Inhibition of a Microbiota-Derived Peptide Ameliorates Established Acute Lung Injury.

Acute lung injury (ALI) is a clinical syndrome characterized by a diffuse lung inflammation that commonly evolves into acute respiratory distress syndrome and respiratory failure. The lung microbiota is involved in the pathogenesis of ALI. Corisin, a proapoptotic peptide derived from the lung microbiota, plays a role in ALI and acute exacerbation of pulmonary fibrosis. Preventive therapeutic intervention with a monoclonal anticorisin antibody inhibits ALI in mice. However, whether inhibition of corisin with the antibody ameliorates established ALI is unknown. Here, the therapeutic effectiveness of the anticorisin antibody in already established ALI in mice was assessed. Lipopolysaccharide was used to induce ALI in mice. After causing ALI, the mice were treated with a neutralizing anticorisin antibody. Mice treated with the antibody showed significant improvement in lung radiological and histopathologic findings, decreased lung infiltration of inflammatory cells, reduced markers of lung tissue damage, and inflammatory cytokines in bronchoalveolar lavage fluid compared with untreated mice. In addition, the mice treated with anticorisin antibody showed significantly increased expression of antiapoptotic proteins with decreased caspase-3 activation in the lungs compared with control mice treated with an irrelevant antibody. In conclusion, these observations suggest that the inhibition of corisin is a novel and promising approach for treating established ALI.

Amelioration of Pulmonary Fibrosis by Matrix Metalloproteinase-2 Overexpression.

Idiopathic pulmonary fibrosis is a progressive and fatal disease with a poor prognosis. Matrix metalloproteinase-2 is involved in the pathogenesis of organ fibrosis. The role of matrix metalloproteinase-2 in lung fibrosis is unclear. This study evaluated whether overexpression of matrix metalloproteinase-2 affects the development of pulmonary fibrosis. Lung fibrosis was induced by bleomycin in wild-type mice and transgenic mice overexpressing human matrix metalloproteinase-2. Mice expressing human matrix metalloproteinase-2 showed significantly decreased infiltration of inflammatory cells and inflammatory and fibrotic cytokines in the lungs compared to wild-type mice after induction of lung injury and fibrosis with bleomycin. The computed tomography score, Ashcroft score of fibrosis, and lung collagen deposition were significantly reduced in human matrix metalloproteinase transgenic mice compared to wild-type mice. The expression of anti-apoptotic genes was significantly increased, while caspase-3 activity was significantly reduced in the lungs of matrix metalloproteinase-2 transgenic mice compared to wild-type mice. Active matrix metalloproteinase-2 significantly decreased bleomycin-induced apoptosis in alveolar epithelial cells. Matrix metalloproteinase-2 appears to protect against pulmonary fibrosis by inhibiting apoptosis of lung epithelial cells.

Long-term prognosis of patients undergoing radiofrequency catheter ablation for atrial fibrillation: comparison between heart failure subtypes based on left ventricular ejection fraction.

AIMS: Heart failure (HF) prognosis has been reported similar in patients with preserved vs. reduced left ventricular ejection fraction (LVEF). This study compared the long-term prognosis of HF patients undergoing radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF). METHODS AND RESULTS: Among 5010 patients undergoing RFCA in Kansai Plus AF registry, 656 patients (13.1%) with a documented history of HF were enrolled in the study before RFCA. The primary endpoint was a composite of all-cause death, HF hospitalization, and stroke or systemic embolism. Patients with reduced (<40%), mid-range (40-49%), and preserved (≥50%) LVEF were 98 (14.9%), 107 (16.3%), and 451 (68.8%) patients, respectively. The prevalence of ischaemic heart disease and cardiomyopathies was higher among patients with reduced as compared with preserved LVEF (27.6% vs. 10.0%, P < 0.05 and 36.7% vs. 15.3%, P < 0.05, respectively). The median follow-up period was 2.9 years. The 3-year cumulative risk for the primary endpoint was higher in patients with reduced LVEF (32.7%) compared to those with mid-range (11.7%) or preserved (11.6%) LVEF (P < 0.001). Reduced LVEF was the most significant independent risk factor for primary endpoint (hazard ratio, 2.83; 95% confidence interval 1.74-4.61, P < 0.001). The 3-year arrhythmia recurrence rate was similar among the groups (48.2%, 42.8%, and 47.3%, respectively, P = 0.75). CONCLUSION: This study raises hypothesis that patients with HFrEF and AF had approximately three times higher risk for a composite of all-cause death, HF hospitalization, and stroke or systemic embolism after AF ablation compared with patients with HFmrEF or HFpEF.

Reverse Remodeling and Non-Contrast T1 Hypointense Infarct Core in Patients With Reperfused Acute Myocardial Infarction.

BACKGROUND: Non-contrast T1 hypointense infarct cores (ICs) within infarcted myocardium detected using cardiac magnetic resonance imaging (CMR) T1 mapping may help assess the severity of left ventricular (LV) injury. However, because the relationship of ICs with chronic LV reverse remodeling (LVRR) is unknown, this study aimed to clarify it.Methods and Results: We enrolled patients with reperfused AMI who underwent baseline CMR on day-7 post-primary percutaneous coronary intervention (n=109) and 12-month follow-up CMR (n=94). Correlations between ICs and chronic LVRR (end-systolic volume decrease ≥15% at 12-month follow-up from baseline CMR) were investigated. We detected 52 (47.7%) ICs on baseline CMR by non-contrast-T1 mapping. LVRR was found in 52.1% of patients with reperfused AMI at 12-month follow-up. Patients with ICs demonstrated higher peak creatine kinase levels, higher B-type natriuretic peptide levels at discharge, lower LV ejection fraction at discharge, and lower incidence of LVRR than those without ICs (26.5% vs. 73.3%, P<0.001) at follow-up. Multivariate logistic regression analysis showed that the presence of ICs was an independent and the strongest negative predictor for LVRR at 12-month follow-up (hazard ratio: 0.087, 95% confidence interval: 0.017-0.459, P=0.004). Peak creatine kinase levels, native T1 values at myocardial edema, and myocardial salvaged indices also correlated with ICs. CONCLUSIONS: ICs detected by non-contrast-T1 mapping with 3.0-T CMR were an independent negative predictor of LVRR in patients with reperfused AMI.

Transforming Growth Factorß1 Overexpression Is Associated with Insulin Resistance and Rapidly Progressive Kidney Fibrosis under Diabetic Conditions.

Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorß1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorß1 is associated with insulin resistance and the rapid progression of transforming growth factorß1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorß1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorß1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorß1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorß1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.

Impact of clinical information on CT diagnosis by radiologist and subsequent clinical management by physician in acute abdominal pain.

OBJECTIVE: The impact of clinical information on radiological diagnoses and subsequent clinical management has not been sufficiently investigated. This study aimed to compare diagnostic performance between radiological reports made with and without clinical information and to evaluate differences in the clinical management decisions based on each of these reports. METHODS: We retrospectively reviewed 410 patients who presented with acute abdominal pain and underwent unenhanced (n = 248) or enhanced CT (n = 162). Clinical information including age, sex, current and past history, physical findings, and laboratory tests were collected. Six radiologists independently interpreted CTs that were randomly assigned with or without clinical information, made radiological diagnoses, and scored the diagnostic confidence level. Four general and emergency physicians simulated clinical management (i.e., followed up in the outpatient clinic, hospitalized for conservative therapy, or referred to other departments for invasive therapy) based on reports made with or without the clinical information. Reference standards for the radiological diagnoses and clinical management were defined by an independent expert panel. RESULTS: The radiological diagnoses made with clinical information were more accurate than those made without clinical information (93.7% vs. 87.8%, p = 0.008). Median interpretation time for radiological reporting with clinical information was significantly shorter than that without clinical information (median 122.0 vs. 139.0 s, p < 0.001). Clinical simulation better matched the reference standard for clinical management when radiological diagnoses were made with reference to clinical information (97.3% vs. 87.8%, p < 0.001). CONCLUSION: Access to adequate clinical information enables accurate radiological diagnoses and appropriate subsequent clinical management of patients with acute abdominal pain. KEY POINTS: • Radiological interpretation improved diagnostic accuracy and confidence level when clinical information was provided. • Providing clinical information did not extend the interpretation time required by radiologists. • Radiological interpretation with clinical information led to correct clinical management by physicians.

Functional assessment of intermediate coronary artery stenosis with 4-Fr catheters.

The 4-Fr catheter system is not recommended for invasive functional assessment of coronary artery stenosis, because it tends to distort the aortic waveform. This study aimed to identify the incidence of aortic waveform distortion and a feasible method for correct diagnosis of coronary artery stenosis with a 4-Fr catheter. We retrospectively investigated 178 lesions with intermediate coronary artery stenosis. Non-hyperemic distal coronary artery pressure (Pd) and aortic pressure (Pa) were measured with a 4-Fr diagnostic or 6-Fr guiding catheter before and after saline flush. The mean Pd/mean Pa (Pd/Pa) and instantaneous wave-free ratio (iFR) were calculated before and after flushing. We compared the effect of flushing on the changes in Pd/Pa and iFR between the 4-Fr diagnostic and 6-Fr guiding catheters. Using the 4-Fr diagnostic catheter, there was a significant decrease in incidence of aortic waveform distortion from 42.0% (47 lesions) before flushing to 1.8% (2 lesions) after flushing (p < 0.001); the incidence was only 3.0% before saline flush and decreased to 0% after saline flush when using the 6-Fr guiding catheter. The presence of aortic waveform distortion influenced the iFR when the 4-Fr system was used. Functional measurements with the 4-Fr diagnostic catheter require adequate saline flush to remove the influence of aortic waveform distortion.

Protein S protects against allergic bronchial asthma by modulating Th1/Th2 balance.

BACKGROUND: Bronchial asthma is a chronic disease characterized by inflammation, obstruction, and hyperresponsiveness of the airways. There is currently no curative therapy for asthma. Type 2 helper T cell response plays a critical role in the pathogenesis of the disease. Protein S is a glycoprotein endowed with anticoagulant, anti-inflammatory, and anti-apoptotic properties. Whether protein S can suppress bronchial asthma and be useful for its therapy is unknown. METHODS: To address this question here we compared the development of allergen-associated bronchial asthma between wild type and protein S-overexpressing transgenic mice. Mice were sensitized and challenged with ovalbumin. We also evaluated the circulating levels of total and active protein S in patients with bronchial asthma and healthy controls. RESULTS: The circulating level of total protein S and of its active form was significantly decreased in patients with bronchial asthma compared to controls. Allergic protein S transgenic mice showed a significant reduction of airway hyperresponsiveness, lung tissue inflammatory cell infiltration, lung levels of Th2 cytokines and IgE compared to their wild-type counterparts. Administration of exogenous human protein S also decreased airway hyperresponsiveness and Th2-mediated lung inflammation in allergic wild-type mice compared with their untreated mouse counterparts. Human protein S significantly shifted the Th1/Th2 balance to Th1 and promoted the secretion of Th1 cytokines (IL-12, tumor necrosis factor-α) from dendritic cells. CONCLUSIONS: These observations suggest the strong protective activity of protein S against the development of allergic bronchial asthma implicating its potential usefulness for the disease treatment.

Factors leading to failure to diagnose pulmonary malignant tumors using endobronchial ultrasound with guide sheath within the target lesion.

BACKGROUND: The diagnostic yield of peripheral pulmonary lesions has significantly increased with the use of radial endobronchial ultrasound with guide sheath within the lesion. Here, we retrospectively evaluated factors leading to misdiagnosis of pulmonary malignant tumors using endobronchial ultrasound with the guide sheath within the lesion. METHODS: We assessed the final histopathological diagnosis of biopsy samples taken from 130 patients with lung malignant tumors that underwent endobronchial ultrasound with guide sheath within the lesion. RESULTS: Among 130 patients, 8 (6%) showed no definite malignant findings in biopsy samples but the presence of malignant cells (primary lung cancer 7, diffuse large B cell lymphoma 1) was subsequently confirmed by histopathological study of specimens taken by computed tomography-guided needle biopsy or surgery. Of the eight cases with diagnostic failure, the size of the biopsy sample was insufficient in five due to technical difficulties during the diagnostic procedure, and the diagnosis of malignant tumor was difficult in five cases because of extensive scarring tissue or central necrosis. CONCLUSIONS: The results of this study showed that technical difficulties and/or pathological heterogeneity of the tumor might lead to failure to diagnose lung malignant tumor in cases using endobronchial ultrasound with guide sheath within the lesion.

Protein S is Protective in Acute Lung Injury by Inhibiting Cell Apoptosis.

Acute lung injury is a fatal disease characterized by inflammatory cell infiltration, alveolar-capillary barrier disruption, protein-rich edema, and impairment of gas exchange. Protein S is a vitamin K-dependent glycoprotein that exerts anticoagulant, immunomodulatory, anti-inflammatory, anti-apoptotic, and neuroprotective effects. The aim of this study was to evaluate whether human protein S inhibits cell apoptosis in acute lung injury. Acute lung injury in human protein S transgenic and wild-type mice was induced by intratracheal instillation of lipopolysaccharide. The effect of human protein S on apoptosis of lung tissue cells was evaluated by Western blotting. Inflammatory cell infiltration, alveolar wall thickening, myeloperoxidase activity, and the expression of inflammatory cytokines were reduced in human protein S transgenic mice compared to the wild-type mice after lipopolysaccharide instillation. Apoptotic cells and caspase-3 activity were reduced while phosphorylation of extracellular signal-regulated kinase was enhanced in the lung tissue from human protein S transgenic mice compared to wild-type mice after lipopolysaccharide instillation. The results of this study suggest that human protein S is protective in lipopolysaccharide-induced acute lung injury by inhibiting apoptosis of lung cells.

Mice overexpressing latent matrix metalloproteinase-2 develop lung emphysema after short-term exposure to cigarette smoke extract.

Chronic obstructive pulmonary disease is the major growing cause of mortality and morbidity worldwide, and it is going to become the third most common cause of death by 2020. Chronic obstructive pulmonary disease is pathologically characterized by lung emphysema and small airway inflammation. Animal models are very important to get insights into the disease pathogenesis but current models of chronic obstructive pulmonary disease take a long time to develop. The need of a new model is compelling. In the present study we focus on the role of matrix metalloproteinases in the pathogenesis of chronic obstructive pulmonary disease and hypothesized that lung overexpression of latent matrix metalloproteinases-2 would allow the development of emphysema after short-term exposure to cigarette smoke extract inhalation. Human latent matrix metalloproteinases-2 transgenic mouse expressing high level of the protein in the lungs and wild type mouse were exposed to aerosolized cigarette smoke extract for two weeks. Transgenic mice showed significant lung emphysematous changes, increased infiltration of inflammatory cells and enhanced lung concentrations of inflammatory cytokines in the lungs compared to their wild type counterparts after inhalation of cigarette smoke extract. This novel mouse model will be a very useful tool for evaluating the mechanistic pathways and for development of novel therapies in cigarette smoke-associated lung emphysema.

Inhibition of Cell Apoptosis and Amelioration of Pulmonary Fibrosis by Thrombomodulin.

Pulmonary fibrosis is the terminal stage of a group of idiopathic interstitial pneumonias, of which idiopathic pulmonary fibrosis is the most frequent and fatal form. Recent studies have shown that recombinant human thrombomodulin (rhTM) improves exacerbation and clinical outcome of idiopathic pulmonary fibrosis, but the mechanism remains unknown. This study evaluated the mechanistic pathways of the inhibitory activity of rhTM in pulmonary fibrosis. Transgenic mice overexpressing human transforming growth factor-ß1 that develop spontaneously pulmonary fibrosis, and wild-type mice treated with bleomycin were used as models of lung fibrosis. rhTM was administered to mice by i.p. injection or by the intranasal route. Therapy with rhTM significantly decreased the concentration of high mobility group box1, interferon-γ, and fibrinolytic markers, the expression of growth factors including transforming growth factor-ß1, and the degree of lung fibrosis. rhTM significantly suppressed apoptosis of lung epithelial cells in in vivo and in vitro experiments. The results of the present study demonstrated that rhTM can inhibit bleomycin-induced pulmonary fibrosis and transforming growth factor-ß1-driven exacerbation and progression of pulmonary fibrosis, and that apart from its well-recognized anticoagulant and anti-inflammatory properties, rhTM can also suppress apoptosis of lung epithelial cells.