Annotated Bibliography

Abbott-Banner, Katharine H., and Clive P. Page. “Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases.Basic & Clinical Pharmacology & Toxicology 114, no. 5 (May 2014): 365–76. doi:10.1111/bcpt.12209.

Phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors, because of their anti-inflammatory effects (from PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) effects. Previous attempts of using such inhibitors have been fruitless, but the authors associate their lack of success with their oral administration and their non-selectivity for subtypes (A,B,C,D). The author claims that inhaled administration of these inhibitors that are subtype-specific may make for potent treatments for COPD.

Barnes, P.J., S.D. Shapiro, and R.A. Pauwels. “Chronic Obstructive Pulmonary Disease: Molecular and Cellular Mechanisms.European Respiratory Journal 22, no. 4 (October 1, 2003): 672–88. doi:10.1183/09031936.03.00040703.

This is a great introductory paper on COPD. It covers background knowledge needed to understand COPD very well – the different types of innate immunity cells, how they act and how they are regulated, how the typical inflammatory response occurs and how it (in a general sense) goes wrong in COPD, how COPD is different from asthma.

Barreiro, Esther, and Joaquim Gea. “Epigenetics and Muscle Dysfunction in Chronic Obstructive Pulmonary Disease.Translational Research: The Journal of Laboratory and Clinical Medicine 165, no. 1 (January 2015): 61–73. doi:10.1016/j.trsl.2014.04.006.

This paper delved into possible epigenetic factors in COPD – namely, muscle-enriched microRNA’s that affect the diaphragm and lower limb muscles (specifically the vastus lateralis). Findings include decreased microRNA’s in the vastus lateralis, increased levels in the blood, and decreased muscle-enriched microRNA’s in the diaphragm.

Burney, Peter, Anamika Jithoo, Bernet Kato, Christer Janson, David Mannino, Ewa Nizankowska-Mogilnicka, Michael Studnicka, et al. “Chronic Obstructive Pulmonary Disease Mortality and Prevalence: The Associations with Smoking and Poverty–a BOLD Analysis.Thorax 69, no. 5 (May 2014): 465–73. doi:10.1136/thoraxjnl-2013-204460.

This paper covers some of the sociological aspects of COPD, including its prevalence in poorer countries with low smoking rates (although smoking is thought to be the main cause of COPD). In addition, the authors claim that spirometric restriction (essentially the diminishing of the air capacity of the lungs) may be a better predictor of mortality than airflow obstruction.

Culpitt, Sarah V., Wasim Maziak, Stelios Loukidis, Julia A. Nightingale, John L. Matthews, and Peter J. Barnes. “Effect of High Dose Inhaled Steroid on Cells, Cytokines, and Proteases in Induced Sputum in Chronic Obstructive Pulmonary Disease.American Journal of Respiratory and Critical Care Medicine 160, no. 5 (November 1999): 1635–39. doi:10.1164/ajrccm.160.5.9811058.

A key distinction between COPD and asthma, although they are both due to some form of stress on the pulmonary system, is that asthma is relieved by corticosteroids, whereas COPD is not. This paper was one of the first to report this finding, but it also showed that corticosteroid treatments did not affect total differential cell counts and concentrations of  eosinophil/neutrophil activation markers, and sputum eosinophil numbetrs were also unaffected in COPD patients by steroids.

Geraghty, Patrick, Edward Eden, Manju Pillai, Michael Campos, Noel G. McElvaney, and Robert F. Foronjy. “α1-Antitrypsin Activates Protein Phosphatase 2A to Counter Lung Inflammatory Responses.American Journal of Respiratory and Critical Care Medicine 190, no. 11 (December 1, 2014): 1229–42. doi:10.1164/rccm.201405-0872OC.

Alpha-1-antitrypsin (A1AT) deficiency has been known to be a genetic biomarker for COPD. ATAT is a plasma protease inhibitor, but more recently has been recognized as a multifunctional protein that modulates immunity, inflammation, apoptosis, and cellular senescence as well. This paper elucidates one of the mechanisms of ATAT’s actions – namely, that it modulates PP2A (protein phosphatase 2A – a major serine-threonine phosphatase) – in order to counter diseases such as COPD.

Hautamaki, R. D., D. K. Kobayashi, R. M. Senior, and S. D. Shapiro. “Requirement for Macrophage Elastase for Cigarette Smoke-Induced Emphysema in Mice.” Science (New York, N.Y.) 277, no. 5334 (September 26, 1997): 2002–4.
This was one of the earliest papers I came across that correlated elastase, cigarette smoke, and emphysema. The findings in this article set the stage for future work in unraveling the biochemical basis of emphysema and COPD.


Jezierski, G., and M. Pasenkiewicz-Gierula. “The Effect of the Glu342Lys Mutation in alpha1-Antitrypsin on Its Structure, Studied by Molecular Modelling Methods.” Acta Biochimica Polonica 48, no. 1 (2001): 65–75.
This paper describes the E342K mutation in A1AT that leads to decreased activity of the enzyme, which can increase inflammation that has been correlated to the severity of COPD.

Kruis, Annemarije L, Nynke Smidt, Willem JJ Assendelft, Jacobijn Gussekloo, Melinde RS Boland, Maureen Rutten-van Mölken, and Niels H Chavannes. “Integrated Disease Management Interventions for Patients with Chronic Obstructive Pulmonary Disease.” In Cochrane Database of Systematic Reviews, edited by The Cochrane Collaboration. Chichester, UK: John Wiley & Sons, Ltd, 2013.

2997 people with COPD were evaluated (average age of 68). People who participated in the researchers’ integrated disease management (IDM), which included education, exercise, smoking cessation, nutrition ,etc. had better quality of life (QoL) during a 12-month period. While there is no known treatment for COPD, management plans such as these can improve quality of life for COPD patients.

Lakshmi, Sowmya P., Aravind T. Reddy, Yingze Zhang, Frank C. Sciurba, Rama K. Mallampalli, Steven R. Duncan, and Raju C. Reddy. “Down-Regulated Peroxisome Proliferator-Activated Receptor Γ (PPARγ) in Lung Epithelial Cells Promotes a PPARγ Agonist-Reversible Pro-inflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD).The Journal of Biological Chemistry 289, no. 10 (March 7, 2014): 6383–93. doi:10.1074/jbc.M113.536805.

Peroxisome proliferator-activated receptor y (PPARy) is a nuclear hormone receptor with anti-inflammatory effects, but whose role in COPD was unknown. The authors found that COPD-induced down-regulation of PPARy expression contributes to the pro-inflammatory characteristics of the disease. Furthermore and importantly, PPARy agonists reverse these effects, and so PPARy agonists may prove to be possible treatments.

Lam, Hilaire C., Suzanne M. Cloonan, Abhiram R. Bhashyam, Jeffery A. Haspel, Anju Singh, J. Fah Sathirapongsasuti, Morgan Cervo, et al. “Histone Deacetylase 6-Mediated Selective Autophagy Regulates COPD-Associated Cilia Dysfunction.The Journal of Clinical Investigation 123, no. 12 (December 2013): 5212–30. doi:10.1172/JCI69636.

The article names some suggested effects of cigarette smoke on epithelial cells – oxidative stress, ER stress, inhibition of ubiquitin-proteasome system, and autophagy. They studied they way by which autophagy regulates airway function and ciliated epithelial cell elngth during cigarette smoke exposure – finding that HDAC6 (and other related regulators) adversely affect the autophagic pathway.

Morimoto, K., J. Gosselink, A. Kartono, J. C. Hogg, S. Hayashi, and E. Ogawa. “Adenovirus E1A Regulates Lung Epithelial ICAM-1 Expression by Interacting with Transcriptional Regulators at Its Promoter.AJP: Lung Cellular and Molecular Physiology 296, no. 3 (January 9, 2009): L361–71. doi:10.1152/ajplung.90331.2008.

Adenoviral E1A gene, when integrated into host DNA, is known to act as a transactivator that interacts with transcription factors, coactivators, and cell cycle regulatory proteins. The modulation of the activity of NF-kB (a transcription factor regulatoing the expression of inflammatory mediator genes)

Nar, Herbert, Karlheinz Werle, Margit M.T Bauer, Horst Dollinger, and Birgit Jung. “Crystal Structure of Human Macrophage Elastase (MMP-12) in Complex with a Hydroxamic Acid Inhibitor.Journal of Molecular Biology 312, no. 4 (September 2001): 743–51. doi:10.1006/jmbi.2001.4953.

Elastase is one of the metalloproteinases an important role in inflammatory processes – and is one of the (many) components that are attributed to COPD. The crystal structure for MMP-12 (human macrophage elastase) is resolved, along with its catalytic domain, and a second structure with a hydroxamic acid inhibitor, CGS27023A, is also shown (both PDB ID = 1JIZ). The authors claim the structure they eluicdate may aid the design of more inhibitors for MMP-12 in the future.

Pauwels, Romain A., A. Sonia Buist, Peter M. A. Calverley, Christine R. Jenkins, and Suzanne S. Hurd. “Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary.American Journal of Respiratory and Critical Care Medicine 163, no. 5 (April 2001): 1256–76. doi:10.1164/ajrccm.163.5.2101039.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) is a collaborative project aimed to increase awareness of COPD and decrease morbidity and mortality from COPD. It describes an ‘effective COPD mamagement plan’ as having 4 components: (1) Assess and Monitor; (2) Reduce Risk Factors; (3) Manage Stable COPD; (4) Manage Exacerbations. I will mainly use this paper for its information on the first component, namely for its input on diagnosis of COPD.

Takimoto, Takayuki, Mitsuhiro Yoshida, Haruhiko Hirata, Yozo Kashiwa, Yoshito Takeda, Sho Goya, Takashi Kijima, Toru Kumagai, Isao Tachibana, and Ichiro Kawase. “4-Hydroxy-2-Nonenal Induces Chronic Obstructive Pulmonary Disease-like Histopathologic Changes in Mice.” Biochemical and Biophysical Research Communications 420, no. 1 (March 2012): 84–90. doi:10.1016/j.bbrc.2012.02.119.
This paper describes the effects of 4-hydroxy-2-nonenal, which is a product of ROS reaction with arachidonic acid, and its effects on “COPD-like diseases” in rats. This study helped to elucidate some of the unknown biochemical effects of ROS and their role in COPD.

Wallace, G.M.F., J.H. Winter, J.E. Winter, A. Taylor, T.W. Taylor, and R.C. Cameron. “Chest X-Rays in COPD Screening: Are They Worthwhile? Respiratory Medicine 103, no. 12 (December 2009): 1862–65. doi:10.1016/j.rmed.2009.07.001.

This study examines the BTS/NICE guidelines that recommends a chest x-ray at an initial COPD evaluation by a physician in order to explore the clinical utility of chest x-rays (are they worth doing?) >500 chest x-ray reports were examined, and 7 questions were asked about each report. Their most important finding was that evaluation by chest x-ray of patients complaint of dyspnea altered the management in 9% of patients – so the authors recommend that the guideline be upgraded from a D to a C.

Wu, Xiaodong, Du Chen, Xiaoling Gu, Xin Su, Yong Song, and Yi Shi. “Prevalence and Risk of Viral Infection in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Meta-Analysis.” Molecular Biology Reports 41, no. 7 (July 2014): 4743–51. doi:10.1007/s11033-014-3345-9.

Acute exacerbations of COPD (AECOPD) can lead to mortality. This article correlates viral infections in COPD patients with frequencies of AECOPD’s (because of the damaged lung epithelial cells).

Xu, Robert X., Warren J. Rocque, Millard H. Lambert, Dana E. Vanderwall, Michael A. Luther, and Robert T. Nolte. “Crystal Structures of the Catalytic Domain of Phosphodiesterase 4B Complexed with AMP, 8-Br-AMP, and Rolipram.Journal of Molecular Biology 337, no. 2 (March 19, 2004): 355–65. doi:10.1016/j.jmb.2004.01.040.

Phosphodiesterases (PDEs) catalyzes the hydrolysis of cAMP into AMP. PDE4 is the major cAMP-specific PDE in inflammatory and immune cells which, when out of control, are thought to cause COPD in pulmonary tissue. PDE4 is an attractive target for both asthma and COPD. The authors of this paper determined the crystal structures of the catalytic domain of PDE4B complex with AMP, 8-Br-AMP (resistant to degradation by PDE), and the inhibitor rolipram (PDB ID’s 1ROR, 1RO9, 1RO6) – which may be a potent treatment for COPD .

Zhang, Xiaojun, Honggao Zheng, Wenjing Ma, Fang Wang, Xiaoning Zeng, Changting Liu, and Shaoheng He. “Tryptase Enzyme Activity Is Correlated with Severity of Chronic Obstructive Pulmonary Disease.The Tohoku Journal of Experimental Medicine 224, no. 3 (2011): 179–87. PMID: 21685721

Tryptase can induce inflammatory cell accumulation in vivo. This paper shows that tryptic and tryptase enzyme activities are increased in COPD plasma, using a rat model (exposed to cigarette smoke for 36 weeks). In addition, the level of tryptase activity is correlated with the severity of COPD.