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      Increased circulating β 2-adrenergic receptor autoantibodies are associated with smoking-related emphysema

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          Abstract

          Smoking is a dominant risk factor for chronic obstructive pulmonary disease (COPD) and emphysema, but not every smoker develops emphysema. Immune responses in smokers vary. Some autoantibodies have been shown to contribute to the development of emphysema in smokers. β 2-adrenergic receptors (β 2-ARs) are important targets in COPD therapy. β 2-adrenergic receptor autoantibodies (β 2-AAbs), which may directly affect β 2-ARs, were shown to be increased in rats with passive-smoking-induced emphysema in our current preliminary studies. Using cigarette-smoke exposure (CS-exposure) and active-immune (via injections of β 2-AR second extracellular loop peptides) rat models, we found that CS-exposed rats showed higher serum β 2-AAb levels than control rats before alveolar airspaces became enlarged. Active-immune rats showed increased serum β 2-AAb levels, and exhibited alveolar airspace destruction. CS-exposed-active-immune treated rats showed more extensive alveolar airspace destruction than rats undergoing CS-exposure alone. In our current clinical studies, we showed that plasma β 2-AAb levels were positively correlated with the RV/TLC (residual volume/total lung capacity) ratio ( r = 0.455, p < 0.001) and RV%pred (residual volume/residual volume predicted percentage, r = 0.454, p < 0.001) in 50 smokers; smokers with higher plasma β 2-AAb levels exhibited worse alveolar airspace destruction. We suggest that increased circulating β 2-AAbs are associated with smoking-related emphysema.

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          Most cited references34

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          Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaB-independent mechanisms.

          Activation of the beta(2) adrenergic receptor (beta(2)AR) located on macrophages has been reported to possess anti-inflammatory properties, inhibiting nuclear factor kappaB (NF-kappaB) activation and cytokine production induced by pro-inflammatory stimuli. Here, we show that activation of the beta(2)AR in the absence of pro-inflammatory stimuli produced up to an 80- and 8-fold increase in IL-1beta and IL-6 transcripts, respectively, in the RAW 264.7 murine macrophage cell line. This increase in mRNA expression was accompanied by a significant increase in IL-1beta and IL-6 protein production. Pre-treatment of RAW cells with pharmacological inhibitors of protein kinase A (PKA) or NF-kappaB pathway failed to block this cytokine increase. Instead, the beta(2)AR-mediated increase in cytokines required activation of both the B-raf-ERK1/2 and p38 pathways. Treatment of RAW cells with the exchange protein directly activated by cAMP (EPAC) agonist also resulted in the up-regulation of IL-1beta and IL-6 transcripts. Examination of the main transcription factors downstream of the ERK1/2 and p38 signaling revealed that beta(2)AR activation resulted in the stimulation of CRE-, but not C/EBPbeta-, ETS-, or NF-kappaB-dependent transcription. Western blot analysis further showed that among the transcription factors which recognize the CRE-binding site, ATF-1 and ATF-2 but not CREB proteins were phosphorylated in an ERK1/2- and p38-dependent manner. Collectively, these results demonstrate that beta(2)ARs possess pro-inflammatory properties and that their activation leads to IL-1beta and IL-6 production through ERK1/2- and p38-dependent activation of ATF-1 and ATF-2 transcription factors.
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            Pathogenesis of emphysema: from the bench to the bedside.

            Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. The imbalance is mostly due to an increase in the numbers of alveolar macrophages and neutrophils. Emphysema can also develop from increased alveolar wall cell death and/or failure in alveolar wall maintenance. Chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair. Genetic factors may play an important role in disease susceptibility because only a minority of smokers develops emphysema. Recent literature implicates surfactant instability, malnutrition, and alveolar cell apoptosis as possible etiologies. Identification of cellular and molecular mechanisms of COPD pathogenesis is an area of active, ongoing research that may help to determine therapeutic targets for emphysema.
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              The development of emphysema in cigarette smoke-exposed mice is strain dependent.

              Only 20% of smokers develop chronic obstructive pulmonary disease. An important determinant of susceptibility is genomic variation. We undertook this study to define strains of mice with different susceptibilities for the development of smoking-induced emphysema because they could help identify genetic factors of susceptibility. NZWLac/J, C57BL6/J, A/J, SJ/L, and AKR/J strains were exposed to cigarette smoke for 6 months. Elastance (Htis), the extent of emphysema (mean linear intercept [Lm]), and the inflammatory cell and cytokine response were measured. NZWLac/J had no change in Lm or Htis (resistant). C57BL6/J, A/J, and SJ/L increased Lm, but not Htis (mildly susceptible). AKR/J increased Lm and Htis (super-susceptible). Only AKR/J had significant inflammation comprising macrophages, neutrophils, and T cells. The AKR/J showed an upregulation of Th1 cytokines whereas in the C57BL/6/J and NZWlac/J, cytokines did not change or were downregulated. We conclude that Lm, elastance, and inflammation are features that are needed to phenotype emphysema in mice. The inflammatory cell and cytokine profile may be an important determinant of the phenotype in response to cigarette smoke exposure. The identification of resistant and susceptible strains for the development of emphysema could be useful for genomic studies of emphysema susceptibility in mice and eventually in humans.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                06 March 2017
                2017
                : 7
                : 43962
                Affiliations
                [1 ]Department of Respiratory Medicine, Peking University Third Hospital , Beijing, China
                [2 ]Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health; Beijing Key Laboratory of cardiovascular Receptors Research , Beijing, China
                Author notes
                Article
                srep43962
                10.1038/srep43962
                5338268
                28262783
                8cb583f9-6b06-44c6-bb69-6559eb0ac661
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 07 November 2016
                : 31 January 2017
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