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1
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Boboltz A, Kumar S, Duncan GA. Inhaled drug delivery for the targeted treatment of asthma. Adv Drug Deliv Rev 2023; 198:114858. [PMID: 37178928 PMCID: PMC10330872 DOI: 10.1016/j.addr.2023.114858] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/14/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023]
Abstract
Asthma is a chronic lung disease affecting millions worldwide. While classically acknowledged to result from allergen-driven type 2 inflammatory responses leading to IgE and cytokine production and the influx of immune cells such as mast cells and eosinophils, the wide range in asthmatic pathobiological subtypes lead to highly variable responses to anti-inflammatory therapies. Thus, there is a need to develop patient-specific therapies capable of addressing the full spectrum of asthmatic lung disease. Moreover, delivery of targeted treatments for asthma directly to the lung may help to maximize therapeutic benefit, but challenges remain in design of effective formulations for the inhaled route. In this review, we discuss the current understanding of asthmatic disease progression as well as genetic and epigenetic disease modifiers associated with asthma severity and exacerbation of disease. We also overview the limitations of clinically available treatments for asthma and discuss pre-clinical models of asthma used to evaluate new therapies. Based on the shortcomings of existing treatments, we highlight recent advances and new approaches to treat asthma via inhalation for monoclonal antibody delivery, mucolytic therapy to target airway mucus hypersecretion and gene therapies to address underlying drivers of disease. Finally, we conclude with discussion on the prospects for an inhaled vaccine to prevent asthma.
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Affiliation(s)
- Allison Boboltz
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, United States
| | - Sahana Kumar
- Biological Sciences Graduate Program, University of Maryland, College Park, MD 20742, United States
| | - Gregg A Duncan
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, United States; Biological Sciences Graduate Program, University of Maryland, College Park, MD 20742, United States.
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2
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Zhang H, Zhang Z, Liao Y, Zhang W, Tang D. The Complex Link and Disease Between the Gut Microbiome and the Immune System in Infants. Front Cell Infect Microbiol 2022; 12:924119. [PMID: 35782111 PMCID: PMC9241338 DOI: 10.3389/fcimb.2022.924119] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
The human gut microbiome is important for human health. The development of stable microbial communities in the gastrointestinal tract is closely related to the early growth and development of host immunity. After the birth of a baby, immune cells and the gut microbiome mature in parallel to adapt to the complex gut environment. The gut microbiome is closely linked to the immune system and influences each other. This interaction is associated with various diseases in infants and young children, such as asthma, food allergies, necrotizing colitis, obesity, and inflammatory bowel disease. Thus, the composition of the infant gut microbiome can predict the risk of disease development and progression. At the same time, the composition of the infant gut microbiome can be regulated in many ways and can be used to prevent and treat disease in infants by modulating the composition of the infant gut microbiome. The most important impacts on infant gut microbiota are maternal, including food delivery and feeding. The differences in the gut microbiota of infants reflect the maternal gut microbiota, which in turn reflects the gut microbiota of a given population, which is clinically significant.
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Affiliation(s)
- Huan Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Zhilin Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Yiqun Liao
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Wenjie Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People’s Hospital, Yangzhou, China
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3
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Gupta A, Andresen JL, Manan RS, Langer R. Nucleic acid delivery for therapeutic applications. Adv Drug Deliv Rev 2021; 178:113834. [PMID: 34492233 DOI: 10.1016/j.addr.2021.113834] [Citation(s) in RCA: 173] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/25/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Recent medical advances have exploited the ability to address a given disease at the underlying level of transcription and translation. These treatment paradigms utilize nucleic acids - including short interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides (ASO), and messenger RNA (mRNA) - to achieve a desired outcome ranging from gene knockdown to induced expression of a selected target protein. Towards this end, numerous strategies for encapsulation or stabilization of various nucleic acid structures have been developed in order to achieve intracellular delivery. In this review, we discuss several therapeutic applications of nucleic acids directed towards specific diseases and tissues of interest, in particular highlighting recent technologies which have reached late-stage clinical trials and received FDA approval.
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Affiliation(s)
- Akash Gupta
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Jason L Andresen
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Rajith S Manan
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Robert Langer
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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4
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Protein and peptide delivery to lungs by using advanced targeted drug delivery. Chem Biol Interact 2021; 351:109706. [PMID: 34662570 DOI: 10.1016/j.cbi.2021.109706] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/16/2021] [Accepted: 10/13/2021] [Indexed: 11/20/2022]
Abstract
The challenges and difficulties associated with conventional drug delivery systems have led to the emergence of novel, advanced targeted drug delivery systems. Therapeutic drug delivery of proteins and peptides to the lungs is complicated owing to the large size and polar characteristics of the latter. Nevertheless, the pulmonary route has attracted great interest today among formulation scientists, as it has evolved into one of the important targeted drug delivery platforms for the delivery of peptides, and related compounds effectively to the lungs, primarily for the management and treatment of chronic lung diseases. In this review, we have discussed and summarized the current scenario and recent developments in targeted delivery of proteins and peptide-based drugs to the lungs. Moreover, we have also highlighted the advantages of pulmonary drug delivery over conventional drug delivery approaches for peptide-based drugs, in terms of efficacy, retention time and other important pharmacokinetic parameters. The review also highlights the future perspectives and the impact of targeted drug delivery on peptide-based drugs in the coming decade.
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5
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Bielec K, Sozanski K, Seynen M, Dziekan Z, Ten Wolde PR, Holyst R. Kinetics and equilibrium constants of oligonucleotides at low concentrations. Hybridization and melting study. Phys Chem Chem Phys 2019; 21:10798-10807. [PMID: 31086926 DOI: 10.1039/c9cp01295h] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Although DNA hybridization/melting is one of the most important biochemical reactions, the non-trivial kinetics of the process is not yet fully understood. In this work, we use Förster resonance energy transfer (FRET) to investigate the influence of temperature, ionic strength, and oligonucleotide length on the kinetic and equilibrium constants of DNA oligonucleotide binding and dissociation. We show that at low reagent concentrations and ionic strength, the time needed to establish equilibrium between single and double strand forms may be of the order of days, even for simple oligonucleotides of a length of 20 base pairs or less. We also identify and discuss the possible artifacts related to fluorescence-based experiments conducted in extremely dilute solutions. The results should prove useful for the judicious design of technologies based on DNA-matching, including sensors, DNA multiplication, sequencing, and gene manipulation.
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Affiliation(s)
- Krzysztof Bielec
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
| | - Krzysztof Sozanski
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
| | - Marco Seynen
- FOM Institute AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands
| | - Zofia Dziekan
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
| | | | - Robert Holyst
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
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6
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Gao ZG, Jacobson KA. Purinergic Signaling in Mast Cell Degranulation and Asthma. Front Pharmacol 2017; 8:947. [PMID: 29311944 PMCID: PMC5744008 DOI: 10.3389/fphar.2017.00947] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 12/14/2017] [Indexed: 11/13/2022] Open
Abstract
Mast cells are responsible for the majority of allergic conditions. It was originally thought that almost all allergic events were mediated directly only via the high-affinity immunoglobulin E receptors. However, recent evidence showed that many other receptors, such as G protein-coupled receptors and ligand-gated ion channels, are also directly involved in mast cell degranulation, the release of inflammatory mediators such as histamine, serine proteases, leukotrienes, heparin, and serotonin. These mediators are responsible for the symptoms in allergic conditions such as allergic asthma. In recent years, it has been realized that purinergic signaling, induced via the activation of G protein-coupled adenosine receptors and P2Y nucleotide receptors, as well as by ATP-gated P2X receptors, plays a significant role in mast cell degranulation. Both adenosine and ATP can induce degranulation and bronchoconstriction on their own and synergistically with allergens. All three classes of receptors, adenosine, P2X and P2Y are involved in tracheal mucus secretion. This review will summarize the currently available knowledge on the role of purinergic signaling in mast cell degranulation and its most relevant disease, asthma.
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Affiliation(s)
- Zhan-Guo Gao
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Kenneth A Jacobson
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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7
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Oligonucleotide-targeting periostin ameliorates pulmonary fibrosis. Gene Ther 2017; 24:706-716. [PMID: 28820502 DOI: 10.1038/gt.2017.80] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 05/30/2017] [Accepted: 07/07/2017] [Indexed: 02/06/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a median survival of 3-4 years after diagnosis. It is the most frequent form of a group of interstitial pneumonias of unknown etiology. Current available therapies prevent deterioration of lung function but no therapy has shown to improve survival. Periostin is a matricellular protein of the fasciclin 1 family. There is increased deposition of periostin in lung fibrotic tissues. Here we evaluated whether small interfering RNA or antisense oligonucleotide against periostin inhibits lung fibrosis by direct administration into the lung by intranasal route. Pulmonary fibrosis was induced with bleomycin and RNA therapeutics was administered during both acute and chronic phases of the disease. The levels of periostin and transforming growth factor-β1 in airway fluid and lung tissue, the deposition of collagen in lung tissue and the lung fibrosis score were significantly reduced in mice treated with siRNA and antisense against periostin compared to control mice. These findings suggest that direct administration of siRNA or antisense oligonucleotides against periostin into the lungs is a promising alternative therapeutic approach for the management of pulmonary fibrosis.
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8
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Varani K, Vincenzi F, Merighi S, Gessi S, Borea PA. Biochemical and Pharmacological Role of A1 Adenosine Receptors and Their Modulation as Novel Therapeutic Strategy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1051:193-232. [DOI: 10.1007/5584_2017_61] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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9
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Oligonucleotide Therapy for Obstructive and Restrictive Respiratory Diseases. Molecules 2017; 22:molecules22010139. [PMID: 28106744 PMCID: PMC6155767 DOI: 10.3390/molecules22010139] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 01/05/2017] [Accepted: 01/08/2017] [Indexed: 12/21/2022] Open
Abstract
Inhaled oligonucleotide is an emerging therapeutic modality for various common respiratory diseases, including obstructive airway diseases like asthma and chronic obstructive pulmonary disease (COPD) and restrictive airway diseases like idiopathic pulmonary fibrosis (IPF). The advantage of direct accessibility for oligonucleotide molecules to the lung target sites, bypassing systemic administration, makes this therapeutic approach promising with minimized potential systemic side effects. Asthma, COPD, and IPF are common chronic respiratory diseases, characterized by persistent airway inflammation and dysregulated tissue repair and remodeling, although each individual disease has its unique etiology. Corticosteroids have been widely prescribed for the treatment of asthma, COPD, and IPF. However, the effectiveness of corticosteroids as an anti-inflammatory drug is limited by steroid resistance in severe asthma, the majority of COPD cases, and pulmonary fibrosis. There is an urgent medical need to develop target-specific drugs for the treatment of these respiratory conditions. Oligonucleotide therapies, including antisense oligonucleotide (ASO), small interfering RNA (siRNA), and microRNA (miRNA) are now being evaluated both pre-clinically and clinically as potential therapeutics. The mechanisms of action of ASO and siRNA are highly target mRNA specific, ultimately leading to target protein knockdown. miRNA has both biomarker and therapeutic values, and its knockdown by a miRNA antagonist (antagomir) has a broader but potentially more non-specific biological outcome. This review will compile the current findings of oligonucleotide therapeutic targets, verified in various respiratory disease models and in clinical trials, and evaluate different chemical modification approaches to improve the stability and potency of oligonucleotides for the treatment of respiratory diseases.
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10
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Abstract
Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug-drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease. The molecular mechanism(s) of action of theophylline are not well understood, but several potential targets have been suggested including non-selective inhibition of phosphodiesterases (PDE), inhibition of phosphoinositide 3-kinase, adenosine receptor antagonism and increased activity of certain histone deacetylases. Although theophylline has a narrow therapeutic window, other xanthines are in clinical use that are claimed to have a better tolerability such as doxofylline and bamifylline. Nonetheless, xanthines still play an important role in the treatment of asthma and COPD as they can show clinical benefit in patients who are refractory to glucocorticosteroid therapy, and withdrawal of xanthines from patients causes worsening of disease, even in patients taking concomitant glucocorticosteroids.More recently the orally active selective PDE4 inhibitor, roflumilast, has been introduced into clinical practice for the treatment of severe COPD on top of gold standard treatment. This drug has been shown to improve lung function in patients with severe COPD and to reduce exacerbations, but is dose limited by a range side effect, particularly gastrointestinal side effects.
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Affiliation(s)
- D Spina
- The Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London, SE1 9NH, UK
| | - C P Page
- The Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London, SE1 9NH, UK.
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11
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George R, Cavalcante R, Jr CC, Marques E, Waugh JB, Unlap MT. Use of siRNA molecular beacons to detect and attenuate mycobacterial infection in macrophages. World J Exp Med 2015; 5:164-181. [PMID: 26309818 PMCID: PMC4543811 DOI: 10.5493/wjem.v5.i3.164] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 05/05/2015] [Accepted: 06/11/2015] [Indexed: 02/06/2023] Open
Abstract
Tuberculosis is one of the leading infectious diseases plaguing mankind and is mediated by the facultative pathogen, Mycobacterium tuberculosis (MTB). Once the pathogen enters the body, it subverts the host immune defenses and thrives for extended periods of time within the host macrophages in the lung granulomas, a condition called latent tuberculosis (LTB). Persons with LTB are prone to reactivation of the disease when the body’s immunity is compromised. Currently there are no reliable and effective diagnosis and treatment options for LTB, which necessitates new research in this area. The mycobacterial proteins and genes mediating the adaptive responses inside the macrophage is largely yet to be determined. Recently, it has been shown that the mce operon genes are critical for host cell invasion by the mycobacterium and for establishing a persistent infection in both in vitro and in mouse models of tuberculosis. The YrbE and Mce proteins which are encoded by the MTB mce operons display high degrees of homology to the permeases and the surface binding protein of the ABC transports, respectively. Similarities in structure and cell surface location impute a role in cell invasion at cholesterol rich regions and immunomodulation. The mce4 operon is also thought to encode a cholesterol transport system that enables the mycobacterium to derive both energy and carbon from the host membrane lipids and possibly generating virulence mediating metabolites, thus enabling the bacteria in its long term survival within the granuloma. Various deletion mutation studies involving individual or whole mce operon genes have shown to be conferring varying degrees of attenuation of infectivity or at times hypervirulence to the host MTB, with the deletion of mce4A operon gene conferring the greatest degree of attenuation of virulence. Antisense technology using synthetic siRNAs has been used in knocking down genes in bacteria and over the years this has evolved into a powerful tool for elucidating the roles of various genes mediating infectivity and survival in mycobacteria. Molecular beacons are a newer class of antisense RNA tagged with a fluorophore/quencher pair and their use for in vivo detection and knockdown of mRNA is rapidly gaining popularity.
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12
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Antonioli L, Csóka B, Fornai M, Colucci R, Kókai E, Blandizzi C, Haskó G. Adenosine and inflammation: what's new on the horizon? Drug Discov Today 2014; 19:1051-68. [DOI: 10.1016/j.drudis.2014.02.010] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 02/06/2014] [Accepted: 02/25/2014] [Indexed: 12/18/2022]
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13
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Tilley S, Volmer J, Picher M. Therapeutic applications. Subcell Biochem 2014; 55:235-76. [PMID: 21560050 PMCID: PMC7120595 DOI: 10.1007/978-94-007-1217-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
The current treatments offered to patients with chronic respiratory diseases are being re-evaluated based on the loss of potency during long-term treatments or because they only provide significant clinical benefits to a subset of the patient population. For instance, glucocorticoids are considered the most effective anti-inflammatory therapies for chronic inflammatory and immune diseases, such as asthma. But they are relatively ineffective in asthmatic smokers, and patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). As such, the pharmaceutical industry is exploring new therapeutic approaches to address all major respiratory diseases. The previous chapters demonstrated the widespread influence of purinergic signaling on all pulmonary functions and defense mechanisms. In Chap. 8, we described animal studies which highlighted the critical role of aberrant purinergic activities in the development and maintenance of chronic airway diseases. This last chapter covers all clinical and pharmaceutical applications currently developed based on purinergic receptor agonists and antagonists. We use the information acquired in the previous chapters on purinergic signaling and lung functions to scrutinize the preclinical and clinical data, and to realign the efforts of the pharmaceutical industry.
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Affiliation(s)
- Stephen Tilley
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, 29799, USA,
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14
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Cicala C, Ialenti A. Adenosine signaling in airways: toward a promising antiasthmatic approach. Eur J Pharmacol 2013; 714:522-5. [PMID: 23850943 DOI: 10.1016/j.ejphar.2013.06.033] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 06/14/2013] [Accepted: 06/21/2013] [Indexed: 12/16/2022]
Abstract
Adenosine participates to asthma physiopathology by signaling through more than just one receptor subtype. Defining the role of each receptor is complicated by evidence that often results obtained on rodents do not coincide with human studies, but what emerges is that an important condition to establish hyperresponsiveness to adenosine in any species of sensitized animals is the exposure to allergen; this feature appears to be very similar to the human situation, since allergic humans regularly undergo exposure to allergen. Furthermore, A₂B in humans, but A₃ receptor in rodents, would mediate, indirectly, the bronchoconstriction in response to adenosine and would play the main role in adenosine-induced airway inflammation and airway hyperreactivity. On the other hand, A₁ receptor over-expressed on asthmatic airways would mediate a direct adenosine bronchoconstrictor effect. Antagonists and agonists to adenosine receptors have been considered as antiasthmatic drugs but often their development has been limited by unwanted effects. Preventing adenosine accumulation in airways should be considered as a novel promising antiasthmatic strategy.
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Affiliation(s)
- Carla Cicala
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131, Naples, Italy.
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15
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Caruso M, Alamo A, Crisafulli E, Raciti C, Fisichella A, Polosa R. Adenosine signaling pathways as potential therapeutic targets in respiratory disease. Expert Opin Ther Targets 2013; 17:761-72. [PMID: 23642090 DOI: 10.1517/14728222.2013.795220] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Adenosine receptors (ARs) and their differential pattern of expression modulate a series of pleiotropic activities that are known to contribute to the control of inflammation, remodeling, and tissue repair. Consequently, pharmacological manipulation of adenosine signaling pathway is of great interest and is currently exploited as a therapeutic target for a number of respiratory diseases with several molecules with agonist and antagonist activities against known ARs being developed for the treatment of different conditions of the respiratory system. AREAS COVERED Herein, we will review the rational basis leading to the development of novel therapies for asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cystic fibrosis. Their most recent clinical development will be also discussed. EXPERT OPINION Advances in our understanding of the pathogenetic role of adenosine in respiratory diseases may be soon translated into effective treatment options. In consideration of the complex interplay driven by the different pattern of receptor distribution and/or affinity of the four known AR subtypes in specific cell types at different stages of the disease, it is likely that combination of selective antagonist/agonists for different AR subtypes will be required to obtain reasonable clinical efficacy. Alternatively, controlling the factors involved in driving adenosine concentrations in the tissue may be also of great significance.
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Affiliation(s)
- Massimo Caruso
- University of Catania-AOU Policlinico-V. Emanuele, Institute of Internal Medicine and Clinical Immunology, Department of Clinical and Molecular Bio-Medicine, Catania, Italy.
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16
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Abstract
Experimental animals in biomedical research provide insights into disease mechanisms and models for determining the efficacy and safety of new therapies and for discovery of corresponding biomarkers. Although mouse and rat models are most widely used, observations in these species cannot always be faithfully extrapolated to human patients. Thus, a number of domestic species are additionally used in specific disease areas. This review summarizes the most important applications of domestic animal models and emphasizes the new possibilities genetic tailoring of disease models, specifically in pigs, provides.
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Affiliation(s)
- A Bähr
- Chair for Molecular Animal Breeding and Biotechnology, Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, Munich, Germany
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17
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Bousquet J, Yssel H, Demoly P. Prospects for a vaccine in allergic diseases and asthma. BioDrugs 2012; 13:61-75. [PMID: 18034513 DOI: 10.2165/00063030-200013010-00006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Allergen-specific immunotherapy is widely used to treat allergic diseases, and current research is now focusing on the development of therapeutic vaccines acting on the IgE immune response following allergen challenge. The IgE immune response is dependent on genetic and environmental factors; production of IgE results from complex interactions among B cells, T cells, mast cells, basophils,surface and adhesion molecules and various cytokines. New vaccination methods under investigation involve allergen-specific or nonspecific methodology. Allergen-specific methods currently being developed include allergoids, passive saturation of effector cells, plasmid DNA immunisation and antigen-antibody complexes. The mechanisms of immunotherapy using allergen-specific methods differ with the allergens and the route of immunisation used (parenteral, intranasal, sublingual, oral or bronchial). Many vaccines being developed at present comprise synthetic, recombinant or highly purified subunit antigens, which although they have increased safety may also be less immunogenic.It is hoped that the addition of adjuvants will overcome this drawback. Methods of increasing the dose of allergen while reducing the possibility of an anaphylactic reaction include the use of non-anaphylactic isoforms of the allergens, alteration of the tertiary structure of the allergens and construction of minimal allergen-derived T cell peptides. Nonspecific approaches include humanised anti-IgE antibodies,moderation of the T(H)2 cytokine network and antisense oligodeoxynucleotide therapy.
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Affiliation(s)
- J Bousquet
- Hôpital Arnaud de Villeneuve, INSERM V454, Montpellier, France.
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18
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Abstract
Evidence for a significant role and impact of purinergic signaling in normal and diseased airways is now beyond dispute. The present review intends to provide the current state of knowledge of the involvement of purinergic pathways in the upper and lower airways and lungs, thereby differentiating the involvement of different tissues, such as the epithelial lining, immune cells, airway smooth muscle, vasculature, peripheral and central innervation, and neuroendocrine system. In addition to the vast number of well illustrated functions for purinergic signaling in the healthy respiratory tract, increasing data pointing to enhanced levels of ATP and/or adenosine in airway secretions of patients with airway damage and respiratory diseases corroborates the emerging view that purines act as clinically important mediators resulting in either proinflammatory or protective responses. Purinergic signaling has been implicated in lung injury and in the pathogenesis of a wide range of respiratory disorders and diseases, including asthma, chronic obstructive pulmonary disease, inflammation, cystic fibrosis, lung cancer, and pulmonary hypertension. These ostensibly enigmatic actions are based on widely different mechanisms, which are influenced by the cellular microenvironment, but especially the subtypes of purine receptors involved and the activity of distinct members of the ectonucleotidase family, the latter being potential protein targets for therapeutic implementation.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Royal Free Campus, London, UK.
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19
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Hyperresponsiveness to adenosine in sensitized Wistar rats over-expressing A1 receptor. Eur J Pharmacol 2012; 695:120-5. [PMID: 23000391 DOI: 10.1016/j.ejphar.2012.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Revised: 09/04/2012] [Accepted: 09/12/2012] [Indexed: 11/23/2022]
Abstract
Airway hyperreactivity is characterized by increased responsiveness to bronchoconstrictor stimuli and it is hallmark of asthma. Adenosine is an ubiquitous signaling nucleoside resulting from ATP catabolism, whose extracellular levels increase following cellular damage or stress. Adenosine plays a role in asthma; asthmatics, but not normal subjects, present bronchoconstriction following inhalation of adenosine or of its precursor, adenosine-5'-monophosphate, most likely via adenosine A(2B) receptor on mast cells. However, the mechanism underling the increased airway smooth muscle sensitivity to adenosine in asthmatics remains to be elucidated. Early experimental studies suggested the involvement of A(1) receptor; this hypothesis has been confirmed by more recent studies on guinea pigs and is corroborated by the finding of an increased adenosine A(1) expression on asthmatic bronchial tissues. Brown Norway rats, the strain usually used to assess asthma models, develop hyperresponsiveness to adenosine 3h following allergen challenge, but not 24h thereafter, without involvement of A(1) receptor. Here, we investigated the role of adenosine A(1) receptor in sensitized Wistar rats showing airway hyperresponsiveness 24h following allergen challenge. We found that on bronchi of sensitized Wistar rats challenged with allergen there is an increased adenosine A(1) receptor expression on smooth muscle that is responsible for hyperresponsiveness to adenosine and ovalbumin.
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Page CP, Spina D. Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol 2012; 12:275-86. [PMID: 22497841 DOI: 10.1016/j.coph.2012.02.016] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Accepted: 02/23/2012] [Indexed: 02/05/2023]
Abstract
Phosphodiesterases (PDEs) are a family of enzymes which catalyse the metabolism of the intracellular cyclic nucleotides, c-AMP and c-GMP that are expressed in a variety of cell types and in the context of respiratory diseases, It is now recognised that the use of PDE3, PDE4 and mixed PDE3/4 inhibitors can provide clinical benefit to patients with asthma or chronic obstructive pulmonary disease (COPD). The orally active PDE4 inhibitor Roflumilast-n-oxide has been approved for treatment of severe exacerbations of COPD as add-on therapy to standard drugs. This review discusses the involvement of PDEs in airway diseases and various strategies that are currently being pursued to improve efficacy and reduce side-effects of PDE4 inhibitors, including delivery via the inhaled route, mixed PDE inhibitors and/or antisense biologicals targeted towards PDE4.
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Affiliation(s)
- Clive P Page
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, Franklin Wilkins Building, King's College London, London SE1 9NH, UK.
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Page CP, Spina D. Phosphodiesterase inhibitors in the treatment of inflammatory diseases. Handb Exp Pharmacol 2011:391-414. [PMID: 21695650 DOI: 10.1007/978-3-642-17969-3_17] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Phosphodiesterase 4 (PDE4) belongs to a family of enzymes which catalyzes the breakdown of 3, 5'-adenosine cyclic monophosphate (cAMP) and is ubiquitously expressed in inflammatory cells. There is little evidence that inflammatory diseases are caused by increased expression of this isoenzyme, although human inflammatory cell activity can be suppressed by selective PDE4 inhibitors. Consequently, there is intense interest in the development of selective PDE4 inhibitors for the treatment of a range of inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and psoriasis. Recent clinical trials with roflumilast in COPD have confirmed the therapeutic potential of targeting PDE4 and recently roflumilast has been approved for marketing in Europe and the USA, although side effects such as gastrointestinal disturbances, particularly nausea and emesis as well as headache and weight loss, may limit the use of this drug class, at least when administered by the oral route. However, a number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects of PDE4 inhibitors, including delivery via the inhaled route, development of nonemetic PDE4 inhibitors, mixed PDE inhibitors, and/or antisense biologicals targeted toward PDE4.
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Affiliation(s)
- C P Page
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.
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Ponnoth DS, Jamal Mustafa S. Adenosine receptors and vascular inflammation. BIOCHIMICA ET BIOPHYSICA ACTA 2011; 1808:1429-34. [PMID: 20832387 PMCID: PMC3010249 DOI: 10.1016/j.bbamem.2010.08.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Revised: 08/26/2010] [Accepted: 08/30/2010] [Indexed: 02/06/2023]
Abstract
Epidemiological studies have shown a positive correlation between poor lung function and respiratory disorders like asthma and the development of adverse cardiovascular events. Increased adenosine (AD) levels are associated with lung inflammation which could lead to altered vascular responses and systemic inflammation. There is relatively little known about the cardiovascular effects of adenosine in a model of allergy. We have shown that A(1) adenosine receptors (AR) are involved in altered vascular responses and vascular inflammation in allergic mice. Allergic A(1)wild-type mice showed altered vascular reactivity, increased airway responsiveness and systemic inflammation. Our data suggests that A(1) AR is pro-inflammatory systemically in this model of asthma. There are also reports of the A(2B) receptor having anti-inflammatory effects in vascular stress; however its role in allergy with respect to vascular effects has not been fully explored. In this review, we have focused on the role of adenosine receptors in allergic asthma and the cardiovascular system and possible mechanism(s) of action.
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Affiliation(s)
- Dovenia S Ponnoth
- Department of Physiology and Pharmacology, West Virginia University. Morgantown, WV, USA
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Abstract
Over the past 20 years, the growing awareness that purinergic signaling events literally shape the immune and inflammatory responses to infection and allergic reactions warranted the development of animal models to assess their importance in vivo in acute lung injury and chronic airway diseases. The pioneer work conducted with the adenosine deaminase (ADA)-deficient mouse provided irrefutable evidence that excess adenosine (ADO) accumulating in the lungs of asthmatic patients, constitutes a powerful mediator of disease severity. These original studies launched the development of murine strains for the two major ectonucleotidases responsible for the generation of airway ADO from ATP release: CD39 and CD73. The dramatic acute lung injury and chronic lung complications, manifested by these knockout mice in response to allergens and endotoxin, demonstrated the critical importance of regulating the availability of ATP and ADO for their receptors. Therapeutic targets are currently evaluated using knockout mice and agonists/antagonists for each ADO receptor (A(1)R, A(2A)R, A(2B)R, and A(3)R) and the predominant ATP receptors (P2Y(2)R and P2X(7)R). This chapter provides an in-depth description of each in vivo study, and a critical view of the therapeutic potentials for the treatment of airway diseases.
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Affiliation(s)
- Maryse Picher
- and Treatment Center, Cystic Fibrosis Pulmonary Research and T, University of North Carolina, Chapel Hill,, 27599 North Carolina USA
| | - Richard C. Boucher
- University of North Carolina, - Cystic Fibrosis Pulmonary Research and, Thurston-Bowles building - 7011, CHAPEL HILL, 27599 North Carolina USA
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Development of new drugs for the treatment of respiratory diseases: from concept to the clinic. J Drug Deliv Sci Technol 2011. [DOI: 10.1016/s1773-2247(11)50053-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Kher G, Trehan S, Misra A. Antisense Oligonucleotides and RNA Interference. CHALLENGES IN DELIVERY OF THERAPEUTIC GENOMICS AND PROTEOMICS 2011. [PMCID: PMC7150054 DOI: 10.1016/b978-0-12-384964-9.00007-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Ponnoth DS, Nadeem A, Tilley S, Mustafa SJ. Involvement of A1 adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma. Am J Physiol Heart Circ Physiol 2010; 299:H81-7. [PMID: 20400685 DOI: 10.1152/ajpheart.01090.2009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Poor lung function and respiratory disorders like asthma have a positive correlation with the development of adverse cardiovascular events. Increased adenosine levels are associated with lung inflammation that could lead to altered vascular responses and systemic inflammation. We hypothesized that asthmatic lung inflammation has systemic effects through A(1) adenosine receptors (A(1)AR) and investigated the effects of aerosolized adenosine on vascular reactivity and inflammation, using A(1)AR knockout (A(1)KO) and corresponding wild-type (A(1)WT) mice that were divided into three experimental groups each: control (CON), allergen sensitized and challenged (SEN), and SEN + aerosolized adenosine (SEN + AD). Animals were sensitized with ragweed (200 microg ip; days 1 and 6), followed by 1% ragweed aerosol challenges (days 11 to 13). On day 14, the SEN + AD groups received one adenosine aerosol challenge (6 mg/ml) for 2 min, and aortae were collected on day 15. 5'-N-ethylcarboxamidoadenosine (NECA; nonselective adenosine analog) induced concentration-dependent aortic relaxation in the A(1)WT CON group, which was impaired in the A(1)WT SEN and SEN + AD groups. All groups of A(1)KO mice showed similar (no significant difference) concentration-dependent relaxation to NECA. The A(1)WT SEN and SEN + AD groups had a significantly higher contraction to selective A(1) agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) compared with the CON group. Western blot data showed that aortic A(1)AR expression was significantly increased in WT SEN and SEN + AD mice compared with CON mice. Gene expression of ICAM-1 and IL-5 was significantly increased in allergic A(1)WT aorta and were undetected in the A(1)KO groups. A(1)WT allergic mice had significantly higher airway hyperresponsiveness (enhanced pause) to NECA, with adenosine aerosol further enhancing it. In conclusion, allergic A(1)WT mice showed altered vascular reactivity, increased airway hyperresponsiveness, and systemic inflammation. These data suggest that A(1)AR is proinflammatory systemically in this model of allergic asthma.
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Affiliation(s)
- Dovenia S Ponnoth
- Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA
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Metal–bipyridine complexes in DNA backbones and effects on thermal stability. J Biol Inorg Chem 2010; 15:629-39. [DOI: 10.1007/s00775-010-0630-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Accepted: 01/22/2010] [Indexed: 10/19/2022]
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Séguin RM, Ferrari N. Emerging oligonucleotide therapies for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2009; 18:1505-17. [PMID: 19715448 DOI: 10.1517/13543780903179294] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are disorders of the airways largely related to the presence of persistent inflammation. The approval of inhaled corticosteroids in the early 1970s pioneered a new age of therapy in treating chronic inflammatory airway diseases. This was the first time that an anti-inflammatory product was available to reduce the characteristic lung inflammation in airways and the associated obstruction, inflammation and hyper-responsiveness. Fast forward 40 years: corticosteroids are still an important therapeutic intervention; however, they exhibit limited use in moderate to severe asthma and COPD. Oligonucleotide therapies are an emerging class which include the antisense, the RNAi (siRNA and miRNA), the immunomodulatory, the aptamer and the decoy approaches. As these approaches are rather recent in the respiratory field, most are still early in development. Nevertheless, with limitations of current small molecule therapies and the hurdles faced with biologics, the use of oligonucleotides is relevant and the door is open to the development of this category of therapeutics. This review focuses on the major classes of oligonucleotides that are currently in late stage preclinical or clinical development for the treatment of asthma and COPD, and discusses the implications for their use as therapies for respiratory diseases.
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Affiliation(s)
- Rosanne M Séguin
- Topigen Pharmaceuticals, Inc., Immunology and Development Support, 2901 Rachel East Street, Suite 13, Montréal, Québec H1W 4A4, Canada.
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Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease. Trends Pharmacol Sci 2009; 30:528-35. [PMID: 19762093 DOI: 10.1016/j.tips.2009.07.005] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 07/02/2009] [Accepted: 07/07/2009] [Indexed: 12/17/2022]
Abstract
Asthma and chronic obstructive pulmonary disease (COPD) are pulmonary disorders characterized by various degrees of inflammation and tissue remodeling. Adenosine is a signaling molecule that is elevated in the lungs of patients with asthma and COPD. Adenosine elicits its actions by engaging cell surface adenosine receptors, and substantial preclinical evidence suggests that targeting these receptors will provide novel approaches for the treatment of asthma and COPD. Studies in animal models of airway disease suggest that there may be clinical benefit to the use of A(1), A(3) and A(2B) adenosine receptor antagonists in the treatment of features of asthma and/or COPD, while A(2A) agonists may also prove effective. Several adenosine receptor based pharmacologic agents have entered clinical development for the treatment of asthma and COPD; however, the studies have been limited and the efficacy of such approaches is not yet clear.
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Zhou Y, Schneider DJ, Blackburn MR. Adenosine signaling and the regulation of chronic lung disease. Pharmacol Ther 2009; 123:105-16. [PMID: 19426761 PMCID: PMC2743314 DOI: 10.1016/j.pharmthera.2009.04.003] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2009] [Accepted: 04/09/2009] [Indexed: 12/20/2022]
Abstract
Chronic lung diseases such as asthma, chronic obstructive pulmonary disease and interstitial lung disease are characterized by inflammation and tissue remodeling processes that compromise pulmonary function. Adenosine is produced in the inflamed and damaged lung where it plays numerous roles in the regulation of inflammation and tissue remodeling. Extracellular adenosine serves as an autocrine and paracrine signaling molecule by engaging cell surface adenosine receptors. Preclinical and cellular studies suggest that adenosine plays an anti-inflammatory role in processes associated with acute lung disease, where activation of the A(2A)R and A(2B)R has promising implications for the treatment of these disorders. In contrast, there is growing evidence that adenosine signaling through the A(1)R, A(2B)R and A(3)R may serve pro-inflammatory and tissue remodeling functions in chronic lung diseases. This review discusses the current progress of research efforts and clinical trials aimed at understanding the complexities of these signaling pathway as they pertain to the development of treatment strategies for chronic lung diseases.
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MESH Headings
- Acute Disease
- Adenosine/metabolism
- Adenosine Deaminase/genetics
- Adenosine Deaminase/physiology
- Animals
- Chronic Disease
- Disease Models, Animal
- Humans
- Lung Diseases, Interstitial/drug therapy
- Lung Diseases, Interstitial/immunology
- Lung Diseases, Interstitial/metabolism
- Lung Diseases, Interstitial/pathology
- Lung Diseases, Obstructive/drug therapy
- Lung Diseases, Obstructive/immunology
- Lung Diseases, Obstructive/metabolism
- Lung Diseases, Obstructive/pathology
- Purinergic P1 Receptor Agonists
- Purinergic P1 Receptor Antagonists
- Receptors, Purinergic P1/metabolism
- Signal Transduction
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Affiliation(s)
- Yang Zhou
- Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, 6431 Fannin St., Houston, Texas, 77030
| | - Daniel J. Schneider
- Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, 6431 Fannin St., Houston, Texas, 77030
| | - Michael R. Blackburn
- Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, 6431 Fannin St., Houston, Texas, 77030
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Abstract
The pathophysiological processes underlying respiratory diseases like asthma are complex, resulting in an overwhelming choice of potential targets for the novel treatment of this disease. Despite this complexity, asthmatic subjects are uniquely sensitive to a range of substances like adenosine, thought to act indirectly to evoke changes in respiratory mechanics and in the underlying pathology, and thereby to offer novel insights into the pathophysiology of this disease. Adenosine is of particular interest because this substance is produced endogenously by many cells during hypoxia, stress, allergic stimulation, and exercise. Extracellular adenosine can be measured in significant concentrations within the airways; can be shown to activate adenosine receptor (AR) subtypes on lung resident cells and migrating inflammatory cells, thereby altering their function, and could therefore play a significant role in this disease. Many preclinical in vitro and in vivo studies have documented the roles of the various AR subtypes in regulating cell function and how they might have a beneficial impact in disease models. Agonists and antagonists of some of these receptor subtypes have been developed and have progressed to clinical studies in order to evaluate their potential as novel antiasthma drugs. In this chapter, we will highlight the roles of adenosine and AR subtypes in many of the characteristic features of asthma: airway obstruction, inflammation, bronchial hyperresponsiveness and remodeling. We will also discuss the merit of targeting each receptor subtype in the development of novel antiasthma drugs.
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Chapter 13 Recent Advances in Adenosine Receptor (AR) Ligands in Pulmonary Diseases. ANNUAL REPORTS IN MEDICINAL CHEMISTRY 2009. [DOI: 10.1016/s0065-7743(09)04413-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register]
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El-Hashim AZ, Abduo HT, Rachid OM, Luqmani YA, Al Ayadhy BY, Alkhaledi GM. Intranasal administration of NECA can induce both anti-inflammatory and pro-inflammatory effects in BALB/c mice: evidence for A 2A receptor sub-type mediation of NECA-induced anti-inflammatory effects. Pulm Pharmacol Ther 2008; 22:243-52. [PMID: 19146972 DOI: 10.1016/j.pupt.2008.12.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2008] [Revised: 12/06/2008] [Accepted: 12/18/2008] [Indexed: 11/30/2022]
Abstract
The role of adenosine in allergic inflammation is unclear. This study investigated the effects of the non-selective adenosine receptor agonist, 5-N-ethylcarboxamidoadenosine (NECA), on immunized only and immunized and airway challenged mice. The adenosine receptor sub-type(s) mediating the NECA effects and the A(2A) receptor mRNA expression were also investigated. In mice that were only immunized, intranasal NECA (1 mM) administration caused a significant increase in bronchoalveolar lavage total cell count (TCC), neutrophils and eosinophils (>1.5-, >6 and >60-fold, respectively). Two and four intranasal ovalbumin (OVA) challenges induced a significant (P < 0.05) increase in TCC (>2.1- and >4-fold, respectively) and eosinophils (>350- and >1700-fold, respectively). Real-time PCR analysis showed that the A(2A) receptor sub-type mRNA was significantly increased (P < 0.05) in the lung tissue of immunized mice following both two and four OVA challenges. NECA (0.3 mM) treatment caused a significant reduction in the increase induced by the two and four OVA challenges in the TCC by 46.1% and 56.6%, respectively, eosinophils by 70.1% and 75.6%, respectively, and in the A(2A) receptor sub-type mRNA by 43.2% and 41.0%, respectively. Treatment with the A(2A) receptor antagonist, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine), SCH-58261, completely reversed both the NECA-mediated reduction in TCC and eosinophilia. Moreover, OVA challenge of immunized mice, over 2 consecutive days, resulted in a significant (P < 0.05) increase in TCC (4.5-fold) and eosinophils (>2000-fold) that was detected 72 h later. NECA (0.3 mM) treatment, at 24 and 48 h post OVA challenge, significantly reduced the increase in both TCC and eosinophils by 45.0% and 74.8%, respectively. Our data show that in immunized, but not OVA-challenged mice, high dose of NECA (1 mM) induces an inflammatory airway response. In contrast, in models of inflammation, NECA, at mainly 0.3 mM, induces a significant anti-inflammatory effect when administered prior to the induction of airway inflammation or therapeutically following its establishment. The data also indicate that the anti-inflammatory action of NECA seems to be mediated via the A(2A) receptor sub-type and hence the use of selective A(2A) receptor agonists as potential therapeutic agents in the treatment of inflammatory diseases such as asthma should be investigated further.
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Affiliation(s)
- Ahmed Z El-Hashim
- Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
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Kim SH, Kim YK, Park HW, Kim SH, Kim SH, Ye YM, Min KU, Park HS. Adenosine deaminase and adenosine receptor polymorphisms in aspirin-intolerant asthma. Respir Med 2008; 103:356-63. [PMID: 19019667 DOI: 10.1016/j.rmed.2008.10.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2008] [Revised: 10/06/2008] [Accepted: 10/06/2008] [Indexed: 11/25/2022]
Abstract
In asthmatic airways, adenosine is a potent bronchoconstrictor with either pro- or anti-inflammatory effects depending on receptor interactions. While aspirin has been suggested to mediate adenosine action, the roles of adenosine and its receptors in aspirin-intolerant asthma (AIA) are not well-defined. Therefore, we evaluated associations between genetic polymorphisms of adenosine deaminase and the four adenosine receptors (A(1), A(2A), A(2B), and A(3)) with the AIA phenotype. The genes for adenosine deaminase (ADA) and the four adenosine receptors (ADORA1, ADORA2A, ADORA2B, and ADORA3) were screened by direct sequencing, and 13 single nucleotide polymorphisms (SNPs) were selected among 23 polymorphisms. Using multivariate logistic regression analysis, we compared the frequencies of SNP genotypes and haplotypes among 136 patients with AIA, 181 patients with aspirin-tolerant asthma (ATA), and 183 normal individuals. We found significant differences between normal and patients with AIA in the ADORA1 SNP genotype frequencies for 1405C>T (P=0.001) and A102A (P=0.013). No other significant associations were detected for the other SNPs. In the haplotype analysis, ht[C-T-G] (P=0.003) and ht[A-C-G] (P=0.032) in ADORA1 and ht[A-T] in ADORA2 (P=0.013) were significantly associated with AIA. Genetic polymorphisms of adenosine receptors A(1) and A(2A) were associated with AIA, suggesting that adenosine might play a crucial role in the development of AIA through interactions with the A(1) and A(2A) receptors.
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Affiliation(s)
- Sang-Heon Kim
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
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Spina D. PDE4 inhibitors: current status. Br J Pharmacol 2008; 155:308-15. [PMID: 18660825 PMCID: PMC2567892 DOI: 10.1038/bjp.2008.307] [Citation(s) in RCA: 261] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2008] [Revised: 06/05/2008] [Accepted: 06/09/2008] [Indexed: 11/08/2022] Open
Abstract
Phosphodiesterase4 inhibitors are currently under development for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease. The rationale for the development of this drug class stems from our understanding of the role of PDE4 in suppressing the function of a range of inflammatory and resident cells thought to contribute toward the pathogenesis of these diseases. Similarly, numerous preclinical in vivo studies have shown that PDE4 inhibitors suppress characteristic features of these diseases, namely, cell recruitment, activation of inflammatory cells and physiological changes in lung function in response to a range of insults to the airways. These potentially beneficial actions of PDE4 inhibitors have been successfully translated in phase II and III clinical trials with roflumilast and cilomilast. However, dose limiting side effects of nausea, diarrhoea and headache have tempered the enthusiasm of this drug class for the treatment of these respiratory diseases. A number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects, including delivery via the inhaled route, and/or development of non-emetic PDE4 inhibitors and mixed PDE inhibitors.
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Affiliation(s)
- D Spina
- King's College London School of Biomedical and Health Science, Pharmaceutical Science Research Division, Sackler Institute of Pulmonary Pharmacology, London, UK.
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Mansoor M, Melendez AJ. Advances in antisense oligonucleotide development for target identification, validation, and as novel therapeutics. GENE REGULATION AND SYSTEMS BIOLOGY 2008; 2:275-95. [PMID: 19787090 PMCID: PMC2733095 DOI: 10.4137/grsb.s418] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Antisense oligonucleotides (As-ODNs) are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18–21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt), 13 for RNA and 17 for DNA, normally occurs only once. The potential applications of As-ODNs are numerous because mRNA is ubiquitous and is more accessible to manipulation than DNA. With the publication of the human genome sequence, it has become theoretically possible to inhibit mRNA of almost any gene by As-ODNs, in order to get a better understanding of gene function, investigate its role in disease pathology and to study novel therapeutic targets for the diseases caused by dysregulated gene expression. The conceptual simplicity, the availability of gene sequence information from the human genome, the inexpensive availability of synthetic oligonucleotides and the possibility of rational drug design makes As-ODNs powerful tools for target identification, validation and therapeutic intervention. In this review we discuss the latest developments in antisense oligonucleotide design, delivery, pharmacokinetics and potential side effects, as well as its uses in target identification and validation, and finally focus on the current developments of antisense oligonucleotides in therapeutic intervention in various diseases.
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Affiliation(s)
- Moizza Mansoor
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Abstract
The prevalence of asthma has increased in developed countries. The efficacy of available drugs in those with severe persistent disease is limited. This has led to a renewed search for the reasons for failures of the existing treatment and for novel concepts. Treatment with inhaled corticosteroids, and to a much lesser extent theophylline, can reduce the survival of inflammatory cells including eosinophils. Emerging trends in treatments for asthma could include strategies to alter the cytokine/chemokine balance. It is evident that the current ICS are already very efficient and safe, it will be difficult to introduce further improved formulations. Perhaps the most fruitful effort shall be in developing patient friendly easy to use targeted delivery systems. The newer therapies are planned for the several upstream targets and may have potential to prevent the disease. Various potential therapies are being worked upon like-targeting prevention of T cell activation, modulation of Th-1/Th-2 differentiation, inhibition of Th-2 related cytokines, Th-1/Th-2 modulation, inhibition of downstream mediators etc. The new strategy shall perhaps lie with matching the patients and their disease with the most suitable therapy.
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Affiliation(s)
- Varinder Singh
- Department of Pediatrics, Lady Hardinge Medical College and Assoc Kalawati Saran Children's Hospital, New Delhi, India.
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Giorgi I, Nieri P. Therapeutic potential of A1adenosine receptor ligands: a survey of recent patent literature. Expert Opin Ther Pat 2008. [DOI: 10.1517/13543776.18.7.677] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Pei DS, Sun YH, Long Y, Zhu ZY. Inhibition of no tail (ntl) gene expression in zebrafish by external guide sequence (EGS) technique. Mol Biol Rep 2008; 35:139-43. [PMID: 17294249 DOI: 10.1007/s11033-007-9063-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2006] [Accepted: 01/17/2007] [Indexed: 11/28/2022]
Abstract
External guide sequence (EGS) technique, a branch of ribozyme strategy, can be enticed to cleave the target mRNA by forming a tRNA-like structure. In the present study, no tail gene (ntl), a key gene participating in the formation of normal tail, was used as a target for ribonuclease (RNase) P-mediated gene disruption in zebrafish in vivo. Transient expression of pH1-m3/4 ntl-EGS or pH1-3/4 ntl-EGS produced the full no tail phenotype at long-pec stage in proportion as 24 or 35%, respectively. As is expected that the full-length ntl mRNA of embryos at 50% epiboly stage decreased relative to control when injected the embryos with 3/4 EGS or m3/4 EGS RNA. Interestingly, ntl RNA transcripts, including the cleaved by EGS and the untouched, increased. Taken together, these results indicate that EGS strategy can work in zebrafish in vivo and becomes a potential tool for degradation of targeted mRNAs.
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Affiliation(s)
- De-Sheng Pei
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
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Reynolds SM, Docherty R, Robbins J, Spina D, Page CP. Adenosine induces a cholinergic tracheal reflex contraction in guinea pigs in vivo via an adenosine A1 receptor-dependent mechanism. J Appl Physiol (1985) 2008; 105:187-96. [PMID: 18420718 DOI: 10.1152/japplphysiol.01048.2007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Adenosine induces dyspnea, cough, and airways obstruction in asthma, a phenomenon that also occurs in various sensitized animal models in which a neuronal involvement has been implicated. Although adenosine has been suggested to activate cholinergic nerves, the precise mechanism has not been established. In the present study, the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) induced a cholinergic reflex, causing tracheal smooth muscle contraction that was significantly inhibited by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 100 microg/kg) (P < 0.05) in anesthetized animals. Furthermore, the adenosine A(2) agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) induced a small reflex, whereas the A(3) selective agonist N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine (IB-MECA) was without effect. The tracheal reflex induced by CPA was also inhibited by recurrent nerve ligation or muscarinic receptor blockade (P < 0.001), indicating that a cholinergic neuronal mechanism of action accounted for this response. The cholinergic reflex in response to aerosolized CPA was significantly greater in passively sensitized compared with naive guinea pigs (P < 0.01). Chronic capsaicin treatment, which inhibited sensory nerve function, failed to inhibit CPA-induced reflex tracheal contractions in passively sensitized guinea pigs, although the local anesthetic lidocaine inhibited CPA-induced tracheal contractions. The effects of CPA on the reflex response was not dependent on the release of histamine from tissue mast cells or endogenous prostaglandins as shown by the lack of effect of the histamine H(1) receptor antagonist pyrilamine (1 mg/kg) or the cyclooxygenase inhibitor meclofenamic acid (3 mg/kg), respectively. In conclusion, activation of pulmonary adenosine A(1) receptors can stimulate cholinergic reflexes, and these reflexes are increased in allergic guinea pigs.
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Affiliation(s)
- Sandra M Reynolds
- Pharmaceutical Science Research Division, The Sackler Institute of Pulmonary Pharmacology, School of Biomedical and Health Science, King's College London, London SE1 1UL, UK
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Cousins DJ, McDonald J, Lee TH. Therapeutic approaches for control of transcription factors in allergic disease. J Allergy Clin Immunol 2008; 121:803-9; quiz 810-1. [PMID: 18395546 DOI: 10.1016/j.jaci.2008.02.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2007] [Revised: 02/08/2008] [Accepted: 02/12/2008] [Indexed: 11/29/2022]
Abstract
The inflammatory response observed in allergic disease involves multiple cell types but is orchestrated in part by the T(H)2 cytokines IL-4, IL-5, and IL-13. In recent years, the transcription factors that control the expression and function of these cytokines have been elucidated, including signal transducer and activator of transcription 6, GATA3, nuclear factor of activated T cells, and nuclear factor kappaB. These molecules are attractive targets for therapeutic intervention because they regulate the expression of numerous effector molecules and functions simultaneously. For instance, the immunosuppressive agents glucocorticoids and cyclosporin A both function by repressing the activity of transcription factors through a variety of mechanisms. In this review we examine the role of each transcription factor in allergic disease and discuss approaches that have been taken to therapeutically interfere with transcription factor function in allergic disease.
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Affiliation(s)
- David J Cousins
- MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.
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43
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Sel S, Wegmann M, Dicke T, Sel S, Henke W, Yildirim AO, Renz H, Garn H. Effective prevention and therapy of experimental allergic asthma using a GATA-3-specific DNAzyme. J Allergy Clin Immunol 2008; 121:910-916.e5. [PMID: 18325571 DOI: 10.1016/j.jaci.2007.12.1175] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2007] [Revised: 12/20/2007] [Accepted: 12/24/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND Allergic bronchial asthma is a chronic inflammatory disease of the airways. The transcription factor GATA-3 was shown to play an important role in TH2 cell activation, but also in the regulation of other cell types involved in bronchial asthma including mast cells, eosinophils, and epithelial cells. DNAzymes represent a new class of antisense molecules that combines the specificity of DNA base pairing with an inherent RNA-cleaving enzymatic activity. OBJECTIVE To develop a GATA-3 mRNA-specific DNAzyme and analyze its allergy-preventing activity in murine models of experimental allergic asthma. METHODS The most active DNAzyme (termed gd21) was selected by in vitro cleavage assays. Allergic airway inflammation was assessed by inflammatory cell and cytokine analysis within bronchoalveolar lavage. Lung histology, including goblet cell hyperplasia and lung function, was analyzed using head-out body-plethysmography. RESULTS Intranasal administration of gd21 prevented airway inflammation and mucus production and inhibited development of airway hyperresponsiveness to methacholine in models of acute allergic airway inflammation. Similar effects were also detected in a model of chronic experimental asthma. Interestingly, gd21 was at least as effective as other antisense molecules, and off-target effects were not detected. Further experiments indicated that pulmonary surfactant may facilitate the cellular uptake of gd21 by acting as an endogenous transfectant. CONCLUSION These results indicate that topical application of the GATA-3-specific DNAzyme is a promising novel approach for the treatment of allergic bronchial asthma.
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Affiliation(s)
- Serdar Sel
- Department of Clinical Chemistry and Molecular Diagnostics, Medical Faculty, Philipps University of Marburg, Marburg, Germany
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Brown RA, Spina D, Page CP. Adenosine receptors and asthma. Br J Pharmacol 2008; 153 Suppl 1:S446-56. [PMID: 18311158 PMCID: PMC2268070 DOI: 10.1038/bjp.2008.22] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Revised: 11/16/2007] [Accepted: 12/13/2007] [Indexed: 12/20/2022] Open
Abstract
The accumulation of evidence implicating a role for adenosine in the pathogenesis of asthma has led to investigations into all adenosine receptor subtypes as potential therapeutic targets for the treatment of asthma. Selective A(1) receptor antagonists are currently in preclinical development since adenosine has been shown experimentally to mediate various features of asthma through this receptor such as bronchoconstriction, mucus secretion and inflammation. The A(2A) receptor is expressed on most inflammatory cells implicated in asthma, and as A(2A) stimulation activates adenylate cyclase and consequently elevates cAMP, selective A(2A) receptor agonists have now reached clinical development. However, initial reports concerning their efficacy are inconclusive. A(2B) receptor antagonists are also under investigation based on the rationale that inhibiting the effects of adenosine on mast cells would be beneficial, in addition to other reported pro-inflammatory effects mediated by the A(2B) receptor on cells such as airway smooth muscle, epithelial cells and fibroblasts. Whilst the effects in pre-clinical models are promising, their efficacy in the clinical setting has also yet to be reported. Finally, adenosine A(3) receptor stimulation has been demonstrated to mediate inhibitory effects on eosinophils since it also elevates cAMP. However, some experimental reports suggest that A(3) antagonists mediate anti-inflammatory effects, thus the rationale for A(3) receptor ligands as therapeutic agents remains to be determined. In conclusion, establishing the precise role of adenosine in the pathogenesis of asthma and developing appropriate subtype selective agonists/antagonists represents an exciting opportunity for the development of novel therapeutics for the treatment of asthma.
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Affiliation(s)
- R A Brown
- King's College London, Sackler Institute of Pulmonary Pharmacology, Division of Biomedical and Health Sciences, London, UK
| | - D Spina
- King's College London, Sackler Institute of Pulmonary Pharmacology, Division of Biomedical and Health Sciences, London, UK
| | - C P Page
- King's College London, Sackler Institute of Pulmonary Pharmacology, Division of Biomedical and Health Sciences, London, UK
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Penn RB. Embracing emerging paradigms of G protein-coupled receptor agonism and signaling to address airway smooth muscle pathobiology in asthma. Naunyn Schmiedebergs Arch Pharmacol 2008; 378:149-69. [PMID: 18278482 DOI: 10.1007/s00210-008-0263-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2007] [Accepted: 01/15/2008] [Indexed: 01/04/2023]
Abstract
G protein-coupled receptors (GPCRs) regulate numerous airway cell functions, and signaling events transduced by GPCRs are important in both asthma pathogenesis and therapy. Indeed, most asthma therapies target GPCRs either directly or indirectly. Within recent years, our understating of how GPCRs signal and are regulated has changed significantly as new concepts have emerged and traditional ideas have evolved. In this review, we discuss current concepts regarding constitutive GPCR activity and receptor agonism, functional selectivity, compartmentalized signaling, and GPCR desensitization. We further discuss the relevance of these ideas to asthma and asthma therapy, while emphasizing their potential application to the GPCR signaling in airway smooth muscle that regulates airway patency and thus disease severity.
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Affiliation(s)
- Raymond B Penn
- Department of Internal Medicine, Wake Forest University Health Sciences Center, Winston-Salem, NC 27157, USA.
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Matera MG, Polosa R. Adenosine receptors: novel targets for drug development in allergic rhinitis. Clin Exp Allergy 2007; 37:4-7. [PMID: 17210035 DOI: 10.1111/j.1365-2222.2006.02647.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
MESH Headings
- Adenosine/metabolism
- Adenosine A3 Receptor Antagonists
- Asthma/drug therapy
- Asthma/metabolism
- Chronic Disease
- Humans
- Purinergic P1 Receptor Antagonists
- Receptor, Adenosine A3/metabolism
- Receptors, Purinergic P1/metabolism
- Rhinitis/drug therapy
- Rhinitis/metabolism
- Rhinitis, Allergic, Perennial/drug therapy
- Rhinitis, Allergic, Perennial/metabolism
- Rhinitis, Allergic, Seasonal/drug therapy
- Rhinitis, Allergic, Seasonal/metabolism
- Signal Transduction/physiology
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van den Berge M, Hylkema MN, Versluis M, Postma DS. Role of adenosine receptors in the treatment of asthma and chronic obstructive pulmonary disease: recent developments. Drugs R D 2007; 8:13-23. [PMID: 17249846 DOI: 10.2165/00126839-200708010-00002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Adenosine is a naturally occurring purine nucleoside with a ubiquitous presence in human tissue, where it plays a key role in many biological processes such as energy generation and protein metabolism. It has been shown that adenosine induces bronchoconstriction in asthmatic and chronic obstructive pulmonary disease (COPD) patients, but not in normal airways. Four different G-protein-coupled adenosine receptors have been described, namely adenosine A(1), A(2A), A(2B) and A(3) receptors. The main mechanism of adenosine-induced bronchoconstriction appears to involve the release of inflammatory mediators from mast cells via activation of the A(2B) receptor. However, adenosine can also act on A(1), A(2A) and A(3) receptors. In recent years there has been an increasing interest in the role of adenosine receptors in asthma and COPD, since it is now clear that they play an important role in the pathophysiology of asthma and COPD. Adenosine receptors are involved in the production and release of a variety of mediators from inflammatory and structural cells. A therapeutic potential for adenosine receptor modulation has even been anticipated. This review focuses on the role of adenosine and adenosine receptors in the treatment of asthma and COPD.
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Affiliation(s)
- Maarten van den Berge
- Department of Pulmonology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
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48
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Crosby JR, Guha M, Tung D, Miller DA, Bender B, Condon TP, York-DeFalco C, Geary RS, Monia BP, Karras JG, Gregory SA. Inhaled CD86 antisense oligonucleotide suppresses pulmonary inflammation and airway hyper-responsiveness in allergic mice. J Pharmacol Exp Ther 2007; 321:938-46. [PMID: 17389243 DOI: 10.1124/jpet.106.119214] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The B7-family molecule CD86, expressed on the surface of pulmonary and thoracic lymph node antigen-presenting cells, delivers essential costimulatory signals for T-cell activation in response to inhaled allergens. CD86-CD28 signaling is involved in priming allergen-specific T cells, but it is unclear whether these interactions play a role in coordinating memory T-helper 2 cell responses. In the ovalbumin (OVA)-induced mouse model of asthma, administration of CD86-specific antibody before systemic sensitization suppresses inhaled OVA-induced pulmonary inflammation and airway hyper-responsiveness (AHR). In previously OVA-sensitized mice, systemic and intranasal coadministration of CD86 antibody is required to produce these effects. To directly assess the importance of pulmonary CD86 expression in secondary immune responses to inhaled allergens, mice were sensitized and locally challenged with nebulized OVA before treatment with an inhaled aerosolized CD86 antisense oligonucleotide (ASO). CD86 ASO treatment suppressed OVA-induced up-regulation of CD86 protein expression on pulmonary dendritic cells and macrophages as well as on recruited eosinophils. Suppression of CD86 protein expression correlated with decreased methacholine-induced AHR, airway inflammation, and mucus production following rechallenge with inhaled OVA. CD86 ASO treatment reduced BAL eotaxin levels, but it did not reduce CD86 protein on cells in the draining lymph nodes of the lung, and it had no effect on serum IgE levels, suggesting a local and not a systemic effect. These results demonstrate that CD86 expression on pulmonary antigen-presenting cells plays a vital role in regulating pulmonary secondary immune responses and suggest that treatment with an inhaled CD86 ASO may have utility in asthma and other chronic inflammatory lung conditions.
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Affiliation(s)
- Jeffrey R Crosby
- Antisense Drug Discovery, ISIS Pharmaceuticals, 1896 Rutherford Rd., Carlsbad, CA 92008, USA.
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Hua X, Erikson CJ, Chason KD, Rosebrock CN, Deshpande DA, Penn RB, Tilley SL. Involvement of A1 adenosine receptors and neural pathways in adenosine-induced bronchoconstriction in mice. Am J Physiol Lung Cell Mol Physiol 2007; 293:L25-32. [PMID: 17468137 DOI: 10.1152/ajplung.00058.2007] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
High levels of adenosine can be measured from the lungs of asthmatics, and it is well recognized that aerosolized 5'AMP, the precursor of adenosine, elicits robust bronchoconstriction in patients with this disease. Characterization of mice with elevated adenosine levels secondary to the loss of adenosine deaminase (ADA) expression, the primary metabolic enzyme for adenosine, further support a role for this ubiquitous mediator in the pathogenesis of asthma. To begin to identify pathways by which adenosine can alter airway tone, we examined adenosine-induced bronchoconstriction in four mouse lines, each lacking one of the receptors for this nucleoside. We show, using direct measures of airway mechanics, that adenosine can increase airway resistance and that this increase in resistance is mediated by binding the A(1) receptor. Further examination of this response using pharmacologically, surgically, and genetically manipulated mice supports a model in which adenosine-induced bronchoconstriction occurs indirectly through the activation of sensory neurons.
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Affiliation(s)
- Xiaoyang Hua
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7219, USA
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Bentley J, Brazier JA, Fisher J, Cosstick R. Duplex stability of DNA·DNA and DNA·RNA duplexes containing 3′-S-phosphorothiolate linkages. Org Biomol Chem 2007; 5:3698-702. [DOI: 10.1039/b713292a] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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