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      Evaluation of plasma antimicrobial peptide LL-37 and nuclear factor-kappaB levels in stable chronic obstructive pulmonary disease

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          Abstract

          Background

          Antimicrobial peptides are effectors of host defence against infection and inflammation and can encourage wound repair.

          Objectives

          The objectives of this study were to investigate the plasma antimicrobial peptide LL-37 and nuclear factor-kappaB (NF-κB) levels in patients with stable COPD compared with a control group and to highlight their importance in immune inflammation.

          Methods

          One hundred and thirty-eight stable COPD patients and 33 control subjects were enrolled in the study. The COPD patients were classified into four groups based on FEV 1 (groups I–IV) and also divided into “low-risk and high-risk” groups (groups A–B [low risk], C–D [high risk]).

          Results

          Plasma LL-37 levels were significantly lower while plasma NF-κB levels of the COPD patients were significantly higher than those of the control subjects ( P<0.001, both). LL-37 levels were significantly lower in group IV than in groups I, II, and III ( P<0.01, all). NF-κB levels were significantly higher in groups III and IV than in groups I and II ( P<0.05, both). There was a positive correlation between FEV 1 and FEV 1/FVC in all COPD patients ( r=0.742, P<0.001) and in group D ( r=0.741, P<0.001). Furthermore, there was an inverse correlation between LL-37 and NF-κB in both the groups C ( r=−0.566, P<0.001) and D ( r=−0.694, P<0.001) and group C+D combined ( r=−0.593, P<0.001). Furthermore, in group C, LL-37 and FEV 1 were positively correlated ( r=0.633, P<0.001).

          Conclusion

          Our study indicated that plasma LL-37 and NF-κB may play an important role in chronic immune inflammation. Decreased LL-37 levels may be particularly high risk for patients in stage IV disease. The role of LL-37 as a target for treatment of the immune system and COPD must be widely evaluated.

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          Most cited references 28

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          LL-37, the only human member of the cathelicidin family of antimicrobial peptides.

          Antimicrobial peptides and their precursor molecules form a central part of human and mammalian innate immunity. The underlying genes have been thoroughly investigated and compared for a considerable number of species, allowing for phylogenetic characterization. On the phenotypical side, an ever-increasing number of very varied and distinctive influences of antimicrobial peptides on the innate immune system are reported. The basic biophysical understanding of mammalian antimicrobial peptides, however, is still very limited. This is especially unsatisfactory since knowledge of structural properties will greatly help in the understanding of their immunomodulatory functions. The focus of this review article will be on LL-37, the only cathelicidin-derived antimicrobial peptide found in humans. LL-37 is a 37-residue, amphipathic, helical peptide found throughout the body and has been shown to exhibit a broad spectrum of antimicrobial activity. It is expressed in epithelial cells of the testis, skin, the gastrointestinal tract, and the respiratory tract, and in leukocytes such as monocytes, neutrophils, T cells, NK cells, and B cells. It has been found to have additional defensive roles such as regulating the inflammatory response and chemo-attracting cells of the adaptive immune system to wound or infection sites, binding and neutralizing LPS, and promoting re-epthelialization and wound closure. The article aims to report the known biophysical facts, with an emphasis on structural evidence, and to set them into relation with insights gained on phylogenetically related antimicrobial peptides in other species. The multitude of immuno-functional roles is only outlined. We believe that this review will aid the future work on the biophysical, biochemical and immunological investigations of this highly intriguing molecule.
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            Increased expression of nuclear factor-kappaB in bronchial biopsies from smokers and patients with COPD.

            The expression of nuclear factor (NF)-kappaB is an indicator of cellular activation and of inflammatory mediator production. The aim of the present study was to characterise the expression and localisation of p65, the major subunit of NF-kappaB, in the bronchial mucosa of patients with chronic obstructive pulmonary disease (COPD), and to examine the relationship between p65 expression and disease status. Bronchial biopsies were obtained from 14 smokers with COPD, 17 smokers with normal lung function and 12 nonsmokers with normal lung function. The number of p65 positive (+) cells was quantified by immunohistochemistry and the expression of p65 in bronchial biopsies from the three groups was examined by Western blotting (WB). Smokers with normal lung function and patients with COPD had increased numbers of p65+ cells in the epithelium and increased p65 nuclear expression. In COPD patients the number of epithelial p65+ cells correlated with the degree of airflow limitation. WB analysis showed an increase in p65 in smokers with normal lung function and COPD patients (p<0.05). Bronchial biopsies in smokers with normal lung function and chronic obstructive pulmonary disease patients show increased expression of p65 protein, predominantly in the bronchial epithelium. Disease severity is associated with an increased epithelial expression of nuclear factor-kappaB.
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              Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations.

              Exacerbations represent an important feature of the clinical manifestation and natural history of chronic obstructive pulmonary disease (COPD). Nuclear localisation of p65 is a signal of nuclear factor-kappaB (NF-kappaB) activation. A study was undertaken to evaluate whether NF-kappaB activation is modified in sputum cells during COPD exacerbations. Total and nuclear p65 immunoreactivity was measured by immunocytochemistry in the sputum cells of 11 smokers with moderate COPD during an exacerbation and after 6-8 weeks of clinical stability. Total sputum cell count was significantly increased during exacerbations from a median (IQR) of 880 (510-1865) to 1914.5 (1065-3205) x 10(3)/ml (p<0.05). The main inflammatory cells in the sputum were neutrophils (83.2 (75.4-92.3)%) and macrophages (14.7 (2.6-21.6)%) and their relative proportion did not change during exacerbations. Nuclear staining for p65 was absent in sputum neutrophils, both during exacerbations and in the stable phase. In contrast, the percentage of macrophages expressing nuclear p65 increased significantly during exacerbations from a median (IQR) of 16 (7-24)% to 41.4 (6-69)% (p<0.05). NF-kappaB appears to be activated in sputum macrophages but not in sputum neutrophils during exacerbations of COPD
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2019
                25 January 2019
                : 14
                : 321-330
                Affiliations
                [1 ]Department of Chest Diseases, Faculty of Medicine, Mehmet Ali Aydınlar University, Atakent Hospital, Istanbul, Turkey
                [2 ]Department of Physiology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
                [3 ]Department of Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey, huzun59@ 123456hotmail.com
                [4 ]Department of Biochemistry, Yildiz Technical University, Istanbul, Turkey
                [5 ]Deparment of Biochemistry, Faculty of Medicine, Halic University, I˙stanbul, Turkey
                [6 ]Clinic of Chest Diseases, Yedikule Chest Diseases and Chest Surgery Training and Research Hospital, I˙stanbul, Turkey
                Author notes
                Correspondence: Hafize Uzun, Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34303 Cerrahpasa, Istanbul, Turkey, Tel +90 212 414 3056, Fax +90 212 633 2987, Email huzun59@ 123456hotmail.com
                Article
                copd-14-321
                10.2147/COPD.S185602
                6354692
                © 2019 Uysal et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Respiratory medicine

                copd, inflammation, antimicrobial peptide ll-37, nuclear factor kappab

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