Yoshitaka Tateishi

Ghrelin Treatment of Cachectic Patients with Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Background Pulmonary cachexia is common in advanced chronic obstructive pulmonary disease (COPD), culminating in exercise intolerance and a poor prognosis. Ghrelin is a novel growth hormone (GH)-releasing peptide with GH-independent effects. The efficacy and safety of adding ghrelin to pulmonary rehabilitation (PR) in cachectic COPD patients were investigated. Methodology/Principal Findings In a multicenter, randomized, double-blind, placebo-controlled trial, 33 cachectic COPD patients were randomly assigned PR with intravenous ghrelin (2 µg/kg) or placebo twice daily for 3 weeks in hospital. The primary outcomes were changes in 6-min walk distance (6-MWD) and the St. George Respiratory Questionnaire (SGRQ) score. Secondary outcomes included changes in the Medical Research Council (MRC) scale, and respiratory muscle strength. At pre-treatment, serum GH levels were increased from baseline levels by a single dose of ghrelin (mean change, +46.5 ng/ml; between-group p<0.0001), the effect of which continued during the 3-week treatment. In the ghrelin group, the mean change from pre-treatment in 6-MWD was improved at Week 3 (+40 m, within-group p = 0.033) and was maintained at Week 7 (+47 m, within-group p = 0.017), although the difference between ghrelin and placebo was not significant. At Week 7, the mean changes in SGRQ symptoms (between-group p = 0.026), in MRC (between-group p = 0.030), and in maximal expiratory pressure (MEP; between-group p = 0.015) were better in the ghrelin group than in the placebo group. Additionally, repeated-measures analysis of variance (ANOVA) indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (p = 0.049) and MEP (p = 0.021). Ghrelin treatment was well tolerated. Conclusions/Significance In cachectic COPD patients, with the safety profile, ghrelin administration provided improvements in symptoms and respiratory strength, despite the lack of a significant between-group difference in 6-MWD. Trial Registration UMIN Clinical Trial Registry C000000061

Virulence of Mycobacterium avium complex strains isolated from immunocompetent patients

Mycobacterium avium complex (MAC) disease has been increasing worldwide not only in immunocompromised but also in immunocompetent humans. However, the relationship between mycobacterial strain virulence and disease progression in immunocompetent humans is unclear. In this study, we isolated 6 strains from patients with pulmonary MAC disease. To explore the virulence, we examined the growth in human THP-1 macrophages and pathogenicity in C57BL/6 mice. We found that one strain, designated 198, which was isolated from a patient showing the most progressive disease, persisted in THP-1 cells. In addition, strain 198 grew to a high bacterial load with strong inflammation in mouse lungs and spleens 16 weeks after infection. To our knowledge, strain 198 is the first isolated MAC strain that exhibits hypervirulence consistently for the human patient, human macrophages in vitro, and even for immunocompetent mice. Other strains showed limited survival and weak virulence both in macrophages and in mice, uncorrelated to disease progression in human patients. We demonstrated that there is a hypervirulent clinical MAC strain whose experimental virulence corresponds to the serious disease progression in the patients. The existence of such strain suggests the involvement of bacterial virulence in the pathogenesis of pulmonary MAC disease in immunocompetent status.

Transient role of CD4+CD25+ regulatory T cells in mycobacterial infection in mice

CD4(+)CD25(+) regulatory T (Treg) cells cause immune suppression by inhibiting T cell effector functions and play pivotal roles not only in self-tolerance but also in immune response to parasitic microbial pathogens. Mycobacteria are major parasitic bacterial pathogens, but the role of CD4(+)CD25(+) Treg cells in mycobacterial infection is not yet defined. In this study we found that, at the early stage of infection, depletion of CD25(+) cells reduced both bacterial load and granuloma formation in mice infected with Mycobacterium tuberculosis strains, such as M. tuberculosis Erdman or M. tuberculosis Kurono. However, at a later stage of infection, bacterial burden and histopathology were similar regardless of depletion of CD25(+) cells. Severe combined immunodeficient (SCID) mice reconstituted with CD4(+)CD25(-) T cells alone or a combination of CD4(+)CD25(+) and CD4(+)CD25(-) T cells showed similar bacterial loads and survival kinetics after infection with M. tuberculosis Erdman. Consistent with in vivo data, in vitro studies revealed that mycobacterial antigens, purified protein derivative of tuberculin (PPD), failed to induce the suppressive function of CD4(+)CD25(+) Treg cells to CD4(+)CD25(-) effector T cells, as demonstrated by the lack of response of CD4(+)CD25(+) T cells to PPD, in mice chronically infected with Mycobacterium bovis bacillus Calmette-Guérin and M. tuberculosis. Our data show that CD4(+)CD25(+) Treg cells have a transient effect at the early stage of mycobacterial infection but, contrary to the expectation, have little impact on the overall course of infection.

A Novel Mechanism of Growth Phase-dependent Tolerance to Isoniazid in Mycobacteria

Background: The mechanism underlying mycobacterial phenotypic tolerance to isoniazid is unknown. Results: MDP1, a mycobacterial histone-like protein, down-regulates KatG expression. Conclusion: Down-regulation of KatG by MDP1 causes growth phase-dependent phenotypic tolerance to isoniazid in mycobacteria. Significance: Understanding the mechanism by which mycobacteria acquire tolerance to isoniazid is important for developing novel therapies. Tuberculosis remains one of the most deadly infectious diseases worldwide and is a leading public health problem. Although isoniazid (INH) is a key drug for the treatment of tuberculosis, tolerance to INH necessitates prolonged treatment, which is a concern for effective tuberculosis chemotherapy. INH is a prodrug that is activated by the mycobacterial enzyme, KatG. Here, we show that mycobacterial DNA-binding protein 1 (MDP1), which is a histone-like protein conserved in mycobacteria, negatively regulates katG transcription and leads to phenotypic tolerance to INH in mycobacteria. Mycobacterium smegmatis deficient for MDP1 exhibited increased expression of KatG and showed enhanced INH activation compared with the wild-type strain. Expression of MDP1 was increased in the stationary phase and conferred growth phase-dependent tolerance to INH in M. smegmatis. Regulation of KatG expression is conserved between M. smegmatis and Mycobacterium tuberculosis complex. Artificial reduction of MDP1 in Mycobacterium bovis BCG was shown to lead to increased KatG expression and susceptibility to INH. These data suggest a mechanism by which phenotypic tolerance to INH is acquired in mycobacteria.

Effects of Ghrelin Treatment on Exercise Capacity in Underweight COPD Patients: a substudy of a multicenter, randomized, double-blind, placebo-controlled trial of ghrelin treatment

BackgroundThe aim of this substudy of the ghrelin treatment, multicenter, randomized, double-blind, placebo-controlled trial was to investigate the effects of ghrelin administration on exercise capacity and the underlying mechanisms in underweight patients with chronic obstructive pulmonary disease (COPD) using cardiopulmonary exercise testing.MethodsTwenty underweight COPD patients were randomized to pulmonary rehabilitation with intravenous ghrelin (2 μg/kg, n = 10) or placebo (n = 10) twice daily for 3 weeks in a double-blind fashion. The primary outcome was changes in peak oxygen uptake V•o2. Secondary outcomes included changes in exertional cardio-respiratory functions: O2-pulse, physiologic dead space/tidal volume-ratio (VD/VT), ventilatory equivalent for oxygen V•E/V•o2, and ventilatory equivalent for carbon dioxide V•E/V•co2.ResultsWith incremental exercise, at peak exercise, there was a significant difference in the mean difference (ghrelin minus placebo), i.e., treatment effect in: i) peak V•o2 (1.2 mL/kg/min, 95% CI: 0.2-2.3 mL/kg/min, between-group p = 0.025); ii) V•E/V•o2 (-4.2, 95% CI: -7.9 to -0.5, between-group p = 0.030); iii) V•E/V•co2 (-4.1, 95% CI: -8.2 to -0.1, between-group p = 0.045); iv) VD/VT (-0.04, 95% CI: -0.08 to -0.00, between-group p = 0.041); and v) O2-pulse (0.7 mL/beat, 95% CI: 0.3 to 1.2 mL/beat, between-group p = 0.003). Additionally, repeated-measures analysis of variance (ANOVA) indicated a significant time-course effect of ghrelin versus placebo in the peak V•o2 (p = 0.025).ConclusionGhrelin administration was associated with improved exertional capacity and improvements in ventilatory-cardiac parameters.Trial registrationUMIN (University Hospital Medical Information Network in Japan) C000000061

Acidosis and raised norepinephrine levels are associated with exercise dyspnoea in idiopathic pulmonary fibrosis

Background and objective:  Exertional dyspnoea limits patients with IPF in their activities of daily living. The mechanism, however, has not been elucidated. This study tested the hypothesis in IPF that exertional dyspnoea correlates with cardiopulmonary exercise responses, specifically changes in arterial blood pH and plasma norepinephrine (NE).

Serodiagnosis of Pulmonary Disease Due to Mycobacterium avium Complex Proven by Bronchial Wash Culture

Affi liations: From the Department of Pharmacy (Drs Ogale and Sullivan), University of Washington; the Center for Management of Complex Chronic Care (Dr Lee), Edward Hines Jr VA Hospital; and the Center for Pharmacoeconomic Research, Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL. Dr Ogale is currently at Genentech, Inc. Financial nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Ogale is an employee of Genentech, Inc. Drs Lee and Sullivan have received funding for their contribution to the Burden of Obstructive Lung Disease (BOLD) Initiative, which has been funded in part by unrestricted educational grants to the Operations Center ( www . boldcopd . org ) from ALTANA, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Novartis, Pfi zer, Schering-Plough, Sepracor, and the University of Kentucky. Drs Lee and Sullivan have received past research grants from AstraZeneca, Boehringer Ingelheim, Pfi zer, Novartis, and Glaxo SmithKline. Dr Lee has participated in past advisory boards for AstraZeneca and Novartis. Correspondence to: Todd A. Lee, PharmD, PhD, Edward Hines Jr VA Hospital (151-H), 5000 S 5th Ave, Hines, IL 60141; e-mail: todd.lee@va.gov

Differences in Physiological Response to Exercise in Patients With Different COPD Severity

BACKGROUND: Patients with COPD have reduced exercise tolerance associated with dyspnea. This exercise intolerance is primarily due to impaired ventilatory mechanics, but it is also associated with a combination of factors, including inefficient gas exchange, lactic acidosis at a low work rate, and exercise-induced hypoxemia. The survival prognosis of COPD patients with severely reduced exercise capacity is extremely poor, but the pathophysiology of these patients during exercise remains to be accurately established. The present study aimed to characterize life-threatening factors such as hypoxemia, acidosis, and sympathetic activation during exercise in these patients. METHODS: We monitored changes in life-threatening factors and compared these factors among quartile groups, defined according to their peak oxygen uptake status. Ninety-one COPD subjects (82 males, 9 females, average age 69.7 ± 6.8 y) consecutively underwent incremental cardiopulmonary exercise testing using a cycle ergometer. Arterial blood gases, lactate, and catecholamines were measured during cardiopulmonary exercise testing. RESULTS: The pathophysiology of the COPD differed among the 4 subject groups. Subjects with the most severely reduced exercise capacity (peak oxygen uptake ≤ 623 mL/min) were characterized by exercise-induced steep decrease in PaO2 slope (−78 ± 70 mm Hg/L/min), rapid progression of respiratory acidosis, little change in lactic acidosis, and sympathetic activation at low-intensity work load (plasma norepinephrine 1.41 ± 0.94 ng/mL at 20 watts work load), in addition to the limitation of increase in ventilation and impaired gas exchange. CONCLUSIONS: The mechanisms of exercise intolerance in COPD patients significantly differed among subjects with different exercise capacities. Subjects with the most severely reduced exercise capacity had the characteristics of exercise-induced hypoxemia, sympathetic overactivity, and progressive respiratory acidosis at low-intensity exercise. These life-threatening pathophysiological conditions could be improved by medication and/or pulmonary rehabilitation.

Effects of oxygen on exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease

Background and objective:  The results of studies on the oxygen response in patients with COPD should provide important clues to the pathophysiology of exertional dyspnoea. We investigated the exercise responses to hyperoxia in relation to dyspnoea profile, as well as cardiopulmonary, acidotic and sympathetic parameters in 35 patients with stable COPD (mean FEV1 46% predicted).

Exertional acidotic responses in idiopathic pulmonary fibrosis: the mechanisms of exertional dyspnea.

To understand the mechanism of exertional dyspnea, we postulated that, despite hyperoxia during exercise, patients with idiopathic pulmonary fibrosis (IPF) might not regulate exertional acidosis by ventilatory compensation to stop exercise. The exercise responses during 30% O(2) or compressed air (CA) were examined in 13 patients with IPF. The PaO(2), PaCO(2), and HCO(3)(-) levels were higher during exercise with hyperoxia than with CA. At peak exercise, hyperoxia reduced the plasma lactate level. The dyspnea-ratio (%) of the ΔV(O(2)) (peak minus resting oxygen uptake) curve reached a break point that occurred at a similar exercise point with hyperoxia and CA, preceded by a break point in the breathing frequency-ratio of the ΔV(O(2)). Accordingly, the dyspnea score and pH each reached similar levels with hyperoxia and CA to stop exercise. Regardless of breathing CA or 30% O(2), IPF patients did not regulate exertional acidosis by ventilatory compensation to stop exercise, resulting in reaching a specific pH.