-old man presenting as a round pulmonary nodule. On dynamic computed tomography (CT) scans, the solitary pulmonary nodule showed early wash-in enhancement with an early washout pattern like a lung malignancy. The patient underwent wedge resection for the tumor. Pathologic examination, including immunohistochemical studies, revealed that the nodule was a benign clear cell tumor, so-called "sugar tumor". Because only a small number of cases have been reported previously, clinical aspects, radiological characteristics on dynamic contrast-enhanced CT, and differential diagnosis of the tumor are not well established. Herein we present a clear cell tumor of the lung and discuss the clinical, radiological, and pathological features of the tumor.

A Case of Huge Pulmonary Blastoma With Multiorgan Invasion / 결핵및호흡기질환

A pulmonary blastoma is a rare malignant tumor of the lung that is composed of epithelial and mesenchymal elements and resembles the structure of an embryonic lung. Pulmonary blastomas have a very poor prognosis and make up 0.25 to 0.5 percent of all primary malignant lung tumors. A pulmonary blastoma usually manifests as a solitary parenchymal mass or nodule and multiple subpleural mass with effusion on chest X-ray and computed tomography. We encountered a very rare case of pulmonary blastoma in a 52 years old male. He complained of abdominal pain, fullness, and dyspnea. The radiology examination revealed a huge lung mass invading the mediastinum, heart, diaphragm, and liver. The percutaneous needle biopsies were performed, and this tumor was diagnosed as a pulmonary blastoma. We report a biopsy confirmed case of a huge pulmonary blastoma invading multiple organs.

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.