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Found in inflammatory zone (FIZZ) 2, also known as resistin-like molecule (RELM)-β, belongs to a novel cysteine-rich secreted protein family named FIZZ/RELM. Its function is unclear, but a closely related family member, FIZZ1, has profibrotic activities. The human ortholog of rodent FIZZ1 has not been identified, but human FIZZ2 has significant sequence homology to both rodent FIZZ2 (59%) and FIZZ1 (50%). Given the greater homology to rodent FIZZ2, analyzing the role of FIZZ2 in a rodent model of bleomycin-induced pulmonary fibrosis would be of greater potential relevance to human fibrotic lung disease. The results showed that FIZZ2 was highly induced in lungs of rodents with bleomycin-induced pulmonary fibrosis and of human patients with idiopathic pulmonary fibrosis. FIZZ2 expression was induced in rodent and human lung epithelial cells by Th2 cytokines, which was mediated via STAT6 signaling. The FIZZ2 induction in murine lungs was found to be essential for pulmonary fibrosis, as FIZZ2 deficiency significantly suppressed pulmonary fibrosis and associated enhanced extracellular matrix and cytokine gene expression. In vitro analysis indicated that FIZZ2 could stimulate type I collagen and a-smooth muscle actin expression in lung fibroblasts. Furthermore, FIZZ2 was shown to have chemoattractant activity for bone marrow (BM) cells, especially BM-derived CD11c+ dendritic cells. Notably, lung recruitment of BM-derived cells was impaired in FIZZ2 knockout mice. These findings suggest that FIZZ2 is a Th2-associated multifunctional mediator with potentially important roles in the pathogenesis of fibrotic lung diseases. [ABSTRACT FROM AUTHOR]

Early detection and appropriate management of treatment-related interstitial lung disease (ILD) are important in cancer treatment. We established an algorithm for quantifying fine crackles using machine learning and reported that the fine crackle quantitative value (FCQV) calculated by this algorithm was more sensitive than chest radiography for detecting interstitial changes. Using this algorithm, we periodically analyzed respiratory sounds in two patients with lung cancer who developed treatment-related ILDs and found that the FCQV was elevated before the diagnosis of ILD. These cases may indicate the usefulness of the FCQV in the early diagnosis of treatment-related ILDs.

Background: A significant number of children with asthma show remission in adulthood. Although these adults are often diagnosed with COPD in later life, the effect of clinically remitted childhood asthma on the decline in lung function during adulthood is uncertain. We examined whether clinical remission of childhood asthma was associated with an accelerated decline in lung function in apparently nonasthmatic adults., Methods: 3584 participants (mean (range) age 48.1 (35-65) years) who did not have adulthood asthma and other lung diseases and had normal lung function at the baseline visit were included. They were categorised as those with remitted childhood asthma (n=121) and healthy controls (n=3463) according to their self-reported childhood asthma history. Spirometry was performed at baseline and follow-up visits., Results: The mean follow-up was 5.3 years. Multivariate regression analysis showed that remitted childhood asthma and smoking were independently associated with a rapid decline in forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC). Smoking was an independent predictor of a rapid decline in FEV 1 /FVC. The annual decline in FEV 1 and FVC was significantly greater in participants with remitted childhood asthma than in healthy controls, and the differences remained significant after adjusting for the propensity score., Conclusions: A history of clinically remitted childhood asthma is an independent risk factor for accelerated decline in lung function in adults. Remitted childhood asthma and smoking may additively accelerate the development of obstructive lung disease., Competing Interests: Conflict of interest: S. Miura has nothing to disclose. Conflict of interest: H. Iwamoto has nothing to disclose. Conflict of interest: K. Omori has nothing to disclose. Conflict of interest: K. Yamaguchi has nothing to disclose. Conflict of interest: S. Sakamoto has nothing to disclose. Conflict of interest: Y. Horimasu has nothing to disclose. Conflict of interest: T. Masuda has nothing to disclose. Conflict of interest: S. Miyamoto has nothing to disclose. Conflict of interest: T. Nakashima has nothing to disclose. Conflict of interest: K. Fujitaka has nothing to disclose. Conflict of interest: H. Hamada has nothing to disclose. Conflict of interest: A. Yokoyama has nothing to disclose. Conflict of interest: N. Hattori reports grants from Teijin Pharma Co., Japan, during the conduct of the study. All other authors have nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Several prognostic factors for pleuroparenchymal fibroelastosis (PPFE) have recently been reported. However, detailed high-resolution computed tomography (HRCT) findings have not yet been evaluated as prognostic factors. This study retrospectively investigated whether HRCT findings are prognostic factors in patients with PPFE compared to those with idiopathic pulmonary fibrosis (IPF)., Methods: Patients with PPFE and IPF diagnosed at our hospital between January 2008 and December 2016 were enrolled. Clinical and HRCT characteristics were obtained. In addition to our patients, we also analyzed data of PPFE patients whose cause of death had been identified in previous studies., Results: We enrolled 15 patients with PPFE and 75 patients with IPF. Consolidation and maximum pleural thickening were significantly higher in patients with PPFE than in those with IPF (both P < .001). Fibrosis score, honeycomb area, and traction bronchiectasis were not significantly different between these patient groups but were significant prognostic factors in patients with PPFE in univariate analysis (P = .021, P = .017, and P = .014, respectively). The proportions of deaths by acute exacerbation or lung cancer were significantly lower in patients with PPFE than in those with IPF (P < .001 and P = .001, respectively), whereas death by respiratory failure was significantly more frequent in PPFE patients (P < .001)., Conclusions: HRCT findings, such as fibrosis score, honeycomb area, and traction bronchiectasis, were independent prognostic factors in patients with PPFE. Respiratory failure, but not acute exacerbation and lung cancer, was the main cause of death in patients with PPFE., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: High-mobility group box 1 (HMGB1) is a pro-inflammatory protein, that is associated with tumorigenesis, interstitial lung disease (ILD), and acute lung injury. Chemotherapy-induced lung injury is a common and serious adverse event in patients with lung cancer and ILD, but its pathogenesis and predictive biomarkers are not known. This study aimed to investigate the predictive potential of serum HMGB1 levels for cytotoxic chemotherapy-induced lung injury in these patients., Methods: From 743 patients with advanced lung cancer, we enrolled 83 consecutive patients with ILD and background-matched 83 patients without ILD. Additionally, 83 healthy subjects were included. After measuring baseline levels of serum HMGB1 in three groups, we evaluated the predictive values of baseline HMGB1 levels for cytotoxic chemotherapy-induced lung injury in patients with lung cancer and ILD., Results: Higher levels of serum HMGB1 were independently associated with higher tumor burden, as assessed by total tumor size, and the presence of ILD. Twenty-five (30.1%) of patients with lung cancer and ILD experienced cytotoxic chemotherapy-induced lung injury within one year. Univariate Cox proportional hazards model showed that higher levels of HMGB1 and higher tumor burden were associated with disease onset. Moreover, multivariate analysis revealed that only HMGB1 was independently associated with this severe complication in patients with lung cancer and ILD., Conclusions: HMGB1 is a potential predictive blood biomarker for cytotoxic chemotherapy-induced lung injury in patients with lung cancer and ILD. This study also suggests a potential pathogenesis of this serious adverse event that tumor- and ILD-derived HMGB1 accelerates lung injury., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The endogenous secretory receptor for advanced glycation end products (esRAGE) is a soluble isoform produced by alternative splicing of the RAGE gene. The isoform has anti-inflammatory properties due to its inhibition of the RAGE/ligand interaction and is reduced in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the association of esRAGE serum and bronchoalveolar lavage fluid (BALF) levels with progression of IPF., Methods: This study included 79 IPF patients and 90 healthy controls. IPF and control serum esRAGE levels were compared, and the correlation between serum and BALF esRAGE levels was analyzed in 57 IPF patient samples. We also investigated the relationship of esRAGE serum and BALF levels with prognoses and lung function parameters in patients with IPF., Results: Serum esRAGE levels in IPF patients were significantly lower than those in healthy controls (162.0 ± 102.4 ng/ml and 200.7 ± 107.3 ng/ml, p = 0.009), although the baseline characteristics of age and smoking history were not matched. Serum levels of esRAGE were correlated with BALF esRAGE levels (r s  = 0.317). The BALF esRAGE levels were also correlated with diffusion capacity for carbon monoxide (r s  = 0.406). A Kaplan-Meier curve analysis and univariate/multivariate Cox hazard proportion analysis revealed that lower levels of esRAGE in blood and BALF were significantly associated with poorer prognoses in patients with IPF., Conclusions: Decreased esRAGE levels in BALF and blood were associated with poor prognoses in patients with IPF. These results suggest that esRAGE could be related to the pathophysiology of IPF and serum esRAGE could be a potential prognostic marker of IPF.

Rationale: Some patients with pulmonary arteriovenous malformation (PAVM) present with hypoxemia and life-threatening complications, including stroke and cerebral abscess. Catheter embolization is currently the preferred treatment for PAVM. However, previous studies have revealed that the incidence of PAVM recanalization is approximately 10% 5 to 7 years after embolization. In contrast, there are no studies where recanalization has occurred over 10 years after embolization., Patient Concerns: Herein, we report 2 cases diagnosed with cerebral embolism due to PAVM recanalization 13 years and 30 years after catheter treatment, in case I and II, respectively., Diagnoses: Both cases were diagnosed with PAVM recanalization on chest computed tomography (CT) examination performed after cerebral embolism development. Furthermore, pulmonary artery angiography revealed blood flow from the pulmonary artery to the vein in the PAVM, confirming PAVM recanalization., Interventions: Coil re-embolization was performed for the all recanalized PAVM., Outcomes: All the target lesions were successfully re-embolized in both cases. However, in case I, the second recanalization of embolized PAVM was confirmed 1 year after coil re-embolization. Consequently, the third embolization was performed in case I. In contrast to case I, the patient in case II was followed up without recanalization for 2 years after embolization., Lessons: We described the first 2 cases diagnosed with PAVM recanalization >10 years after the first catheter embolization. These cases suggest that patients with PAVMs should undergo life-long follow-up after catheter embolization.

Background: Anti-programmed cell death receptor (PD)-1 antibody treatment results in better prognosis than standard chemotherapy in patients with non-small cell lung cancer (NSCLC), especially those with high PD-ligand 1 (PD-L1) expression. However, several studies have reported a lack of antitumor effect of PD-1 antibody, even in patients with high PD-L1 expression. Therefore, reliable predictors of treatment response are urgently needed. The albumin-globulin ratio (AGR) is associated with prognosis in several cancers. We aimed to determine whether AGR is a predictive biomarker of anti-PD-1 antibody response in patients with NSCLC., Patients and Methods: Seventy-four NSCLC patients treated with anti-PD-1 antibody were retrospectively enrolled. Patients with driver mutations were excluded., Results: The mean AGR was significantly higher in the disease control (DC) group than in the progressive disease (PD) group (p < 0.001). Receiver operating characteristic curve analysis revealed an AGR cutoff value for dividing patients into the DC or PD groups of 1.17. Multivariate logistic regression analysis showed that a high AGR (≥1.17, cutoff value) was an independent predictor of DC (p = 0.001). Progression-free survival (PFS) and overall survival (OS) were significantly longer in the high-AGR group than in the low-AGR group (p = 0.008, p = 0.002, respectively). Multivariate Cox regression analysis of PFS and OS showed that high AGR was an independent prognostic factor (p = 0.020, p < 0.001, respectively)., Conclusion: Pretreatment serum AGR may be a useful predictor for DC and prognostic factor of anti-PD-1 antibody in patients with NSCLC. The clinical utility of AGR still needs to be confirmed in a prospective analysis.

Background: Approximately 5% of non-small cell lung cancer (NSCLC) patients develop immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD), 10% of whom die. However, there are no established risk factors for its occurrence. Interstitial lung abnormalities (ILA) are areas of increased lung density on lung computed tomography (CT) in individuals with no known ILD. This study retrospectively investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with NSCLC., Methods: NSCLC patients who received anti-programmed death (PD)-1 antibody treatment at our hospital between September 2015 and December 2017 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained., Results: Among 83 enrolled patients, the incidence of ICI-ILD was 16.9% (14/83). All ICI-ILD cases developed by the third line of treatment. The incidence of ICI-ILD was significantly higher in patients with pre-existing ILA than that in those without (p = 0.007). Furthermore, patients with ground glass attenuation (GGA) in ILA had a higher incidence of ICI-ILD than that in those without (p < 0.001). In univariate logistic analysis, ILA were significant risk factors for ICI-ILD (p = 0.005). Multivariate logistic analysis revealed that only GGA in ILA was a significant risk factor for ICI-ILD (p < 0.001)., Conclusions: Pre-existing ILA are risk factors for ICI-ILD and GGA in ILA is an independent risk factor for ICI-ILD. Therefore, we should be more aware of the development of ICI-ILD in patients with ILA, especially those with GGA., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Patients with anti-aminoacyl-tRNA synthetase (ARS) antibodies frequently experience complications of interstitial pneumonia (ARS-IP), and the computed tomography (CT) of ARS-IP frequently shows nonspecific interstitial pneumonia (NSIP) pattern. The CT pattern of ARS-IP might be different from that of idiopathic IP. However, the clinical differences in patients with ARS-IP and idiopathic IP showing the similar CT patterns have not yet been well studied. The objective of this study was to evaluate the clinical differences between patients with ARS-NSIP and idiopathic NSIP (I-NSIP)., Methods: Two groups of 34 patients each, with ARS-NSIP and I-NSIP, who visited Hiroshima University Hospital between January 2005 and December 2017, were enrolled. Clinical features and outcomes were retrospectively compared between the two groups., Results: The ARS-NSIP group included more female patients and significantly younger patients than the I-NSIP group. The percentage of lymphocytes in bronchoalveolar lavage fluid (BALF) was significantly higher, and the CD4/CD8 ratio in BALF was significantly lower in the ARS-NSIP group compared with the I-NSIP group. The proportion of patients with traction bronchiectasis detected by CT was significantly higher in I-NSIP compared with ARS-NSIP. The number of patients who received corticosteroid and/or immunosuppressant therapy was significantly larger in the ARS-NSIP group than in the I-NSIP group. In addition, the patients in the I-NSIP group who underwent the immunosuppressive therapy demonstrated shorter survival than those who underwent no treatment; this tendency was not observed in the ARS-NSIP group. The 10-year survival rate of patients in the ARS-NSIP group was significantly higher than that of patients in the I-NSIP group (91.8% vs. 43.0%; log-rank, p = 0.012). The multivariate survival analysis revealed that positive anti-ARS antibody was an independent favorable prognostic factor in the patients with NSIP (OR, [95% CI]:0.12 [0.02-0.55], p = 0.013)., Conclusions: Patients with ARS-NSIP had a significantly better prognosis than those with I-NSIP; this may be associated with the sensitivity to immunosuppressive therapies, and the different findings of BALF and HRCT between the two groups., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Several studies have investigated the incidence of and risk factors for acute exacerbation (AE) in patients with interstitial lung disease (ILD) after lung resection surgery. However, the incidence and risk factors for AE-ILD after non-pulmonary surgery are not known. The aim of this study was to investigate the incidence of and risk factors for AE-ILD after non-pulmonary surgery.Eighty patients who were diagnosed with ILD on preoperative chest computed tomography (CT) imaging and underwent non-pulmonary surgery under general anesthesia at Hiroshima University Hospital between September 2011 and September 2017 were enrolled. We retrospectively compared the preoperative patient characteristics, laboratory findings, and factors associated with anesthetic management between the patients who developed AE-ILD and those who did not.The incidence of AE-ILD after non-pulmonary surgery was 6.3% and the mortality rate was 80%. Univariate logistic analysis showed that a usual interstitial pneumonia pattern on computed tomography, a high C-reactive protein (CRP) level, a long operating time, high blood loss, and blood transfusion during surgery were significant risk factors for AE-ILD. In multivariate analysis, only a high CRP level (odds ratio 2.556, 95% confidence interval 1.110-5.889, P = .028) was identified as an independent risk factor for AE-ILD after non-pulmonary surgery.The risk of AE-ILD should be kept in mind in patients with ILD and a high CRP level before non-pulmonary surgery. These patients should also be monitored carefully for development of AE-ILD after surgery.

The aim of this study was to evaluate whether serial measurements of serum Krebs von den Lungen-6 (KL-6) could be used to monitor disease activity and to detect recurrence in patients with interstitial pneumonia (IP) with anti-aminoacyl-tRNA synthetase antibodies (ARS-IP).This retrospective cohort study included 44 patients with ARS-IP. Thirty-six patients had serial data of blood tests and pulmonary function tests. Baseline and longitudinal analyses were performed to investigate whether lung function parameters were associated with serum biomarkers (KL-6, lactate dehydrogenase [LDH], and C-reactive protein [CRP]) using Pearson correlation coefficient. Additionally, the diagnostic accuracy of changes in these biomarkers for detecting ARS-IP recurrence was analyzed by receiver operating characteristic curve analysis.Baseline levels of serum KL-6 were significantly associated with vital capacity (VC) and diffusion capacity for carbon monoxide (DLco) (r = -0.40, P = .015, and r = -0.44, P = .010, respectively). Longitudinal changes in KL-6 were inversely correlated with changes in VC and DLco (r = -0.57, P <.001 and r = -0.42, P <.001, respectively), whereas those in LDH and CRP were not. Moreover, longitudinal changes in serum KL-6 were significantly associated with recurrence of ARS-IP and could be used to detect ARS-IP recurrence; the area under the curve was 0.79 (P = .002).The present study demonstrated that serial measurement of KL-6 is useful for monitoring disease activity and detecting recurrence of ARS-IP.

Background: The receptor for advanced glycation end-product (RAGE) is a multi-ligand receptor involved in inflammation. In the gene encoding RAGE ( AGER ), there are three well-known polymorphisms; rs2070600, rs1800624, and rs1800625, which potentially increase the risk of lung cancer. Remarkably, AGER rs2070600 polymorphism, which increases ligand-binding affinity, is a potential prognostic factor in non-small cell lung cancer, but the underlying mechanism is unclear. The neutrophil-lymphocyte ratio (NLR) reflects tumor-associated systemic inflammatory conditions; high ratios are associated with poor prognosis in multiple cancers. Additionally, some humoral factors via RAGE-signaling are associated with elevated NLR in cancer patients., Objectives: Associations of AGER polymorphisms with disease susceptibility, prognosis, and NLR were investigated in Japanese patients with lung adenocarcinoma., Methods: We included 189 patients with lung adenocarcinoma, 96 of which had distant metastases, and 303 healthy controls. The correlation between AGER polymorphisms (rs2070600, rs1800624, rs1800625) and disease susceptibility and factors elevating the mortality and NLR in patients with metastases were evaluated., Results: Only the minor allele of rs2070600 was associated with a higher NLR ( β = 0.209, p = 0.043) and a poor prognosis (Hazard ratio = 2.06, 95% Confidence interval = 1.09-3.77, p = 0.028) in patients with metastatic disease, independently of background characteristics, including EGFR mutation status. All three polymorphisms were not associated with the risk of lung adenocarcinoma., Conclusions: The AGER rs2070600 polymorphism was independently associated with systemic inflammation and poor prognosis in patients with metastatic lung adenocarcinoma., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interests.

Background: Pituitary metastasis of lung cancer is rare; however, it often causes diabetes insipidus. Although the majority of such patients are treated with radiation therapy, it remains unclear whether diabetes insipidus can be controlled by radiation therapy., Case: A 72-year-old man was admitted to our hospital for hemosputum, headache, and polyuria. A chest CT scan showed a 3.0 cm mass in the left upper lobe of his lung. Bronchofiberscopy results confirmed the pathological diagnosis of lung adenocarcinoma. Based on the findings from PET-CT, head MRI, and endocrine tests, the diagnosis of lung adenocarcinoma( cT1bN0M1b, stage IV)accompanied with central diabetes insipidus caused by pituitary metastasis was made. Oral administration of desmopressin reduced urine volumes; however, chemotherapy for achieving stable disease in the primary tumor was ineffective in controlling the symptoms of diabetes insipidus. Chemotherapy was discontinued after 4 months because of severe hematological toxicity. During 2 months after the cessation of chemotherapy, polyuria worsened and, therefore, radiation therapy for pituitary metastasis was started. Following the radiation therapy, an apparent reduction in urine volume was observed., Conclusion: Our experience of this case suggests that radiation therapy for pituitary metastasis should be considered at the time when diabetes insipidus becomes clinically overt.

Prolonged exposure to hyperoxia produces extraordinary amounts of reactive oxygen species (ROS) in the lung and causes hyperoxic lung injury. Although supraphysiological oxygen is routinely administered for the management of respiratory failure, there is no effective strategy to prevent hyperoxic lung injury. In our previous study, we showed that suplatast tosilate, an asthma drug that inhibits T helper 2 (Th2) cytokines, ameliorated bleomycin-induced lung injury and fibrosis through Th2-independent mechanisms. Because bleomycin also generates ROS, we hypothesized that suplatast tosilate might have antioxidant activity and protect the lung against hyperoxic lung injury. To test this hypothesis, mice exposed to hyperoxia were given suplatast tosilate through drinking water. Treatment with suplatast tosilate significantly prolonged mouse survival, reduced the increases in the numbers of inflammatory cells, levels of the pro-inflammatory cytokines/chemokines IL-6 and MCP-1, and protein in bronchoalveolar lavage fluid, and ameliorated lung injury in histological assessment. Suplatast tosilate treatment also significantly inhibited hyperoxia-induced elevations in the levels of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, in bronchoalveolar lavage fluid and 8-isoprostane, a marker of lipid peroxidation, in lung tissue. This finding suggests that suplatast tosilate exerts an antioxidant activity in vivo. In addition, we investigated whether suplatast tosilate has a scavenging effect on hydroxyl radical, the most reactive and harmful ROS, using electron paramagnetic resonance spin-trapping. Suplatast tosilate was shown to scavenge hydroxyl radicals in a dose-dependent manner, and its reaction rate constant with hydroxyl radical was calculated as 2.6×10 11 M -1 S -1 , which is faster than that of several well-established antioxidants, such as ascorbate, glutathione, and cysteine. These results suggest that suplatast tosilate protects the lung against hyperoxic lung injury by decreasing the degree of oxidative stress induced by ROS, particularly by scavenging hydroxyl radicals. Suplatast tosilate might become a potential therapeutic for hyperoxic lung injury., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Objective: While adult asthma has been shown to be a risk factor for COPD, the effect of remitted childhood asthma on adult lung function has not been clarified. The aim of this study was to examine whether remitted childhood asthma is a risk factor for airflow obstruction in a middle-aged general population., Methods: A total of 9896 participants (range: 35-60 years) from five healthcare centres were included in the study. The participants were classified into four categories based on the presence or absence of physician-diagnosed childhood/adulthood asthma and asthma symptoms as follows: healthy controls (n = 9154), remitted childhood asthma (n = 287), adulthood-onset asthma (n = 354) and childhood-adulthood asthma (n = 101)., Results: The prevalence of respiratory symptoms was similar in both the participants with remitted childhood asthma and healthy controls. The prevalence of airflow obstruction (forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) < 0.7) was significantly higher in the participants with remitted childhood asthma, those with adult-onset asthma and those with childhood-adulthood asthma (5.2%, 14.4% and 16.8%, respectively) compared with healthy controls (2.2%). Multivariate logistic regression showed that remitted childhood asthma was independently associated with airflow obstruction. Among the participants with remitted childhood asthma, ever-smokers had significantly lower FEV 1 /FVC than never-smokers., Conclusion: Clinically remitted childhood asthma is associated with airflow obstruction in middle-aged adults. Smoking and remitted childhood asthma may be additive factors for the development of airflow obstruction., (© 2016 Asian Pacific Society of Respirology.)

Purpose: The use of small-interfering RNA (siRNA) as an inhalation therapy has recently received much attention. Some reports have confirmed the suppression of gene expression in whole lungs following intratracheal administration of dry powdered siRNA; however, the anatomical location in the lung where gene silencing occurs has not been precisely identified. Here, we aimed to histologically evaluate gene silencing efficacy in murine lungs by intratracheal administration of an siRNA/chitosan complex as a dry powder., Methods: Enhanced green fluorescence protein (EGFP)-specific siRNA (EGFP-siRNA)/chitosan powder was prepared and administered intratracheally to EGFP transgenic mice or mice carrying metastatic lung tumors consisting of Lewis lung carcinoma (LLC) cells stably expressing EGFP (EGFP-LLCs). Thereafter, green fluorescence intensities were quantified in the airways, parenchyma, and lung tumors., Results: Intratracheal administration of the EGFP-siRNA/chitosan powder suppressed EGFP expression in the bronchi, bronchioles, and alveolar walls of EGFP transgenic mice. Additionally, EGFP-siRNA/chitosan effectively silenced EGFP expression in lung tumors consisting of EGFP-LLC cells., Conclusions: Pulmonary administration of siRNA/chitosan powder suppressed gene expression throughout the lung and in lung tumors. Therefore, this may become a powerful strategy to target genes expressed in a wide range of respiratory diseases involving the airways, parenchyma, and lung tumors.

Aminopeptidase N (APN/CD13) is involved in tumor cell invasion and tumor angiogenesis and is considered a promising therapeutic target in the treatment of cancer. To develop a novel monoclonal antibody-based cancer therapy targeting APN/CD13, we established a fully humanized anti-APN/CD13 monoclonal antibody, MT95-4. In vitro, MT95-4 inhibited APN/CD13 enzymatic activity on the tumor cell surface and blocked tumor cell invasion. B16 mouse melanoma cells stably expressing human APN/CD13 were also established and were inoculated s.c. or injected i.v. into nude mice. We found that expression of human APN/CD13 in murine melanoma cells increased the size of subcutaneous tumors, extent of lung metastasis and degree of angiogenesis in the subcutaneous tumors; these tumor-promoting and angiogenesis-promoting characteristics were reduced by the i.p. administration of MT95-4. To further verify the specificity of MT95-4 for neutralization of APN/CD13 activity, MT95-4 was administered into NOD/SCID mice inoculated s.c. with H1299 or PC14 cells, which exhibit high expression of APN/CD13, or with A549 cells, which exhibit weak expression of APN/CD13. MT95-4 reduced tumor growth and angiogenesis in mice bearing H1299-derived and PC14-derived tumors, but not in mice bearing A549-derived tumors. These results suggested that the antitumor and anti-angiogenic effects of MT95-4 were dependent on APN/CD13 expression in tumor cells. Given that MT95-4 is the first fully humanized monoclonal antibody against APN/CD13, MT95-4 should be recognized as a promising candidate for monoclonal antibody therapy against tumors expressing APN/CD13., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Objective: To evaluate the safety profile of nicergoline compared with placebo and other active agents from published randomised controlled trials., Design: Systematic review and meta-analysis of nicergoline compared with placebo and other active agents across various indications., Data Sources: MEDLINE, Medline-in-process, Cochrane, EMBASE, EMBASE alerts, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR) and Cochrane Methodology Register (CMR) for all the randomised controlled trials, open-label or blinded, in adults treated with nicergoline. Studies published until August 2013 were included., Review Method: 29 studies were included for data extraction. The studies included in this review were majorly from European countries and mostly in cerebrovascular disease (n=15) and dementia (n=8)., Results: The treatment withdrawals were comparatively lower in the nicergoline group as compared with the placebo group (RR=0.92; 95% CI 0.7 to 1.21) and other active comparators (RR=0.45; 95% CI 0.10 to 1.95), but the difference was non-significant. Incidence of any adverse events (AEs) was slightly higher (RR=1.05; 95% CI 0.93 to 1.2) while incidence of serious AEs was lower (RR=0.85; 95% CI 0.50 to 1.45) in the nicergoline compared with placebo group. Frequency of anxiety was significantly lower in nicergoline as compared with placebo (p=0.01). Other AEs including diarrhoea, gastric upset, dizziness and drowsiness were less frequent in the nicergoline group when compared with placebo/active drugs, but the difference was non-significant. Frequency of hypotension and hot flushes was slightly higher in the nicergoline group but the difference was non-significant. None of the studies reported any incidence of fibrosis or ergotism with nicergoline treatment., Conclusions: Nicergoline is an ergot derivative, but its safety profile is better than other ergot derivatives like ergotamine and ergotoxine. This systematic review and meta-analysis suggests that nicergoline has a good safety profile. None of the studies included in this systematic review reported any incidence of fibrosis or ergotism with nicergoline., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The CCAAT/enhancer-binding protein β (C/EBPβ) regulates a variety of factors and cellular responses associated with pulmonary fibrosis. To distinguish its role in the mesenchyme from that in other compartments, the effects of mesenchymal-specific deletion of C/EBPβ on pulmonary fibrosis was examined. Crossing of mice with the floxed C/EBPβ gene with α2(I) collagen enhancer-CreER(T)-bearing mice successfully generated progeny with a conditional knockout (CKO) of C/EBPβ in collagen I-expressing ("mesenchymal") cells only on treatment with tamoxifen (C/EBPβ CKO). When treated with an endotracheal bleomycin injection, C/EBPβ CKO mice showed significant attenuation of pulmonary fibrosis relative to control C/EBPβ-intact mice. C/EBPβ CKO mice also had reduced myofibroblasts in the lung. However, no significant differences in inflammatory/immune cell influx were noted in the mutant mice relative to the control mice. DNA microarray and real-time PCR analyses identified a series of myofibroblast differentiation regulators as novel target genes of C/EBPβ. Interestingly, C/EBPβ deficiency caused a marked induction of matrix metalloproteinase 12 expression, suggesting its potential role as a repressor, which could account for the noted reduction in fibrosis in the C/EBPβ-deficient mice. Thus, these findings indicate an essential role for C/EBPβ in the mesenchymal compartment in pulmonary fibrosis that is independent of its effects on inflammation or immune cell infiltration., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Chronic hepatitis C virus (HCV) infection causes intra- and extra-hepatic complications. The elimination of HCV has been reported to be beneficial for asthmatic patients with HCV infection. Therefore, we hypothesized that chronic HCV infection might be associated with the severity of asthma., Methods: Asthmatic patients were prospectively enrolled from 13 outpatient settings. Hepatitis B surface (HBs) antigen and HCV-RNA were measured at the time of enrollment and evaluated along with the clinical characteristics of the patients including the age, sex, duration of asthma, atopic status, smoking history, and treatment step according to the Global Initiative for Asthma guideline., Results: Of 1327 asthmatic patients, 1258 patients (94.8%) were treated with inhaled corticosteroids, 18 patients were positive for HBs antigen (1.4%), and 32 patients (2.4%) were positive for HCV-RNA. When compared with HCV-RNA-negative patients, HCV-RNA-positive patients required significantly more drugs for the treatment of asthma. No such relationship was observed in patients with positive HBs antigen. A multivariate logistic regression analysis showed that the male sex, a long duration of asthma, status as a current smoker, and HCV-RNA positivity were independently associated with more severe asthma., Conclusions: These results suggest that chronic HCV infection is an independent factor that predisposes asthmatic patients to more severe asthma. The evaluation of chronic HCV infection may be helpful for the management of severe asthmatic patients without obvious factors associated with severe asthma.

Background: ARDS patients present with intrapulmonary and systemic coagulation abnormalities. We previously demonstrated that circulating KL-6/MUC1 could predict complications of disseminated intravascular coagulation (DIC) in ARDS. Recent studies indicate that circulating mucin can induce intravascular coagulation via interactions with selectin. We, therefore, investigated whether circulating mucins carrying selectin ligands are associated with DIC in ARDS., Methods: We evaluated newly diagnosed patients with ARDS (n = 46) or bacterial pneumonia (n = 17), and healthy control subjects (n = 60). Using serum collected at diagnosis, circulating levels of KL-6/MUC1, KL-6/MUC1 carrying sialyl Lewis(a) (SLAK), KL-6/MUC1 carrying sialyl Lewis(x) (SLXK), and P-selectin glycoprotein ligand-1 (PSGL-1) were measured., Results: Serum mucins with selectin ligands were significantly elevated in patients with ARDS compared with healthy control subjects. Significantly elevated levels of SLAK and SLXK were found in patients with ARDS subsequently complicated with DIC, as compared with those without DIC. In contrast, serum PSGL-1 levels were significantly decreased in ARDS patients with DIC. Furthermore, SLAK was discovered to be an independent predictor of DIC complication in ARDS. Using cutoff levels obtained by receiver operating characteristic curves, we found that these mucins can be used to distinguish between patients with ARDS with and without subsequently occurring DIC. Among the analyzed mucins, SLAK has the highest sensitivity and specificity for predicting future DIC development., Conclusions: These results suggest that mucins with selectin ligands are novel markers for ARDS with future complications of DIC, and KL-6/MUC1 carrying selectin ligands may be involved in the pathogenesis of DIC in patients with ARDS.