July 25, 2013

Adenosine and prostaglandin E2production by human inducible regulatory T cells in health and disease

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Front. Immunol., 25 July 2013 | doi: 10.3389/fimmu.2013.00212

Adenosine and prostaglandin E₂production by human inducible regulatory T cells in health and disease

Theresa L. Whiteside¹* and Edwin K. Jackson²

¹Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
²Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Regulatory T cells (Treg) play a key role in maintaining the balance of immune responses in human health and in disease. Treg come in many flavors and can utilize a variety of mechanisms to modulate immune responses. In cancer, inducible (i) or adaptive Treg expand, accumulate in tissues and peripheral blood of patients, and represent a functionally prominent component of CD4+ T lymphocytes. Phenotypically and functionally, iTreg are distinct from natural (n) Treg. A subset of iTreg expressing ectonucleotidases CD39 and CD73 is able to hydrolyze ATP to 5′-AMP and adenosine (ADO) and thus mediate suppression of those immune cells which express ADO receptors. iTreg can also produce prostaglandin E₂ (PGE₂). The mechanisms responsible for iTreg-mediated suppression involve binding of ADO and PGE₂ produced by iTreg to their respective receptors expressed on T effector cells (Teff), leading to the up-regulation of adenylate cyclase and cAMP activities in Teff and to their functional inhibition. The potential for regulating these mechanisms by the use of pharmacologic inhibitors to relieve iTreg-mediated suppression in cancer suggests the development of therapeutic strategies targeting the ADO and PGE₂ pathways.

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Keywords: cancer inducible regulatory T cells, natural regulatory T cells, tumor microenvironment

Citation: Whiteside TL and Jackson EK (2013) Adenosine and prostaglandin E₂ production by human inducible regulatory T cells in health and disease. Front. Immunol. 4:212. doi: 10.3389/fimmu.2013.00212

Received: 15 May 2013; Paper pending published: 25 May 2013;
Accepted: 11 July 2013; Published online: 25 July 2013.

Edited by:

Eyad Elkord, United Arab Emirates University, UAE; University of Salford and University of Manchester, UK

Reviewed by:

Masahide Tone, Cedars-Sinai Medical Center, USA
Lionel Apetoh, Institut National de la Santé et de la Recherche Médicale, France

Copyright: © 2013 Whiteside and Jackson. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: Theresa L. Whiteside, Department of Pathology, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, USA e-mail: whitesidetl@upmc.edu

Indacaterol: a comprehensive review

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Authors: Rossi A, Polese G

Published Date July 2013 Volume 2013:8 Pages 353 - 363
DOI: http://dx.doi.org/10.2147/COPD.S21625

Received:	18 January 2013
Accepted:	12 April 2013
Published:	25 July 2013

Andrea Rossi,¹ Guido Polese²

¹Pulmonary Unit, Cardiovascular and Thoracic Department, University and General Hospital,²Pulmonary Service, Department of Rehabilitation, Verona, Italy

Abstract: At present there is no cure for chronic obstructive pulmonary disease (COPD). However, some nonpharmacologic treatments, such as rehabilitation and lung volume reduction surgery, as well as pharmacologic intervention, can relieve some of the patient's symptoms and improve quality of life, while also reducing the rate of exacerbations and hospitalizations. There needs to be a paradigm shift away from the unjustified nihilistic approach to COPD towards considering it a preventable and treatable disease. After patients quit smoking and start to lead healthier lifestyles, long-acting bronchodilators, such as long-acting beta-adrenergic agents (LABA) and long-acting antimuscarinic agents (LAMA), are recommended as the cornerstone of treatment for COPD, either as monotherapy or in combination. COPD is characterized by a reduced maximum expiratory flow and slow forced emptying of the lungs, which progress over time and are not completely reversible. In this condition, gas gets trapped in the lungs and pulmonary hyperinflation occurs. LABA and LAMA improve airway patency and deflate the lungs. Indacaterol is the first once-daily LABA approved for treatment of COPD, and is administered by inhalation through the Breezhaler^® device. The speed of bronchodilation is similar to that with salbutamol (ie, about five minutes) and longer (ie, 24 hours) than that with traditional LABA, with the same 12-hour effect as salmeterol and formoterol, both of which require twice-daily administration. This is why indacaterol has been called the ‘‘ultra-LABA’’. On the one hand, the fast onset of action provides immediate relief of symptoms, and on the other, its constant 24-hour bronchodilation provides ‘‘pharmacologic stenting’’ which facilitates lung emptying, thereby decreasing trapped gas and pulmonary hyperinflation. Once-daily administration of a fast and long-acting bronchodilator can improve patient adherence with therapy, which is known to be a major problem for many medical treatments. Dose-finding trials have shown that 75 µg is the minimum dose needed to achieve clinically important improvement. However, indacaterol 150 µg and 300 µg achieve an even greater improvement in lung function and patient-oriented outcomes. Further, these two doses of indacaterol significantly reduce pulmonary hyperinflation, thereby improving exercise tolerance and ability to perform day-to-day activities. It is more effective on lung volumes at the 300 µg dose than formoterol, and better than salmeterol and tiotropium at the 150 µg dose, at least in the acute setting. It is noteworthy that few studies document these results in patients with COPD and moderate airflow obstruction. These are exactly the kind of patients our research should be concentrating on, in view of the accelerated decay in forced expiratory volume in one second at this stage of the disease. Finally, all the relevant studies show that indacaterol is consistently well tolerated by patients with COPD at every stage, and that it has a high safety profile.

Keywords: indacaterol, chronic obstructive pulmonary disease

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Behind a Mask: Tricks, Pitfalls, and Prejudices for Noninvasive Ventilation

Behind a Mask: Tricks, Pitfalls, and Prejudices for

Noninvasive Ventilation

Stefano Nava, MD ⇑

+Author Affiliations

Pneumologia e Terapia Intensiva Respiratoria, Azienda Opedaliera Universitaria Sant Orsola-Malpighi, and the Department of Specialistic, Diagnostic, and Experimental Medicine, School of Medicine, Alma Mater Studiorum Università di Bologna, Bologna, Italy.

Abstract

It is difficult to exactly date the beginning of mechanical ventilation, but there are no doubts that noninvasive ventilation (NIV) was the first method of ventilatory support in clinical practice. The technique had a sudden increase in popularity, so that it is now considered, according to criteria of evidence-based medicine, the first-line treatment for an episode of acute respiratory failure in 4 pathologies (the Fabulous Four): COPD exacerbation, cardiogenic pulmonary edema, pulmonary infiltrates in immunocompromised patients, and in the weaning of extubated COPD patients. The so-called emerging applications are those for which the evidence has not achieved level A, mainly because the number or sample size of the published studies does not allow conclusive meta-analysis. These emerging applications are the post-surgical period, palliation of dyspnea, asthma attack, obesity hypoventilation syndrome, and to prevent extubation failure. Potentially “risky business” uses include for respiratory failure from pandemic diseases and ARDS, where probably the “secret” for success is early use. Healthcare is rich in evidence-based innovations, yet even when such innovations are implemented successfully in one location, they often disseminate slowly, if at all, so their clinical use remains limited and heterogeneous. The low rate of NIV use in some hospitals relates to lack of knowledge about or experience with NIV, insufficient confidence in the technique, lack of NIV equipment, and inadequate funding. But NIV use has been increasing around the world, thanks partly to improved technologies. The skill and confidence of clinicians in NIV have improved with time and experience, but NIV is and should remain a team effort, rather than the property of a single local “champion,” because, overall, NIV is beautiful!

This Article

doi:10.4187/respcare.02457Respiratory Care August 1, 2013 vol. 58 no. 8 1367-1376

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Footnotes

Correspondence: Stefano Nava MD, Pneumologia e Terapia Intensiva Respiratoria, Azienda Opedaliera Universitaria Sant Orsola-Malpighi, via Massarenti no. 9, Bologna 40138 Italy. E-mail: stefano.nava@aosp.bo.it.
Dr Nava presented a version of this paper as the 39th Donald F Egan Scientific Memorial Lecture at the 58th AARC Congress, held November 10–13, 2012, in New Orleans, Louisiana.
The author has disclosed no conflicts of interest.

July 24, 2013

MicroRNAs: New Insights into Chronic Childhood Diseases

BioMed Research International
Volume 2013 (2013), Article ID 291826, 13 pages
http://dx.doi.org/10.1155/2013/291826

Review Article

MicroRNAs: New Insights into Chronic Childhood Diseases

Ahmed Omran,^1,2 Dalia Elimam,¹ and Fei Yin²

¹Department of Pediatrics and Neonatology, Suez Canal University, Ismailia 41522, Egypt
²Department of Pediatrics, Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China

Received 16 April 2013; Accepted 7 June 2013

Academic Editor: Glen Jickling

Copyright © 2013 Ahmed Omran et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chronic diseases are the major cause of morbidity and mortality worldwide and have shown increasing incidence rates among children in the last decades. Chronic illnesses in the pediatric population, even if well managed, affect social, psychological, and physical development and often limit education and active participation and increase the risk for health complications. The significant pediatric morbidity and mortality rates caused by chronic illnesses call for serious efforts toward better understanding of the pathogenesis of these disorders. Recent studies have shown the involvement of microRNAs (miRNAs) in various aspects of major pediatric chronic non-neoplastic diseases. This review focuses on the role of miRNAs in four major pediatric chronic diseases including bronchial asthma, diabetes mellitus, epilepsy and cystic fibrosis. We intend to emphasize the importance of miRNA-based research in combating these major disorders, as we believe this approach will result in novel therapies to aid securing normal development and to prevent disabilities in the pediatric population.

July 23, 2013

Abrogation of IL-4 receptor-α-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing Th2 response

Abrogation of IL-4 receptor-α-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing T_h2 response

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Abstract

In the murine model of pulmonary infection with Cryptococcus neoformans, IL-4 receptor α (IL-4Rα)-dependent polyfunctional T_h2 cells induce disease progression associated with alternative activation of lung macrophages. To characterize the effector role of IL-4Rα-dependent alternatively activated macrophages (aaMph), we intra-nasally infected mice with genetically ablated IL-4Rα expression on macrophages (LysM^CreIL-4Rα^–/lox mice) and IL-4Rα^–/lox littermates. LysM^CreIL-4Rα^–/lox mice were significantly more resistant to pulmonary cryptococcosis with higher survival rates and lower lung burden than non-deficient heterozygous littermates. Infected LysM^CreIL-4Rα^–/lox mice had reduced but detectable numbers of aaMph expressing arginase-1, chitinase-like enzyme (YM1) and CD206. Similar pulmonary expression of inducible nitric oxide synthase was found in LysM^CreIL-4Rα^–/lox and IL-4Rα^–/lox control mice, but macrophages from LysM^CreIL-4Rα^–/lox mice showed a higher potential to produce nitric oxide. In contrast to the differences in the macrophage phenotype, pulmonary T_h2 responses were similar in infected LysM^CreIL-4Rα^–/lox and IL-4Rα^–/lox mice with each mouse strain harboring polyfunctional T_h2 cells. Consistently, type 2 pulmonary allergic inflammation associated with eosinophil recruitment and epithelial mucus production was present in lungs of both LysM^CreIL-4Rα^–/lox and IL-4Rα^–/lox mice. Our results demonstrate that, despite residual IL-4Rα-independent alternative macrophage activation and ongoing T_h2-dependent allergic inflammation, abrogation of IL-4Rα-dependent aaMph is sufficient to confer resistance in pulmonary cryptococcosis. This is even evident on a relatively resistant heterozygous IL-4Rα^+/– background indicating a key contribution of macrophage IL-4Rα expression to susceptibility in allergic bronchopulmonary mycosis.

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Int. Immunol. (2013) 25 (8): 459-470. doi: 10.1093/intimm/dxt003 First published online: March 26, 2013

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Effect of Lifestyle on Asthma Control in Japanese Patients: Importance of Periodical Exercise and Raw Vegetable Diet

OPEN ACCESS PEER-REVIEWED

RESEARCH ARTICLE

Effect of Lifestyle on Asthma Control in Japanese Patients: Importance of Periodical Exercise and Raw Vegetable Diet

Motoyasu Iikura mail,
Siyan Yi,
Yasunori Ichimura,
Ai Hori,
Shinyu Izumi,
Haruhito Sugiyama,
Koichiro Kudo,
Tetsuya Mizoue,
Nobuyuki Kobayashi

Abstract

Background

The avoidance of inhaled allergens or tobacco smoke has been known to have favorable effects on asthma control. However, it remains unclear whether other lifestyle-related factors are also related to asthma control. Therefore, a comprehensive study to examine the associations between various lifestyle factors and asthma control was conducted in Japanese asthmatic patients.

Methods

The study subjects included 437 stable asthmatic patients recruited from our outpatient clinic over a one-year period. A written, informed consent was obtained from each participant. Asthma control was assessed using the asthma control test (ACT), and a structured questionnaire was administered to obtain information regarding lifestyle factors, including tobacco smoking, alcohol drinking, physical exercise, and diet. Both bivariate and multivariate analyses were conducted.

Results

The proportions of total control (ACT = 25), well controlled (ACT = 20-24), and poorly controlled (ACT < 20) were 27.5%, 48.1%, and 24.5%, respectively. The proportions of patients in the asthma treatment steps as measured by Global Initiative for Asthma 2007 in step 1, step 2, step 3, step 4, and step 5 were 5.5%, 17.4%, 7.6%, 60.2%, and 9.4%, respectively. Body mass index, direct tobacco smoking status and alcohol drinking were not associated with asthma control. On the other hand, younger age (< 65 years old), passive smoking, periodical exercise (> 3 metabolic equivalents-h/week), and raw vegetable intake (> 5 units/week) were significantly associated with good asthma control by bivariate analysis. Younger age, periodical exercise, and raw vegetable intake were significantly associated with good asthma control by multiple linear regression analysis.

Conclusions

Periodical exercise and raw vegetable intake are associated with good asthma control in Japanese patients.

Citation: Iikura M, Yi S, Ichimura Y, Hori A, Izumi S, et al. (2013) Effect of Lifestyle on Asthma Control in Japanese Patients: Importance of Periodical Exercise and Raw Vegetable Diet. PLoS ONE 8(7): e68290. doi:10.1371/journal.pone.0068290

Editor: Hong Wei Chu, National Jewish Health, United States of America

Received: March 4, 2013; Accepted: May 28, 2013; Published: July 9, 2013

Copyright: © 2013 Iikura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by grants-in-aid from the Ministry of Health and Welfare of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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Allergy, Asthma and Immunology

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July 25, 2013

Adenosine and prostaglandin E2production by human inducible regulatory T cells in health and disease

REVIEW ARTICLE