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      Therapeutic Applications

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          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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          Most cited references178

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          Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.

          Interleukin (IL)-13 is a pleiotropic cytokine produced in large quantities by activated CD4(+) Th2 lymphocytes. To define further its potential in vivo effector functions, the Clara cell 10-kDa protein promoter was used to express IL-13 selectively in the lung, and the phenotype of the resulting transgenic mice was characterized. In contrast to transgene-negative littermates, the lungs of transgene-positive mice contained an inflammatory response around small and large airways and in the surrounding parenchyma. It was mononuclear in nature and contained significant numbers of eosinophils and enlarged and occasionally multinucleated macrophages. Airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden-like crystals, and subepithelial airway fibrosis were also prominently noted. Eotaxin protein and mRNA were also present in large quantities in the lungs of the transgene-positive, but not the transgene-negative, mice. IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-5 were not similarly detected. Physiological evaluations revealed significant increases in baseline airways resistance and airways hyperresponsiveness (AHR) to methacholine in transgene-positive animals. Thus, the targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, the deposition of Charcot-Leyden-like crystals, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR. IL-13 may play an important role in the pathogenesis of similar responses in asthma or other Th2-polarized tissue responses.
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            Evidence for airway surface dehydration as the initiating event in CF airway disease.

            R Boucher (2007)
            Cystic fibrosis (CF) lung disease reflects persistent bacterial infection of airway lumens. Several hypotheses have been advanced to link mutations in the CFTR gene to the failure of the CF lung to defend itself against bacterial infection. Amongst the most productive hypotheses at present is the ''low airway surface liquid (ASL) volume'' or ''dehydration'' hypothesis. This hypothesis predicts that airway surface dehydration produces the mucus adhesion, inflammation, and bacterial biofilm formation characteristic of CF. Clinical trials of inhaled hypertonic saline have demonstrated therapeutic benefit of manoeuvres designed to rehydrate CF airway surfaces.
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              Muscarinic receptor signaling in the pathophysiology of asthma and COPD

              Anticholinergics are widely used for the treatment of COPD, and to a lesser extent for asthma. Primarily used as bronchodilators, they reverse the action of vagally derived acetylcholine on airway smooth muscle contraction. Recent novel studies suggest that the effects of anticholinergics likely extend far beyond inducing bronchodilation, as the novel anticholinergic drug tiotropium bromide can effectively inhibit accelerated decline of lung function in COPD patients. Vagal tone is increased in airway inflammation associated with asthma and COPD; this results from exaggerated acetylcholine release and enhanced expression of downstream signaling components in airway smooth muscle. Vagally derived acetylcholine also regulates mucus production in the airways. A number of recent research papers also indicate that acetylcholine, acting through muscarinic receptors, may in part regulate pathological changes associated with airway remodeling. Muscarinic receptor signalling regulates airway smooth muscle thickening and differentiation, both in vitro and in vivo. Furthermore, acetylcholine and its synthesizing enzyme, choline acetyl transferase (ChAT), are ubiquitously expressed throughout the airways. Most notably epithelial cells and inflammatory cells generate acetylcholine, and express functional muscarinic receptors. Interestingly, recent work indicates the expression and function of muscarinic receptors on neutrophils is increased in COPD. Considering the potential broad role for endogenous acetylcholine in airway biology, this review summarizes established and novel aspects of muscarinic receptor signaling in relation to the pathophysiology and treatment of asthma and COPD.
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                Author and article information

                Contributors
                picherm@gmail.com
                rboucher@med.unc.edu
                stephen_tilley@med.unc.edu
                jvolm@email.unc.edu
                picherm@gmail.com
                Journal
                978-94-007-1217-1
                10.1007/978-94-007-1217-1
                Purinergic Regulation of Respiratory Diseases
                Purinergic Regulation of Respiratory Diseases
                978-94-007-1216-4
                978-94-007-1217-1
                12 April 2011
                2011
                : 55
                : 235-276
                Affiliations
                [ID1 ]GRID grid.10698.36, ISNI 0000000122483208, and Treatment Center, Cystic Fibrosis Pulmonary Research and T, , University of North Carolina, ; Chapel Hill,, 27599 North Carolina USA
                [ID2 ]GRID grid.410711.2, ISNI 0000 0001 1034 1720, University of North Carolina, , - Cystic Fibrosis Pulmonary Research and, ; Thurston-Bowles building - 7011, CHAPEL HILL, 27599 North Carolina USA
                [1_9 ]GRID grid.10698.36, ISNI 0000000122483208, Division of Pulmonary and Critical Care Medicine, Department of Medicine, , University of North Carolina, ; Chapel Hill, NC 29799 USA
                [2_9 ]GRID grid.10698.36, ISNI 0000000122483208, Cystic Fibrosis Pulmonary Research and Treatment Center, , University of North Carolina, ; 7011 Thurston-Bowles building, Chapel Hill, NC 27599 USA
                Article
                9
                10.1007/978-94-007-1217-1_9
                7120595
                21560050
                143e66ac-1bde-446b-92de-fe54b27eef15
                © Springer Science+Business Media B.V. 2011

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Science+Business Media B.V. 2011

                airway obstruction,bronchoconstriction,ischemia-reperfusion,lung transplant,pulmonary fibrosis

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