Lymphocyte Kv1.3-channels in the pathogenesis of chronic obstructive pulmonary disease: novel therapeutic implications of targeting the channels by commonly used drugs
© The Author(s) 2016
Received: 11 July 2016
Accepted: 15 November 2016
Published: 29 November 2016
In patients with chronic obstructive pulmonary disease (COPD), over-activated T-lymphocytes produce pro-inflammatory cytokines and proliferate in situ in the lower airways and pulmonary parenchyma, contributing substantially to the pathogenesis of the disease. Despite our understanding of the molecular mechanisms by which lymphocytes are activated, we know little about the physiological mechanisms. T-lymphocytes predominantly express delayed rectifier K+-channels (Kv1.3) in their plasma membranes and these channels play crucial roles in inducing the lymphocyte activation and proliferation. In the pathogenesis of chronic inflammatory diseases, such as chronic kidney disease (CKD) or inflammatory bowel disease (IBD), these channels, which are overexpressed in proliferating lymphocytes within the inflamed organs, are responsible for the progression of the diseases. Since the over-activation of cellular immunity is also mainly involved in the pathogenesis of COPD, this disease could share similar pathophysiological features as those of CKD or IBD. From a literature review including ours, it is highly likely that the Kv1.3-channels are overexpressed or over-activated in T-lymphocytes isolated from patients with COPD, and that the overexpression of the channels would contribute to the development or progression of COPD. The involvement of the channels leads to novel therapeutic implications of potentially useful Kv1.3-channel inhibitors, such as calcium channel blockers, macrolide antibiotics, HMG-CoA reductase inhibitors and nonsteroidal anti-inflammatory drugs, in the treatment of COPD.
KeywordsChronic obstructive pulmonary disease (COPD) Over-activated T-lymphocytes Delayed rectifier K+-channels (Kv1.3) Therapeutic implications for COPD Kv1.3-channel inhibitor
T-lymphocytes in the pathogenesis of COPD
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in the world, due to increased cigarette smoking, environmental exposure to air pollution particles and occupational exposure to various types of dust and fumes [1, 2]. This disease is histopathologically characterized by chronic inflammation of the airways, with large numbers of inflammatory leukocytes, such as lymphocytes, neutrophils, eosinophils, macrophages and mast cells, infiltrating into the central or peripheral airways [3–7]. These inflammatory cells initially trigger the inflammatory response in the bronchi or bronchioles, which subsequently leads to fibrosis in the smaller airways and alveolar destruction, thus contributing to the pathogenesis of the disease . Of note, in patients with COPD, a prominent increase was found in the total numbers of T-lymphocytes and their production of pro-inflammatory cytokines, such as interferon-γ and tumor necrosis factor (TNF), in the airways and lung parenchyma . Among T-lymphocytes, CD8+ cells, which are more predominant than CD4+ cells in COPD patients, have the capacity to cause cytolysis and apoptosis of alveolar epithelial cells through the release of perforins, granzyme-B and TNF . Therefore, the increased number of T-lymphocytes and their activity actually correlated well with the severity of airway obstruction and the amount of alveolar destruction in COPD .
Involvement of lymphocyte Kv1.3-channels in chronic inflammatory diseases
T-lymphocytes, such as CD4+ and CD8+ cells, predominantly express delayed rectifier K+-channels (Kv1.3) in their plasma membranes [10, 11]. Patch-clamp studies revealed that the channels play crucial roles in facilitating the calcium influx necessary to trigger the lymphocyte activation and proliferation [11, 12]. In pathological conditions, such as in chronic kidney disease (CKD) or inflammatory bowel disease (IBD), the channels were overexpressed in proliferating lymphocytes within the inflamed kidneys or intestines, and the over-activation of the channels largely contributed to the progression of the diseases [13–15]. Previously, we demonstrated in an animal study that the overexpression of Kv1.3-channels in lymphocytes was deeply associated with their in situ proliferation in kidneys and the progression of chronic renal failure (CRF) . In this study, we further demonstrated that margatoxin, a selective inhibitor of the Kv1.3-channels , actually ameliorated the progression of renal fibrosis in rat models with advanced CRF . Along with COPD, CKD and IBD are also nowadays categorized as chronic inflammatory diseases, in which chronic inflammation or the overstimulation of cellular immunity is responsible for the pathogenesis . Therefore, these diseases could share similar pathophysiological features as those of COPD.
Involvement of lymphocyte Kv1.3-channels in COPD
Potential future studies
To substantiate the hypothesis that the activity of Kv1.3 expressed in lymphocytes is important in the pathogenesis in COPD, T-lymphocytes could be isolated from the airways of COPD patients. As previously described by Pizzichini et al. , spontaneous or induced sputum and peripheral blood samples could be obtained from patients with COPD and from healthy volunteers. Using the isolated lymphocytes, the patch-clamp recording technique could be applied to identify the Kv1.3-channels by detecting the voltage-dependent activation and inactivation patterns characteristic to Kv1.3 [16, 23–27]. Then, using these cells, how the selective blocking of the channels by the drugs, such as margatoxin or ShK-186 [20, 28], affected the activation or proliferation of the lymphocytes could be examined in vitro. To determine the effects of these drugs on the lymphocyte activation kinetics, detailed functional analyses will be required. Possible approaches could include measurement of the cytokine production , leukocyte migration assay  and the measurement of [3H] thymidine incorporation into the lymphocyte DNA . The proliferation of lymphocytes could be detected by either Ki-67 antibody staining or 5′-bromo-2′-deoxyuridine (BrdU) incorporation assay.
To clarify the roles of lymphocyte Kv1.3-channels in the pathogenesis of COPD, the following in vivo experiments could be conducted. Based on previous studies, mouse or rat models of COPD, such as pulmonary emphysema, can be induced by exposure to cigarette-smoke or the intra-tracheal instillation of chemical substances, such as lipopolysaccharides (LPS), cadmium chloride, nitrogen dioxide, inorganic dusts and ozone [30, 31]. Using these animal models, the expressional abundance of Kv1.3-channels in lymphocytes within the airways or lung parenchyma could histologically be examined. To reveal the actual involvement of the channels in the pathogenesis of COPD, selective inhibitors of the channels, such as margatoxin, ShK, Psora-4 or PAP-1 [13, 32–35], could therapeutically administered to the animals and quantify the production of pro-inflammatory cytokines in the airways or alveolar parenchyma. The degrees of bronchial inflammation, small airway fibrosis and alveolar destruction could also be analyzed histopathologically .
Cigarette smoking is by far the most important environmental risk factor for the development of COPD. However, not all smokers develop COPD, suggesting that genetic factors that increase the susceptibility to the disease are also important in the pathogenesis of COPD . So far, previous linkage analysis studies have identified many candidate genes that are associated with the development of COPD, such as PI MZ α-1 antitrypsin gene , matrix metalloproteinase 12 (MMP12) , transforming growth factor β-1 (TGFB 1 ) and glutathione S-transferase Mu 1 (GSTM1) . Due to recent developments in high-throughput genotyping screening techniques, genome-wide association study (GWAS) could be performed in a relatively rapid and inexpensive manner [41, 42]. By the case–control basis, this study enables to examine a genome-wide panel of single-nucleotide polymorphisms (SNPs) in association with phenotypes of interest. Recently, using this approach, Ota et al. demonstrated that the polymorphism in the KCNA3 gene, which encodes Kv1.3, was associated with the susceptibility to autoimmune pancreatitis, in which T cell-mediated over-activation of cellular immunity is responsible for the pathogenesis . The similar approach could be applied to detect the genetic variants of the human Kv1.3 gene in association with the phenotypes of COPD, such as the severity of the disease, the results of lung function tests and the findings of chest CT scanning . Such genetic variance could also be linked with the epidemiological factors of COPD, including its prevalence, morbidity, mortality and comorbidity rates [44, 45].
Therapeutic implications of targeting Kv1.3-channels in the treatment of COPD
Kv1.3-channels can be pharmacologically targeted by a variety of blockers of the channels [11, 46]. Additionally, in our series of patch-clamp studies, commonly used drugs, such as calcium channel blockers (CCBs) [25, 27], macrolide antibiotics , HMG-CoA reductase inhibitors (statins)  and nonsteroidal anti-inflammatory drugs (NSAIDs) , also effectively inhibited the Kv1.3-channel currents in thymus-derived murine lymphocytes. Of note, benidipine, one of the dihydropyridine-type CCBs, which most strongly and persistently inhibited the channel currents , actually suppressed the proliferation of kidney lymphocytes, and thus ameliorated the progression of renal fibrosis . In this regard, in addition to using the previously developed selective blockers for the channels [48–50], the use of CCBs, macrolide antibiotics or statins could also potentially be useful in the treatment of COPD (Fig. 1).
In recent systematic review, statins were actually shown to prevent the exacerbation of COPD and reduce the risk of mortality in these patients [51, 52]. This could be explained by their pleiotropic effects, including anti-inflammatory and immunomodulatory effects, which was demonstrated by the significant decrease in systemic inflammation markers such as C-reactive protein and IL-6 [53, 54]. Additionally, statins were demonstrated to regulate the balance between Th1 and Th2 cells by inhibiting the Th1 development but augmenting the Th2 development of CD4+ cells . In addition to statins, NSAIDs, such as ibuprofen or indomethacin, were also effective in patients with COPD, since these drugs ameliorated the production of bronchorrhea in these patients by reducing the concentration of prostaglandin E2 in their sputum . Using lymphocytes isolated from patients with COPD, we would apply the patch-clamp recording technique and examine the production of pro-inflammatory cytokines from lymphocytes. Thus, we could reveal how the statins or NSAIDs-induced inhibition of Kv1.3-channels affects the activation of lymphocytes in vitro. To further reveal the therapeutic efficacy of these drugs in the pathogenesis of COPD, we would administer them to the experimental animal models of COPD [30, 31]. Then we would quantify the production of pro-inflammatory cytokines in the airways or alveolar parenchyma, or histopathologically analyze the degrees of bronchial inflammation, small airway fibrosis and alveolar destruction.
Recently, the continuous use of low-dose macrolide antibiotics was actually shown to be an effective treatment for COPD [57–59]. In randomized, double-blinded and placebo-controlled studies, Suzuki et al. and Seemungal et al. demonstrated that long-term erythromycin therapy was beneficial in the prevention of COPD exacerbations, which eventually contributed to the reduced number of hospitalizations [60, 61]. In other prospective, parallel-group and placebo-controlled studies, Blasi et al. and Albert et al. additionally revealed that the continuous administration of azithromycin decreased the rate of COPD exacerbations, and thus improved the quality of life of these patients [62, 63]. Besides, in some case reports, macrolide antibiotics, such as clarithromycin, ameliorated the extra-pulmonary symptoms of Mycoplasma pneumonia infection, such as cold agglutinins-induced hemoglobinuria, which are primarily attributable to the increased activity of T-lymphocytes [64, 65]. Concerning the therapeutic efficacies of macrolide antibiotics apart from their anti-microbial properties, several in vitro studies revealed that macrolide antibiotics, such as clarithromycin and azithromycin, suppress the production of pro-inflammatory cytokines from T-lymphocytes and thus exert immunomodulatory effects [66, 67]. In our recent patch-clamp study using murine thymocytes, clarithromycin markedly suppressed the Kv1.3-channel currents in a dose-dependent manner, suggesting its higher potency an useful channel inhibitor . In T-lymphocytes, the Kv1.3-channels trigger calcium influx, which is necessary for IL-2 synthesis [11, 68], and channel blockade by highly selective inhibitors, such as margatoxin and ShK-Dap22, actually represses the immune response in the cells [28, 69]. Therefore, the potency of macrolide antibiotics as a Kv1.3-channel inhibitor was likely to be responsible for their immunomodulatory properties that have recently been demonstrated in the treatment of COPD [57–59].
From our recent findings and the literature review, Kv1.3-channels are very likely to be overexpressed or over-activated in T-lymphocytes isolated from patients with COPD, which may contribute to the development or progression of the disease. Based on this, we suggest novel therapeutic implications of potentially useful Kv1.3-channel inhibitors, such as CCBs, macrolide antibiotics, statins and NSAIDs, in the treatment of COPD.
IK Involvement in conception, hypothesis delineation, data analysis and its interpretation and writing. TT Involvement in data analysis and its interpretation. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
This work was supported by The Salt Science Research Foundation, No.1633 and MEXT KAKENHI Grant No. 16K08484 to IK.
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- Pauwels RA, Rabe KF. Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet. 2004;364(9434):613–20.View ArticlePubMedGoogle Scholar
- Harber P, Tashkin DP, Simmons M, Crawford L, Hnizdo E, Connett J. Lung health study G: effect of occupational exposures on decline of lung function in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(10):994–1000.View ArticlePubMedPubMed CentralGoogle Scholar
- Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma. J Allergy Clin Immunol. 2003;112(5):819–27.View ArticlePubMedGoogle Scholar
- Barnes PJ. Mediators of chronic obstructive pulmonary disease. Pharmacol Rev. 2004;56(4):515–48.View ArticlePubMedGoogle Scholar
- Holgate ST. Pathogenesis of asthma. Clin Exp Allergy. 2008;38(6):872–97.View ArticlePubMedGoogle Scholar
- Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. Int J Chron Obstr Pulm Dis. 2006;1(1):39–47.Google Scholar
- Crapo RO, Jensen RL, Hargreave FE. Airway inflammation in COPD: physiological outcome measures and induced sputum. Eur Respir J Suppl. 2003;41:19s–28s.View ArticlePubMedGoogle Scholar
- Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J. 2003;22(4):672–88.View ArticlePubMedGoogle Scholar
- Hodge S, Hodge G, Nairn J, Holmes M, Reynolds PN. Increased airway granzyme b and perforin in current and ex-smoking COPD subjects. Copd. 2006;3(4):179–87.View ArticlePubMedGoogle Scholar
- Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, Chandy KG. The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS. J Clin Invest. 2003;111(11):1703–13.View ArticlePubMedPubMed CentralGoogle Scholar
- Kazama I. Physiological significance of delayed rectifier K(+) channels (Kv1.3) expressed in T lymphocytes and their pathological significance in chronic kidney disease. J Physiol Sci. 2015;65(1):25–35.View ArticlePubMedGoogle Scholar
- Hu L, Pennington M, Jiang Q, Whartenby KA, Calabresi PA. Characterization of the functional properties of the voltage-gated potassium channel Kv1.3 in human CD4 + T lymphocytes. J Immunol. 2007;179(7):4563–70.View ArticlePubMedGoogle Scholar
- Kazama I, Maruyama Y, Endo Y, Toyama H, Ejima Y, Matsubara M, Kurosawa S. Overexpression of delayed rectifier K(+) channels promotes in situ proliferation of leukocytes in rat kidneys with advanced chronic renal failure. Int J Nephrol. 2012;2012:581581.PubMedPubMed CentralGoogle Scholar
- Kazama I. Roles of lymphocyte Kv1. 3-channels in gut mucosal immune system: novel therapeutic implications for inflammatory bowel disease. Med Hypotheses. 2015;85(1):61–3.View ArticlePubMedGoogle Scholar
- Koch Hansen L, Sevelsted-Moller L, Rabjerg M, Larsen D, Hansen TP, Klinge L, Wulff H, Knudsen T, Kjeldsen J, Kohler R. Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis. J Crohn’s Colitis. 2014;8(11):1378–91.View ArticleGoogle Scholar
- Kazama I, Maruyama Y, Murata Y, Sano M. Voltage-dependent biphasic effects of chloroquine on delayed rectifier K(+)-channel currents in murine thymocytes. J Physiol Sci. 2012;62(3):267–74.View ArticlePubMedGoogle Scholar
- Heap GA, van Heel DA. The genetics of chronic inflammatory diseases. Hum Mol Genet. 2009;18(R1):R101–6.View ArticlePubMedGoogle Scholar
- Pelaia G, Gallelli L, Vatrella A, Grembiale RD, Maselli R, De Sarro GB, Marsico SA. Potential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease. Life Sci. 2002;70(9):977–90.View ArticlePubMedGoogle Scholar
- Malerba M, Radaeli A, Mancuso S, Polosa R. The potential therapeutic role of potassium channel modulators in asthma and chronic obstructive pulmonary disease. J Biol Regul Homeost Agents. 2010;24(2):123–30.PubMedGoogle Scholar
- Koshy S, Huq R, Tanner MR, Atik MA, Porter PC, Khan FS, Pennington MW, Hanania NA, Corry DB, Beeton C. Blocking KV1.3 channels inhibits Th2 lymphocyte function and treats a rat model of asthma. J Biol Chem. 2014;289(18):12623–32.View ArticlePubMedPubMed CentralGoogle Scholar
- Domagala-Kulawik J, Hoser G, Dabrowska M, Safianowska A, Chazan R. CD4 +/CD25 + cells in systemic inflammation in COPD. Scand J Immunol. 2011;73(1):59–65.View ArticlePubMedGoogle Scholar
- Pizzichini E, Pizzichini MM, Leigh R, Djukanovic R, Sterk PJ. Safety of sputum induction. Eur Respir J Suppl. 2002;37:9s–18s.PubMedGoogle Scholar
- Kazama I, Maruyama Y, Murata Y. Suppressive effects of nonsteroidal anti-inflammatory drugs diclofenac sodium, salicylate and indomethacin on delayed rectifier K + -channel currents in murine thymocytes. Immunopharmacol Immunotoxicol. 2012;34(5):874–8.View ArticlePubMedGoogle Scholar
- Kazama I, Maruyama Y. Differential effects of clarithromycin and azithromycin on delayed rectifier K(+)-channel currents in murine thymocytes. Pharm Biol. 2013;51(6):760–5.View ArticlePubMedGoogle Scholar
- Kazama I, Maruyama Y, Matsubara M. Benidipine persistently inhibits delayed rectifier K(+)-channel currents in murine thymocytes. Immunopharmacol Immunotoxicol. 2013;35(1):28–33.View ArticlePubMedGoogle Scholar
- Kazama I, Baba A, Maruyama Y. HMG-CoA reductase inhibitors pravastatin, lovastatin and simvastatin suppress delayed rectifier K(+)-channel currents in murine thymocytes. Pharmacol Rep. 2014;66(4):712–7.View ArticlePubMedGoogle Scholar
- Baba A, Tachi M, Maruyama Y, Kazama I. Suppressive effects of diltiazem and verapamil on delayed rectifier K + -Channel currents in murine thymocytes. Pharmacol Rep. 2015;67:959–64.View ArticlePubMedGoogle Scholar
- Villalonga N, David M, Bielanska J, Gonzalez T, Parra D, Soler C, Comes N, Valenzuela C, Felipe A. Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels. Biochem Pharmacol. 2010;80(6):858–66.View ArticlePubMedGoogle Scholar
- Sullivan KE, Cutilli J, Piliero LM, Ghavimi-Alagha D, Starr SE, Campbell DE, Douglas SD. Measurement of cytokine secretion, intracellular protein expression, and mRNA in resting and stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol. 2000;7(6):920–4.PubMedPubMed CentralGoogle Scholar
- Wright JL, Cosio M, Churg A. Animal models of chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2008;295(1):L1–15.View ArticlePubMedPubMed CentralGoogle Scholar
- Shapiro SD. Animal models for chronic obstructive pulmonary disease: age of klotho and marlboro mice. Am J Respir Cell Mol Biol. 2000;22(1):4–7.View ArticlePubMedGoogle Scholar
- Jang SH, Choi SY, Ryu PD, Lee SY. Anti-proliferative effect of Kv1.3 blockers in A549 human lung adenocarcinoma in vitro and in vivo. Eur J Pharmacol. 2011;651(1–3):26–32.View ArticlePubMedGoogle Scholar
- Hyodo T, Oda T, Kikuchi Y, Higashi K, Kushiyama T, Yamamoto K, Yamada M, Suzuki S, Hokari R, Kinoshita M, et al. Voltage-gated potassium channel Kv1.3 blocker as a potential treatment for rat anti-glomerular basement membrane glomerulonephritis. Am J Physiol Renal Physiol. 2010;299(6):F1258–69.View ArticlePubMedPubMed CentralGoogle Scholar
- Grgic I, Wulff H, Eichler I, Flothmann C, Kohler R, Hoyer J. Blockade of T-lymphocyte KCa3.1 and Kv1.3 channels as novel immunosuppression strategy to prevent kidney allograft rejection. Transplant Proc. 2009;41(6):2601–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Kundu-Raychaudhuri S, Chen YJ, Wulff H, Raychaudhuri SP. Kv1.3 in psoriatic disease: pAP-1, a small molecule inhibitor of Kv1.3 is effective in the SCID mouse psoriasis–xenograft model. J Autoimmun. 2014;55:63–72.View ArticlePubMedPubMed CentralGoogle Scholar
- McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, Wright AC, Gefter WB, Litzky L, Coxson HO, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567–75.View ArticlePubMedPubMed CentralGoogle Scholar
- Lomas DA, Silverman EK. The genetics of chronic obstructive pulmonary disease. Respir Res. 2001;2(1):20–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Molloy K, Hersh CP, Morris VB, Carroll TP, O’Connor CA, Lasky-Su JA, Greene CM, O’Neill SJ, Silverman EK, McElvaney NG. Clarification of the risk of chronic obstructive pulmonary disease in alpha1-antitrypsin deficiency PiMZ heterozygotes. Am J Respir Crit Care Med. 2014;189(4):419–27.View ArticlePubMedGoogle Scholar
- Hunninghake GM, Cho MH, Tesfaigzi Y, Soto-Quiros ME, Avila L, Lasky-Su J, Stidley C, Melen E, Soderhall C, Hallberg J, et al. MMP12, lung function, and COPD in high-risk populations. N Engl J Med. 2009;361(27):2599–608.View ArticlePubMedPubMed CentralGoogle Scholar
- Castaldi PJ, Cho MH, Cohn M, Langerman F, Moran S, Tarragona N, Moukhachen H, Venugopal R, Hasimja D, Kao E, et al. The COPD genetic association compendium: a comprehensive online database of COPD genetic associations. Hum Mol Genet. 2010;19(3):526–34.View ArticlePubMedGoogle Scholar
- Wan ES, Castaldi PJ, Cho MH, Hokanson JE, Regan EA, Make BJ, Beaty TH, Han MK, Curtis JL, Curran-Everett D, Lynch DA. Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISM) in COPDGene. Respir Res. 2014;15(1):1.View ArticleGoogle Scholar
- Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, Curran-Everett D, Silverman EK, Crapo JD, Investigators C. Genetic epidemiology of COPD (COPDGene) study design. Copd. 2010;7(1):32–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Ota M, Ito T, Umemura T, Katsuyama Y, Yoshizawa K, Hamano H, Kawa S. Polymorphism in the KCNA3 gene is associated with susceptibility to autoimmune pancreatitis in the Japanese population. Dis Mark. 2011;31(4):223–9.View ArticleGoogle Scholar
- Raherison C, Girodet PO. Epidemiology of COPD. Eur Respir Rev. 2009;18(114):213–21.View ArticlePubMedGoogle Scholar
- Rycroft CE, Heyes A, Lanza L, Becker K. Epidemiology of chronic obstructive pulmonary disease: a literature review. Int J Chron Obstr Pulm Dis. 2012;7:457–94.View ArticleGoogle Scholar
- Kazama I. Roles of lymphocyte kv1.3-channels in the pathogenesis of renal diseases and novel therapeutic implications of targeting the channels. Mediat Inflamm. 2015;2015:436572.View ArticleGoogle Scholar
- Kazama I, Baba A, Matsubara M, Endo Y, Toyama H, Ejima Y. Benidipine suppresses in situ proliferation of leukocytes and slows the progression of renal fibrosis in rat kidneys with advanced chronic renal failure. Nephron Exp Nephrol. 2014;128(1–2):67–79.View ArticlePubMedGoogle Scholar
- Schmitz A, Sankaranarayanan A, Azam P, Schmidt-Lassen K, Homerick D, Hansel W, Wulff H. Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases. Mol Pharmacol. 2005;68(5):1254–70.View ArticlePubMedGoogle Scholar
- Hamilton DL, Beall C, Jeromson S, Chevtzoff C, Cuthbertson DJ, Ashford ML. Kv1.3 inhibitors have differential effects on glucose uptake and AMPK activity in skeletal muscle cell lines and mouse ex vivo skeletal muscle. J Physiol Sci. 2014;64(1):13–20.View ArticlePubMedGoogle Scholar
- Beeton C, Pennington MW, Wulff H, Singh S, Nugent D, Crossley G, Khaytin I, Calabresi PA, Chen CY, Gutman GA, et al. Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Mol Pharmacol. 2005;67(4):1369–81.View ArticlePubMedPubMed CentralGoogle Scholar
- Cao C, Wu Y, Xu Z, Lv D, Zhang C, Lai T, Li W, Shen H. The effect of statins on chronic obstructive pulmonary disease exacerbation and mortality: a systematic review and meta-analysis of observational research. Sci Rep. 2015;5:16461.View ArticlePubMedPubMed CentralGoogle Scholar
- Dobler CC, Wong KK, Marks GB. Associations between statins and COPD: a systematic review. BMC Pulm Med. 2009;9:32.View ArticlePubMedPubMed CentralGoogle Scholar
- Lee TM, Lin MS, Chang NC. Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. Am J Cardiol. 2008;101(4):530–5.View ArticlePubMedGoogle Scholar
- Undas A, Kaczmarek P, Sladek K, Stepien E, Skucha W, Rzeszutko M, Gorkiewicz-Kot I, Tracz W. Fibrin clot properties are altered in patients with chronic obstructive pulmonary disease. Beneficial effects of simvastatin treatment. Thromb Haemost. 2009;102(6):1176–82.PubMedGoogle Scholar
- Hakamada-Taguchi R, Uehara Y, Kuribayashi K, Numabe A, Saito K, Negoro H, Fujita T, Toyo-oka T, Kato T. Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th1 development and promotes Th2 development. Circ Res. 2003;93(10):948–56.View ArticlePubMedGoogle Scholar
- Montuschi P, Macagno F, Parente P, Valente S, Lauriola L, Ciappi G, Kharitonov SA, Barnes PJ, Ciabattoni G. Effects of cyclo-oxygenase inhibition on exhaled eicosanoids in patients with COPD. Thorax. 2005;60(10):827–33.View ArticlePubMedPubMed CentralGoogle Scholar
- Suresh Babu K, Kastelik J, Morjaria JB. Role of long term antibiotics in chronic respiratory diseases. Respir Med. 2013;107(6):800–15.View ArticlePubMedGoogle Scholar
- Yamaya M, Azuma A, Takizawa H, Kadota J, Tamaoki J, Kudoh S. Macrolide effects on the prevention of COPD exacerbations. Eur Respir J. 2012;40(2):485–94.View ArticlePubMedGoogle Scholar
- Martinez FJ, Curtis JL, Albert R. Role of macrolide therapy in chronic obstructive pulmonary disease. Int J Chron Obstr Pulm Dis. 2008;3(3):331–50.View ArticleGoogle Scholar
- Suzuki T, Yanai M, Yamaya M, Satoh-Nakagawa T, Sekizawa K, Ishida S, Sasaki H. Erythromycin and common cold in COPD. Chest. 2001;120(3):730–3.View ArticlePubMedGoogle Scholar
- Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178(11):1139–47.View ArticlePubMedGoogle Scholar
- Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689–98.View ArticlePubMedPubMed CentralGoogle Scholar
- Blasi F, Bonardi D, Aliberti S, Tarsia P, Confalonieri M, Amir O, Carone M, Di Marco F, Centanni S, Guffanti E. Long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy. Pulm Pharmacol Ther. 2010;23(3):200–7.View ArticlePubMedGoogle Scholar
- Kazama I, Tamada T, Nakajima T. Macroscopic haemoglobinuria associated with Mycoplasma pneumoniae infection successfully treated by clarithromycin. Infez Med. 2015;23(1):74–8.PubMedGoogle Scholar
- Khan FY. M Ay: mycoplasma pneumoniae associated with severe autoimmune hemolytic anemia: case report and literature review. Braz J Infect Dis. 2009;13(1):77–9.View ArticlePubMedGoogle Scholar
- Sugiyama K, Shirai R, Mukae H, Ishimoto H, Nagata T, Sakamoto N, Ishii H, Nakayama S, Yanagihara K, Mizuta Y, et al. Differing effects of clarithromycin and azithromycin on cytokine production by murine dendritic cells. Clin Exp Immunol. 2007;147(3):540–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Morikawa K, Zhang J, Nonaka M, Morikawa S. Modulatory effect of macrolide antibiotics on the Th1- and Th2-type cytokine production. Int J Antimicrob Agents. 2002;19(1):53–9.View ArticlePubMedGoogle Scholar
- Chandy KG, Wulff H, Beeton C, Pennington M, Gutman GA, Cahalan MD. K+ channels as targets for specific immunomodulation. Trends Pharmacol Sci. 2004;25(5):280–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Kazama I, Tamada T, Tachi M. Usefulness of targeting lymphocyte Kv1.3-channels in the treatment of respiratory diseases. Inflamm Res. 2015;64(10):753–65.View ArticlePubMedGoogle Scholar