The blunted vascular endothelial growth factor-A (VEGF-A) response to high-altitude hypoxia and genetic variants in the promoter region of the VEGFA gene in Sherpa highlanders.

Background: Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, which may be achieved by mechanisms promoting microcirculatory blood flow and capillary density at high altitudes for restoring oxygen supply to tissues. Vascular endothelial growth factors (VEGFs) are important signaling proteins involved in vasculogenesis and angiogenesis which are stimulated by hypoxia. We hypothesize that the VEGF-A, the major member of the VEGF family, and the gene encoding VEGF-A (VEGFA) play a part in the adaptation to high-altitude hypoxia in Sherpa highlanders. Methods: Fifty-one Sherpa highlanders in Namche Bazaar village at a high altitude of 3,440 meters (m) above sea level and 76 non-Sherpa lowlanders in Kathmandu city at 1,300 m in Nepal were recruited for the study. Venous blood was sampled to obtain plasma and extract DNA from each subject. The plasma VEGF-A concentrations were measured and five single-nucleotide polymorphisms (SNPs, rs699947, rs833061, rs1570360, rs2010963, and rs3025039) in the VEGFA were genotyped. The VEGF-A levels and allelic frequencies of the SNPs were compared between the two populations. Results: A significant difference in oxygen saturation (SpO2) was observed between the two ethnic groups locating at different elevations (93.7 ± 0.2% in Sherpas at 3,440 m vs. 96.7 ± 0.2% in non-Sherpas at 1,300 m, P < 0.05). The plasma VEGF-A concentration in the Sherpas at high altitude was on the same level as that in the non-Sherpas at low altitude (262.8 ± 17.9 pg/ml vs. 266.8 ± 21.8 pg/ml, P = 0.88). This result suggested that the plasma VEGF-A concentration in Sherpa highlanders was stable despite a high-altitude hypoxic stimulus and that therefore the Sherpas exhibited a phenotype of blunted response to hypoxic stress. Moreover, the allele frequencies of the SNPs rs699947, rs833061, and rs2010963 in the promoter region of the VEGFA were different between the Sherpa highlanders and non-Sherpa lowlanders (corrected P values = 3.30 ×10-5, 4.95 ×10-4, and 1.19 ×10-7, respectively). Conclusions: Sherpa highlanders exhibited a blunted VEGF-A response to hypoxia at high altitudes, which was speculated to be associated with the distinctive genetic variations of the SNPs and haplotype in the promoter region of VEGFA in Sherpa highlanders.

Associations Between Morphological Phenotypes of COPD and Clinical Characteristics in Surgically Resected Patients with COPD and Concomitant Lung Cancer.

Purpose: The associations between morphological phenotypes of COPD based on the chest computed tomography (CT) findings and clinical characteristics in surgically resected patients with COPD and concomitant lung cancer are unclear. The purpose of this study was to clarify the differences in clinical characteristics and prognosis among morphological phenotypes based on the chest CT findings in these patients. Patients and Methods: We retrospectively reviewed the medical records of 132 patients with COPD and concomitant lung cancer who had undergone pulmonary resection for primary lung cancer. According to the presence of emphysema and bronchial wall thickness on chest CT, patients were classified into three phenotypes: non-emphysema phenotype, emphysema phenotype, or mixed phenotype. Results: The mixed phenotype was associated with poorer performance status, higher score on the modified British Medical Research Council (mMRC) dyspnea scale, higher residual volume in pulmonary function, and higher proportion of squamous cell carcinoma than the other phenotypes. Univariate and multivariate Cox proportional hazards regression analyses showed that the extent of emphysema on chest CT, presented as a low attenuation area (LAA) score, was an independent determinant that predicted prognosis. In the Kaplan-Meier analysis, the Log rank test showed significant differences in survival between the non-emphysema and mixed phenotypes, and between the emphysema and mixed phenotypes. Conclusion: The cross-sectional pre-operative LAA score can predict the prognosis in surgically resected patients with COPD and concomitant lung cancer. The COPD phenotype with both emphysema and bronchial wall thickness on chest CT was associated with poorer performance status, greater extent of dyspnea, greater impairment of pulmonary function, and worse prognosis.

Hierarchical cluster analysis based on disease-associated manifestations of patients with lymphangioleiomyomatosis: An analysis of the national database of designated intractable diseases of Japan.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes. METHODS: Using cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations. RESULTS: Four clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required. CONCLUSIONS: Hierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future.

Automated Diseased Lung Volume Percentage Calculation in Quantitative CT Evaluation of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis.

OBJECTIVE: Several software-based quantitative computed tomography (CT) analysis methods have been developed for assessing emphysema and interstitial lung disease. Although the texture classification method appeared to be more successful than the other methods, the software programs are not commercially available, to our knowledge. Therefore, this study aimed to investigate the usefulness of a commercially available software program for quantitative CT analyses. METHODS: This prospective cohort study included 80 patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). RESULTS: The percentage of low attenuation volume and high attenuation volume had high sensitivity and high specificity for detecting emphysema and pulmonary fibrosis, respectively. The percentage of diseased lung volume (DLV%) was significantly correlated with the lung diffusion capacity for carbon monoxide in all patients with COPD and IPF patients. CONCLUSIONS: The quantitative CT analysis may improve the precision of the assessment of DLV%, which itself could be a useful tool in predicting lung diffusion capacity in patients with the clinical diagnosis of COPD or IPF.

The Gly82Ser mutation in AGER contributes to pathogenesis of pulmonary fibrosis in combined pulmonary fibrosis and emphysema (CPFE) in Japanese patients.

The dominant pathogenesis underlying the combined pulmonary fibrosis and emphysema (CPFE) remains unresolved. The receptor for advanced glycation end-products (RAGE) is highly expressed in lung tissues and interacts with distinct multiple ligands, implicating it in certain lung diseases. To elucidate the pathogenesis of CPFE, we genotyped three single nucleotide polymorphisms (SNPs: rs2070600, rs1800625, and rs2853807) of the gene encoding RAGE (AGER) in 111 CPFE patients and 337 chronic obstructive pulmonary disease (COPD) patients of Japanese by using StepOne Real-Time PCR System for SNP genotyping assay. Serum levels of soluble RAGE (sRAGE) were measured by ELISA. We found that the allele frequency of rs2070600 was significantly different between the two groups [corrected P (Pc) = 0.015]. In addition, the minor allele was associated with CPFE patients relative to COPD patients in a dominant effect model (Odds Ratio = 1.93; Pc = 0.018). Moreover, the serum sRAGE level was significantly lower in the CPFE group than the COPD group (P = 0.014). The rs2070600 minor allele was significantly associated with reduced sRAGE level in CPFE patients and independently affected sRAGE level reduction in this group (P = 0.020). We concluded that the AGER rs2070600 minor allele (Gly82Ser mutation) is associated with the pathogenesis of pulmonary fibrosis in CPFE in Japanese patients.

Differences Between Central Airway Obstruction and Chronic Obstructive Pulmonary Disease Detected with the Forced Oscillation Technique.

Background: Obstructive ventilatory disturbances occur in both chronic obstructive pulmonary disease (COPD), a typical disease representative of peripheral airway obstruction, and central airway obstruction (CAO). Pulmonary function tests (PFTs), which depend on patient effort, are traditionally used to evaluate lung function. The forced oscillation technique (FOT) is an effort-independent method for examining lung function during tidal breathing. The FOT is used universally to assess respiratory function in patients with COPD. Several studies have measured FOT to assess ventilatory disturbances in CAO. The results showed that FOT measurements in patients with CAO were similar to those reported in patients with COPD. However, no studies have compared FOT measurements directly between CAO and COPD. The aim of this study was to identify differences in ventilatory disturbances between peripheral and central airway obstructions in COPD and CAO, before patients received pharmacological therapy or bronchoscopic interventions, respectively. Patients and Methods: We retrospectively included 16 patients with CAO (10 cases of tracheal obstruction and 6 cases of bronchial obstruction) and 75 treatment-naïve patients with COPD (60 cases in Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II and 15 cases in GOLD stage III) that were admitted from December 2013 to May 2017. Prior to treatment, patients were examined with the FOT and PFTs. Results: All parameters measured with the FOT in the inspiratory phase were significantly worse in patients with CAO than in patients with COPD. The PFTs showed that the CAO group had a significantly lower peak expiratory flow rate. In the airway wall thickening phenotype of COPD, a difference between the inspiratory and expiratory phases of the resonance frequency (ΔFres) was the best indicator for distinguishing between peripheral and central airway obstructions. Conclusion: This study compared differences between CAO and COPD (mainly GOLD stage II). We found that the FOT measurement, ΔFres, was the optimal indicator of the difference between the airway wall thickening COPD phenotype and CAO. Thus, the difference might be due to mechanical changes that occur in COPD with airway wall thickening.

The Interstitial Lung Disease-Gender-Age-Physiology Index Can Predict the Prognosis in Surgically Resected Patients with Interstitial Lung Disease and Concomitant Lung Cancer.

BACKGROUND: The interstitial lung disease-gender-age-physiology (ILD-GAP) index and staging system have been reported as a clinical prognostic factor for ILD, including all ILD subtypes. OBJECTIVES: The purpose of this study was to clarify the association of various prognostic indices, including the ILD-GAP index, with the prognosis, the incidence of acute exacerbations of ILD (ILD-AE), and the use of long-term oxygen therapy (LTOT) after surgery in surgically resected patients with ILD and concomitant lung cancer, to provide additional information when considering whether it is safe to perform surgery. METHODS: The medical records of patients with ILD and concomitant lung cancer who had undergone surgery at Shinshu University Hospital between August 2001 and September 2016 were retrospectively analyzed. RESULTS: There were significant differences in survival between the ILD-GAP index: 0-1 and ≥4 groups (p = 0.0001) and between the ILD-GAP index: 2-3 and ≥4 groups (p = 0.0236). A higher ILD-GAP index was independently associated with the risk of death (hazard ratio [HR] 1.32030; p = 0.0059). A higher body mass index (BMI) and a higher serum C-reactive protein (CRP) level were independently associated with the incidence of ILD-AE (HR 1.28336; p = 0.0206 and HR 26.3943; p = 0.0165, respectively). A higher severity of ILD on chest high-resolution computed tomography (HRCT) was independently associated with the use of LTOT (HR 2.78670; p = 0.0313). CONCLUSIONS: The ILD-GAP index can predict the prognosis in surgically resected patients with ILD and concomitant lung cancer. The BMI and serum CRP levels were independent determinants that predicted the incidence of ILD-AE. The severity of ILD on chest HRCT was an independent determinant that predicted the use of LTOT.