Targeting Phosphodiesterase 4 to Block the Link between Acute Exacerbation of Chronic Obstructive Pulmonary Disease and the Metabolic Complications
Author(s)
Eric Cho
ABSTRACT
The metabolic disorders such as obesity and diabetes are found to be more frequent in chronic obstructive pulmonary disease (COPD). The chronic systemic inflammation orchestrated by macrophages constitutes one critical pathophysiological process underlying both acute exacerbation of COPD (AECOPD) and its metabolic complications such as obesity and diabetes. The cyclic adenosine monophosphate (cAMP) signaling controlled by phosphodiesterase (PDE) 4 is a pivotal intracellular modulator for macrophages functions in immune inflammatory response underlying AECOPD as well as obesity and diabetes. Targeting PDE4/cAMP signaling has been suggested to be effective in treating AECOPD or the metabolic disorders of obesity and diabetes. It is therefore reasonable to hypothesize that the chronic systemic inflammation can be a critical link between AECOPD and the metabolic disorders and targeting the PDE4/cAMP signaling can be effective to block this link between AECOPD and the associated metabolic complications.
The metabolic disorders such as obesity and diabetes are found to be more frequent in chronic obstructive pulmonary disease (COPD). The chronic systemic inflammation orchestrated by macrophages constitutes one critical pathophysiological process underlying both acute exacerbation of COPD (AECOPD) and its metabolic complications such as obesity and diabetes. The cyclic adenosine monophosphate (cAMP) signaling controlled by phosphodiesterase (PDE) 4 is a pivotal intracellular modulator for macrophages functions in immune inflammatory response underlying AECOPD as well as obesity and diabetes. Targeting PDE4/cAMP signaling has been suggested to be effective in treating AECOPD or the metabolic disorders of obesity and diabetes. It is therefore reasonable to hypothesize that the chronic systemic inflammation can be a critical link between AECOPD and the metabolic disorders and targeting the PDE4/cAMP signaling can be effective to block this link between AECOPD and the associated metabolic complications.
Cite this paper
Cho, E. (2015) Targeting Phosphodiesterase 4 to Block the Link between Acute Exacerbation of Chronic Obstructive Pulmonary Disease and the Metabolic Complications. Journal of Biosciences and Medicines, 3, 62-67. doi: 10.4236/jbm.2015.311007.
Cho, E. (2015) Targeting Phosphodiesterase 4 to Block the Link between Acute Exacerbation of Chronic Obstructive Pulmonary Disease and the Metabolic Complications. Journal of Biosciences and Medicines, 3, 62-67. doi: 10.4236/jbm.2015.311007.
References
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http://dx.doi.org/10.1111/acel.12013 [25] Jeon, B.T., Jeong, E.A., Shin, H.J., Lee, Y., Lee, D.H., Kim, H.J., et al. (2012) Resveratrol Attenuates Obesity-Asso- ciated Peripheral and Central Inflammation and Improves Memory Deficit in Mice Fed a High-Fat Diet. Diabetes, 61, 1444-1454.
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http://dx.doi.org/10.1210/jc.2011-2886 [27] Jensterle, M., Kocjan, T. and Janez, A. (2014) Phosphodiesterase 4 Inhibition as a Potential New Therapeutic Target in Obese Women with Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology and Metabolism, 99, E1476-E1481.
http://dx.doi.org/10.1210/jc.2014-1430 [28] Fabbri, L.M., Beghe, B., Yasothan, U. and Kirkpatrick, P. (2010) Roflumilast. Nature Reviews Drug Discovery, 9, 761-762.
http://dx.doi.org/10.1038/nrd3276 [29] Buenestado, A., Chaumais, M.C., Grassin-Delyle, S., Risse, P.-A., Naline, E., Longchampt, E., et al. (2013) Roflumilast Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-Alpha and Chemokine Production by Human Lung Parenchyma. PLoS ONE, 8, e74640.
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http://dx.doi.org/10.1016/S0140-6736(14)62410-7
[1] Pauwels, R.A. and Rabe, K.F. (2004) Burden and Clinical Features of Chronic Obstructive Pulmonary Disease (COPD). Lancet, 364, 613-620.
http://dx.doi.org/10.1016/S0140-6736(04)16855-4 [2] Brody, H. (2012) Chronic Obstructive Pulmonary Disease. Nature, 489, S1.
http://dx.doi.org/10.1038/489S1a [3] MacIntyre, N. and Huang, Y.C. (2008) Acute Exacerbations and Respiratory Failure in Chronic Obstructive Pulmonary Disease. Proceedings of the American Thoracic Society, 5, 530-535.
http://dx.doi.org/10.1513/pats.200707-088ET [4] Garcia-Olmos, L., Alberquilla, A., Ayala, V., et al. (2013) Comorbidity in Patients with Chronic Obstructive Pulmonary Disease in Family Practice: A Cross Sectional Study. BMC Family Practice, 14, 11.
http://dx.doi.org/10.1186/1471-2296-14-11 [5] Celli, B.R., Thomas, N.E., Anderson, J.A., et al. (2008) Effect of Pharmacotherapy on Rate of Decline of Lung Function in Chronic Obstructive Pulmonary Disease: Results from the TORCH Study. American Journal of Respiratory and Critical Care Medicine, 178, 332-338.
http://dx.doi.org/10.1164/rccm.200712-1869OC [6] Rana, J.S., Mittleman, M.A., Sheikh, J., et al. (2004) Chronic Obstructive Pulmonary Disease, Asthma, and Risk of Type 2 Diabetes in Women. Diabetes Care, 27, 2478-2484.
http://dx.doi.org/10.2337/diacare.27.10.2478 [7] Neukamm, A., Hoiseth, A.D., Einvik, G., et al. (2015) Rosuvastatin Treatment in Stable Chronic Obstructive Pulmonary Disease (RODEO): A Randomized Controlled Trial. Journal of Internal Medicine, 278, 59-67.
http://dx.doi.org/10.1111/joim.12337 [8] Horita, N., Miyazawa, N., Kojima, R., et al. (2014) Statins Reduce All-Cause Mortality in Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis of Observational Studies. Respiratory Research, 15, 80. [9] Suissa, S., Dell’Aniello, S. and Ernst, P. (2012) Long-Term Natural History of Chronic Obstructive Pulmonary Disease: Severe Exacerbations and Mortality. Thorax, 67, 957-963.
http://dx.doi.org/10.1136/thoraxjnl-2011-201518 [10] Chang, C., Zhu, H., Shen, N., et al. (2015) Bacterial Infection, Airway and Systemic Inflammation and Clinical Outcomes before and after Treatment of AECOPD, a Longitudinal and Cross-Sectional Study. Copd, 12, 19-30.
http://dx.doi.org/10.3109/15412555.2014.898043 [11] Boorsma, C.E., Draijer, C. and Melgert, B.N. (2013) Macrophage Heterogeneity in Respiratory Diseases. Mediators of Inflammation, 2013, Article ID: 769214.
http://dx.doi.org/10.1155/2013/769214 [12] Barnes, P.J. (2013) New Anti-Inflammatory Targets for Chronic Obstructive Pulmonary Disease. Nature Reviews Drug Discovery, 12, 543-559.
http://dx.doi.org/10.1038/nrd4025 [13] Chawla, A., Nguyen, K.D. and Goh, Y.P. (2011) Macrophage-Mediated Inflammation in Metabolic Disease. Nature Reviews Immunology, 11, 738-749.
http://dx.doi.org/10.1038/nri3071 [14] Xu, H.Y., Barnes, G.T., Yang, Q., Tan, G., Yang, D., Chou, C.J., et al. (2003) Chronic Inflammation in Fat Plays a Crucial Role in the Development of Obesity-Related Insulin Resistance. The Journal of Clinical Investigation, 112, 1821-1830. http://dx.doi.org/10.1172/JCI200319451 [15] Lumeng, C.N., Bodzin, J.L. and Saltiel, A.R. (2007) Obesity Induces a Phenotypic Switch in Adipose Tissue Macrophage Polarization. The Journal of Clinical Investigation, 117, 175-184.
http://dx.doi.org/10.1172/JCI29881 [16] Zhao, L., Zhong, S., Qu, H.Y., Xie, Y.X., Cao, Z.N., Li, Q., et al. (2015) Chronic Inflammation Aggravates Metabolic Disorders of Hepatic Fatty Acids in High-Fat Diet-Induced Obese Mice. Scientific Reports, 5, Article No.: 10222.
http://dx.doi.org/10.1038/srep10222 [17] Pierce, K.L., Premont, R.T. and Lefkowitz, R.J. (2002) Seven-Transmembrane Receptors. Nature Reviews Molecular Cell Biology, 3, 639-650.
http://dx.doi.org/10.1038/nrm908 [18] Sprenger, J.U., Perera, R.K., Steinbrecher, J.H., Lehnart, S.E., Maier, L.S., Hasenfuss, G. and Nikolaev, V.O. (2015) In Vivo Model with Targeted cAMP Biosensor Reveals Changes in Receptor-Microdomain Communication in Cardiac Disease. Nature Communications, 6, Article No.: 6965.
http://dx.doi.org/10.1038/ncomms7965 [19] Jin, S.L., Lan, L., Zoudilova, M. and Conti, M. (2005) Specific Role of Phosphodiesterase 4B in Lipopolysaccharide-Induced Signaling in Mouse Macrophages. Journal of Immunology, 175, 1523-1531.
http://dx.doi.org/10.4049/jimmunol.175.3.1523 [20] Jin, S.L. and Conti, M. (2002) Induction of the Cyclic Nucleotide Phosphodiesterase PDE4B Is Essential for LPS-Activated TNF-Alpha Responses. Proceedings of the National Academy of Sciences of the United States of America, 99, 7628-7633.
http://dx.doi.org/10.1073/pnas.122041599 [21] Zhang, R., Maratos-Flier, E. and Flier, J.S. (2009) Reduced Adiposity and High-Fat Diet-Induced Adipose Inflammation in Mice Deficient for Phosphodiesterase 4B. Endocrinology, 150, 3076-3082.
http://dx.doi.org/10.1210/en.2009-0108 [22] Luan, B., Goodarzi, M.O., Phillips, N.G., Guo, X.Q., Chen, Y.-D.I., Yao, J., et al. (2014) Leptin-Mediated Increases in Catecholamine Signaling Reduce Adipose Tissue Inflammation via Activation of Macrophage HDAC4. Cell Metabolism, 19, 1058-1065.
http://dx.doi.org/10.1016/j.cmet.2014.03.024 [23] Vollert, S., Kaessner, N., Heuser, A., Hanauer, G., Dieckmann, A., Knaack, D., et al. (2012) The Glucose-Lowering Effects of the PDE4 Inhibitors Roflumilast and Roflumilast-N-Oxide in db/db Mice. Diabetologia, 55, 2779-2788.
http://dx.doi.org/10.1007/s00125-012-2632-z [24] Yan, L., Park, J.Y., Dillinger, J.G., De Lorenzo, M.S., Yuan, C.J., Lai, L., et al. (2012) Common Mechanisms for Calorie Restriction and Adenylyl Cyclase Type 5 Knockout Models of Longevity. Aging Cell, 11, 1110-1120.
http://dx.doi.org/10.1111/acel.12013 [25] Jeon, B.T., Jeong, E.A., Shin, H.J., Lee, Y., Lee, D.H., Kim, H.J., et al. (2012) Resveratrol Attenuates Obesity-Asso- ciated Peripheral and Central Inflammation and Improves Memory Deficit in Mice Fed a High-Fat Diet. Diabetes, 61, 1444-1454.
http://dx.doi.org/10.2337/db11-1498 [26] Wouters, E.F., Bredenbroker, D., Teichmann, P., Brose, M., Rabe, K.F., Fabbri, L.M. and Goke, B. (2012) Effect of the Phosphodiesterase 4 Inhibitor Roflumilast on Glucose Metabolism in Patients with Treatment-Naive, Newly Diagnosed Type 2 Diabetes Mellitus. The Journal of Clinical Endocrinology and Metabolism, 97, E1720-E1725.
http://dx.doi.org/10.1210/jc.2011-2886 [27] Jensterle, M., Kocjan, T. and Janez, A. (2014) Phosphodiesterase 4 Inhibition as a Potential New Therapeutic Target in Obese Women with Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology and Metabolism, 99, E1476-E1481.
http://dx.doi.org/10.1210/jc.2014-1430 [28] Fabbri, L.M., Beghe, B., Yasothan, U. and Kirkpatrick, P. (2010) Roflumilast. Nature Reviews Drug Discovery, 9, 761-762.
http://dx.doi.org/10.1038/nrd3276 [29] Buenestado, A., Chaumais, M.C., Grassin-Delyle, S., Risse, P.-A., Naline, E., Longchampt, E., et al. (2013) Roflumilast Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-Alpha and Chemokine Production by Human Lung Parenchyma. PLoS ONE, 8, e74640.
http://dx.doi.org/10.1371/journal.pone.0074640 [30] Martinez, F.J., Calverley, P.M., Goehring, U.M., Brose, M., Fabbri, L.M. and Rabe, K.F. (2015) Effect of Roflumilast on Exacerbations in Patients with Severe Chronic Obstructive Pulmonary Disease Uncontrolled by Combination Therapy (REACT): A Multicentre Randomised Controlled Trial. The Lancet, 385, 857-866.
http://dx.doi.org/10.1016/S0140-6736(14)62410-7