Treatments and Disease Management

COPD, by definition, involves irreversible damage to lung parenchyma and airways. Such damage only accumulates over time, and there is not a mode of treatment currently available to “cure” COPD and regain normal lung function. There a few methods to slow the progression of COPD, however.

Smoking Cessation

The cessation of smoking is the single most potent “therapy” for COPD. Cigarette smoking accounts for more than 95% of the clinical cases of COPD. The ROS formed by cigarette smoking recruit inflammatory cells, increasing the risk of lung tissue damage. Cessation of smoking avoids further risk of lung tissue damage. The interrelationships involved in COPD are outlined in Figure 8. It should be noted that cigarette smoking is not especially highlighted in this figure; in reality, it is the most prevalent and most preventable cause of COPD.

BCM441 - COPD interrelationship
Figure 8 – Interrelationship of factors involved in COPD – including ROS and their many sources (including cigarette smoking) and the inflammatory cells and their increased activity (Source: American Journal of Physiology).

 

Dual PDE3/PDE4 Inhibitors

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) regulate many cellular processes. One such regulatory role of cAMP and cGMP is the inhibition of inflammatory mediator release. Phosphodiesterase (PDE) enzymes hydrolyze cAMP and cGMP to the inactive forms 5’AMP and 5’GMP respectively. The use of phosphodiesterase inhibitors as possible therapies for inflammatory diseases, such as COPD, has been proposed. A summary of the effects of these inhibitors is shown in Figure 9.

BCM441 - PDE3-4 inhibitors figure
Figure 9 – Structures of cAMP, cGMP and their conversion to AMP and GMP by phosphodiesterase (PDE). PDE inhibition could be a potential target for COPD management. (Original Figure)

 

PDE4 is a phosphodiesterase that favors cAMP, while PDE3 hydrolyses both cAMP and cGMP with high affinities. PDE4 inhibitors have been found to be efficacious at inhibiting the activation and release of inflammatory mediators from certain cells, such as neutrophils and eosinophils. However, there is little evidence that suggests the inhibition of PDE3 inhibits inflammation. The dual inhibition of PDE3 and PDE4 was found to be synergistic at suppressing inflammatory mediator release, however. Therefore, this dual inhibition is a possible management option for COPD patients.

Cilomilast and roflumilast-n-oxide are two examples of PDE4 inhibitors, while SDZ ISQ 844 is an inhalable PDE3/4 inhibitor. Combinations of PDE4 and dual PDE3/4 inhibitors was found to cause bronchodilation and decreased inflammation in mice, which is potentially promising news in terms of the development of an efficacious COPD management option (Abbot-Banner 2014).

 Alpha-1-Antitrypsin Deficiency Treatment

Concentrates of the functional enzyme can be provided to those with A1AT deficiency. It is generally taken intravenously on a weekly basis. Prolastin-C is the most commonly-used augmentation therapy currently. The NIH reports a 1.5x increased overall death rate for those who did not receive this augmentation therapy than those who did – which is promising. Again, this treatment option is only for those whose genetics yields a deficiency in A1AT, and may not have significant effects in smokers who are not deficient in this enzyme.

Lung Transplantation and Stem Cell Therapy

Lung transplantation is currently an option for patients with COPD. Generally, the two main factors that determine whether or not a patient is eligible for a transplant is (a) the severity of the COPD symptoms, and (b) age under 65. Often, only one lobe is replaced by transplant, but has been shown to be at least mildly effective in patients with advanced COPD.

Stem cell therapy, which could potentially yield new lung tissue (that is not damaged), is not currently an approved mode of treatment, but is undergoing several clinical trials, and may in fact be an option in the near future. Besides lung transplantation, this may be one of the only methods of truly treating the irreversible nature of COPD.

Symptomatic Management

Besides true “treatment” of COPD, there are methods of symptomatic management. Bronchodilators are one of the most common and effective methods to improve airway movement in acute exacerbations of COPD. Steroids, while not effective in COPD treatment as they are in asthma treatment, can have mildly beneficial effects, and are often used as well. Oxygen treatment is often used in severe cases that require hospitalization. Lastly, if the acute exacerbation is caused by a bacterial infection, antibiotics are provided and can prevent fatality.

6 Replies to “Treatments and Disease Management”

  1. Hey Besher! This gave great details about the mechanisms of these drugs. I just had a couple questions.
    1.) I know on the history page you mentioned that corticosteroids are not effective like they are in asthma. Did you come across anything that said why the cAMP/cGMP is a more effective approach to chronic treatment?
    2. You also said that the “flare-ups” are potentially life-threatening. What is the treatment for these acute attacks?

    1. Hey Matt! Thanks for reading.

      1) While corticosteroids do not “treat” COPD as they do during asthma attacks, they can provide some symptomatic relief. However, from what I understand, cAMP and cGMP affect the underlying basis of these symptoms better. A 2005 paper notes the findings: “cAMP suppresses immune and inflammatory cell activity (in inflammatory cells such as neutrophils, T-lymphocytes and macrophages), relaxes airway smooth muscle and modulates pulmonary nerve activity.” These effects, especially in the long-term, can help prevent increasing severity of COPD, and get to the source of the problem rather than just the symptoms.

      2) For acute attacks, medical bronchodilation is the most effective form of management. There are inhalable forms, as well as IV (as you can imagine, people undergoing COPD exacerbations might have a hard time inhaling in the first place). If the exacerbation is caused by an infection, antibiotics can be thrown in the mix, and oxygen treatment is almost always used. Steroids can be added as well; some say because those with COPD may have some asthmatic qualities to their disease that are relieved by steroids, and other think that steroids do have mild effects even on “pure” COPD.

      Source – Soto FJ & Hanania NA. Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease. Curr Opin Pulm Med 2005;11:129-34.

  2. Hi Besher,

    Good work! I noticed you mentioned on several different pages that smoking causes 95% of COPD cases. What accounts for the other 5%? Are there any trends for why non-smokers might get this disease? You did mention the A1AT mutation, but do you think that there might be other environmental causes, rather than genetic ones, for non-smokers? Perhaps those that work with chemicals or in manufacturing might be exposed to harmful chemicals that mimic cigarette smoke? This would be especially interesting because an additional identifiable genetic mutation would help us better understand the molecular basis of the disease, which may help with the development of treatment options for both non-smokers and smokers. Also, is it known precisely what ingredient in cigarettes causes the changes in MMPs and ROSs that eventually result in COPD? Perhaps this specific compound could be eliminated, creating a “safer” cigarette?

    You also mentioned that cigarette smoke could cause epigenetic changes by impairing the activity of HDACs in macrophages. This epigenetic modification seems to affect only a small subset of cells, so are there other epigenetic changes caused by cigarette smoke, or is this one change sufficient to drastically increase the probability of getting COPD?

    Finally, you note that increased concentration of reactive oxygen species is correlated with damage to lipids, proteins, and DNA, which is linked to increased tissue damage seen in COPD. We learned in class that the large majority of ROS are produced by the mitochondria, due to problems with the electron transport chain; are there any connections here between electron transport chain and increased likelihood of getting COPD? Could patients with known mutations in the ETC be more likely to get COPD, especially if they have other risk factors?

    1. Hey Mike,

      A1AT deficiency is the major genetic cause (that accounts for an estimated 2-3% of cases). Otherwise, environmental factors, and genetic deficiencies in anti-oxidant enzyme expression are also common. Usually, it is some mix of many of these factors that causes moderate-severe COPD. From what I’ve read on cigarettes specifically, it is thought that nicotine plays a major role, as well as the actual smoke. E-cigarettes that are smokeless were shown to nonetheless cause some emphysema in non-smokers in a study, indicating that smoke-less nicotine was still toxic to the lungs, as it still generates ROS. I believe the main ROS is thought to be NO2, but superoxide and peroxide can be formed at different stages in the body as well.

      In terms of the epigenetic changes, I cannot say confidently that the effects on the specific HDAC(s) is enough to significantly increase the probability & severity of COPD. However, I think you could make a case for it – HDAC2 is one such target that is affected by ROS, which, when impaired, has been shown to increase cytokine expression. Since cytokines are largely responsible for the recruitment of more inflammatory cells, you could imagine how one epigenetic effect can have large consequences, given the role of cytokines.

      In terms of your last question, I think what you’re saying makes a lot of sense. I have found a few articles that have noted that impaired mitophagy has been correlated with the severity of COPD in certain patients – not to the point where it can be said with great certainty, however. When mitophagy goes bad, significantly-damaged mitochondria can remain in cells and increase the concentration of ROS, which would then worsen the symptoms of COPD. Great questions!

  3. Great article on treatment options of COPD. As you say, there is really only one “treatment” that slows the progression the disease, and that is smoking cessation. (Another treatment that slows degradation of lung function is to give patients supplemental oxygen for at least 18 hours of the day for those who need it based on tests). However, in the day-to-day treatment of COPD, and especially for those with mild-to-moderate cases, the mainstay of therapy is to use bronchodilatory inhalers, which, for example, can be beta-adrenergic agonists or cholinergic antagonists. Although these therapies do not affect progression of disease, they are useful for symptomatic treatment. And you are correct that steroids do not alter the course of disease, and they also do not work as well as they do in asthma, but they are still added to therapy when just using a bronchodilator isn’t enough. They are found in inhalers are a mixture with a bronchodilator, and can be given IV in acute exacerbations that require hospitalization. Great job!

    1. Hey Mazen,

      Thanks for the clarifications! I think I should add a section called “Management of symptoms”. I intended to use the word “treatment” only when it refers to reversing the phenotype involved in COPD, so maybe “management” can indicate symptomatic relief, especially in exacerbations.

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