Yuji Higashimoto

Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease

BACKGROUND Recent studies show that COPD patients exhibit low-grade systemic inflammation, and that plasma fibrinogen and high neutrophil counts are related to faster declines in lung function. We examined correlations between serum biomarkers and the decline of lung function in COPD patients. METHOD Baseline levels of 9 serum biomarkers (TIMP-1, alpha1-antitrypsin, MMP-9, TNF-alpha, TGF-beta, IL-6, IL-8, neutrophil elastase and CRP), fibrinogen and white blood cell counts (WCC) were measured in 96 COPD patients. Lung function was measured at the time of blood sampling and every 3-6 months during the observation period (median 25.0 months). RESULTS Twenty patients were rapid decliners of lung function and 53 patients were non-decliners. Neutrophil counts, serum CRP and MMP-9 were significantly higher in the rapid decliners (p<0.05). The annual change of % predicted FEV(1) was inversely correlated with MMP-9 (r=-0.288; p<0.01) and CRP (r=-0.354; p<0.005) (partial correlation coefficients adjusted for age, sex, cardiovascular disease, smoking history, and baseline % predicted FEV(1)). The remaining biomarkers were not correlated with the annual change of % predicted FEV(1). CONCLUSION Serum CRP and MMP-9 levels were related to FEV(1) decline. These markers are good candidates as predictors for rapid decline of FEV(1) in COPD patients. Additional long-term and larger size studies of COPD patients could help determine the exact roles for these biomarkers.

Systemic inflammation in chronic obstructive pulmonary disease and asthma: Similarities and differences

Background and objective:  While recent studies have shown that patients with COPD and patients with asthma exhibit evidence of airway and systemic inflammation, markers of systemic inflammation have not been compared between the two diseases.

Increased serum concentrations of tissue inhibitor of metalloproteinase-1 in COPD patients

Matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinase (TIMP)-1 concentrations are increased in the sputum of asthma and chronic bronchitis patients, and are thought to be related to airflow obstruction. However, serum concentrations of these enzymes have not been clearly evaluated in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to examine the serum concentrations of these enzymes in COPD and asthmatic patients in order to determine their relationship with airway obstruction. Serum samples were obtained from 72 patients with COPD: 66 control subjects and 26 patients with asthma. Smoking histories of control subjects were matched with those of COPD patients. Serum concentrations of TIMP-1 and MMP-9 were determined by ELISA. The circulating TIMP-1 concentration was significantly higher in stable COPD patients than in control and asthmatic subjects, and was significantly negatively correlated with forced expiratory volume in one second/forced vital capacity in COPD patients. The molar ratio between MMP-9 and TIMP-1 was significantly lower in COPD patients than in control subjects. In patients with COPD, the serum TIMP-1 concentration was significantly increased during disease exacerbation. In conclusion, the current findings suggest that serum tissue inhibitors of metalloproteinase-1 concentration can be used as a serum marker of airway obstruction and exacerbation in chronic obstructive pulmonary disease patients.

Adenoviral E1A Suppresses Secretory Leukoprotease Inhibitor and Elafin Secretion in Human Alveolar Epithelial Cells and Bronchial Epithelial Cells

Background: An imbalance between neutrophil protease and surrounding antiprotease levels has been shown to be important in the pathogenesis of chronic obstructive pulmonary disease (COPD). Adenoviral E1A DNA and protein are frequently detected in the lungs of COPD patients. As secretory leukoprotease inhibitor (SLPI) and elafin/skin-derived antileukoproteinase (SKALP) are locally produced in the lung and inhibit neutrophil elastase activity, we hypothesized that adenoviral E1A might affect the production of these antiproteases. Objectives: To examine the effect of E1A on SLPI and elafin/SKALP secretion in A549 (alveolar epithelial) cells and primary human bronchial epithelial (HBE) cells. Methods: SLPI and elafin/SKALP were quantitated from cell culture supernatants using an ELISA. SLPI mRNA expression was examined by Northern blotting, and SLPI promoter activity was measured using a reporter gene assay. Results: E1A significantly suppressed SLPI and elafin/SKALP secretion by A549 cells upon interleukin (IL)-1β stimulation. E1A also suppressed SLPI and elafin/SKALP secretion by HBE cells. SLPI mRNA expression in A549 cells was suppressed by E1A regardless of IL-1β stimulation. IL-1β-induced SLPI promoter activity was suppressed by E1A gene transfection into A549 cells. Conclusions: Our findings of adenoviral E1A-mediated suppression of SLPI and elafin/SKALP secretion suggest that E1A may be involved in the enhancement of alveolar damage and play a role in the COPD process.

Activation of the Prefrontal Cortex Is Associated with Exertional Dyspnea in Chronic Obstructive Pulmonary Disease

Background: Exertional dyspnea is the primary symptom that limits exercise in patients with chronic obstructive pulmonary disease (COPD). It is unknown which activated brain area is associated with this symptom in COPD patients. Objectives: To investigate the activation of cortical areas associated with dyspnea during exercise in COPD patients. Methods: COPD patients (n = 10) and age-matched controls (n = 10) performed mild-intensity constant work rate cycle exercise (40% of their symptom-limited peak work rates) for 10 min, while cerebral hemodynamics and oxygenation were measured by near-infrared spectroscopy (NIRS). Ventilatory responses (breathing pattern and pulmonary gas exchange) and Borg scale ratings of dyspnea and leg fatigue were measured during exercise. Three NIRS probes were placed over the prefrontal and temporoparietal cortical regions of the subjects’ heads. Changes in cortical oxyhemoglobin (oxy-Hb), deoxyhemoglobin (deoxy-Hb), and total hemoglobin (total Hb) concentrations from baseline recordings were measured. Increased oxy-Hb (oxygenation) was assumed to reflect cortical activation. Results: Oxy-Hb concentration was significantly increased in the prefrontal region during exercise in both groups but not in the temporoparietal regions. The change in prefrontal oxy-Hb concentration of COPD patients was not different from that of controls. Dyspnea scores were positively correlated with changes in oxy-Hb concentrations of the prefrontal regions in both groups. Multivariate analysis showed that oxy-Hb concentration in the prefrontal region was the best predictor of dyspnea in both groups. Conclusions: Exertional dyspnea was related to activation (oxygenation) of the prefrontal cortex in COPD patients and control subjects.

Reorganization of sensorimotor function after functional hemispherectomy studied using near-infrared spectroscopy.

Hemimegalencephaly is a rare congenital disease that occurs with intractable epilepsy and is a childhood developmental disorder. A functional hemispherectomy is indicated for the treatment of hemimegalencephaly with intractable epilepsy. We present a case of hemimegalencephaly in a 6-month-old male. After hemispherectomy, his seizures disappeared completely and postoperative neurological examination showed right hemiplegia. His right arm and limb function were recovered gradually by rehabilitation with passive movement. We investigated cortical activation using near-infrared spectroscopy (NIRS). Serial NIRS showed right cortical activation by passive movement of his right arm. We suggest that NIRS showed the ipsilateral reorganization process as an effect of neurorehabilitation for disconnection of the brain.

Effect of therapeutic touch on brain activation of preterm infants in response to sensory punctate stimulus: a near-infrared spectroscopy-based study

Objective The purpose of this study was to determine whether therapeutic touch in preterm infants can ameliorate their sensory punctate stimulus response in terms of brain activation measured by near-infrared spectroscopy. Methods The study included 10 preterm infants at 34–40 weeks’ corrected age. Oxyhaemoglobin (Oxy-Hb) concentration, heart rate (HR), arterial oxygen saturation (SaO2) and body movements were recorded during low-intensity sensory punctate stimulation for 1 s with and without therapeutic touch by a neonatal development specialist nurse. Each stimulation was followed by a resting phase of 30 s. All measurements were performed with the infants asleep in the prone position. Results sensory punctate stimulus exposure significantly increased the oxy-Hb concentration but did not affect HR, SaO2 and body movements. The infants receiving therapeutic touch had significantly decreased oxy-Hb concentrations over time. Conclusions Therapeutic touch in preterm infants can ameliorate their sensory punctate stimulus response in terms of brain activation, indicated by increased cerebral oxygenation. Therefore, therapeutic touch may have a protective effect on the autoregulation of cerebral blood flow during sensory punctate stimulus in neonates.

Complex effect of adenovirus early region proteins on innate immune system.

Adenoviruses (Ads) cause acute and persistent infections. The genome of Ads has five early transcription units that are the first viral genes expressed during an active infection. The Early Region 1A (E1A) gene of the adenovirus genome is crucial for adenovirus transformation of the host cell. Ads E1A block some aspects of the innate immune system to enable viruses to invade the host cell. E1A suppresses nitric oxide (NO) production through transcriptional control of the inducible NO synthase (iNOS) gene. This inhibition of NO production may enable the virus to persist in human tissue because NO is an antiviral effector of the innate immune system. E1A also blocks secretory leukoprotease inhibitor (SLPI) and elafin/skin-derived antileukoproteinase (SKALP) secretion by alveolar epithelial cells. Recent scientific evidence suggests that SLPI and elafin/SKALP have broad-spectrum antibiotic activities that include bactericidal and antifungal properties. The inhibition of inflammation by Ad early region proteins is complex, as certain early region proteins can promote as well as inhibit inflammation depending on the genetic context of the virus. E1A DNA and protein are frequently detected in the lungs of chronic obstructive pulmonary disease (COPD) patients and it is associated with an increased inflammatory response. E1A enhances intercellular adhesion molecule-1 and interleukin-8 mRNA expression with lipopolysaccharide stimulation. Understanding the roles of the Ad gene products in the induction and inhibition of innate inflammatory functions will help us to clarify the pathogenesis of the chronic respiratory illness including COPD.

Immunological rapid urease test using monoclonal antibody for Helicobacter pylori.

Background and Aim:  The current diagnostic methods for detecting Helicobacter pylori infection include rapid urease test (RUT), urea breath test (UBT), histology, culture, and serum antibody detection. The present study evaluated the efficacy of a novel highly specific test, an immunological RUT (IRUT), that uses a monoclonal antibody against H. pylori urease.

Effect of a postoperative outpatient pulmonary rehabilitation program on physical activity in patients who underwent pulmonary resection for lung cancer

Physical activity (PA) has been associated with an improvement in survival for individuals with cancer. However, little is known about the effect of postoperative pulmonary rehabilitation on PA after lobectomy in patients with lung cancer. The present study investigated the effect of outpatient rehabilitation on PA in patients with cancer after lung resection.