Corticosteroids in COPD. A brief review

Not going to talk a lot of this and that studies. Will post articles in references.

How corticosteroids work in COPD (and in asthma)?

  • What’s a histone? Basically histone is a protein present in nucleus. Histones act as centres in which DNA can wind around. When DNA wraps around histones, it forms chromatin.
  • Gene transcription only happens when the DNA is unwound allowing the RNA polymerase to bind and initiate transcription.(basic biochemistry, haha)
  • So what happens? Histone acetylation changes its charges, basically opens up the chromatin and allows DNA to unwind. So transcription now starts when RNA polymerase binds.
  • When DNA encoding for inflammatory gene is unwound, transcription of pro-inflammatory proteins starts. And this process is central to pathogenesis of inflammatory airway diseases. Expression of cytokines in these diseases lead to histone acetylation which leads to synthesis of more pro-inflammatory proteins.

Ok, so basically, inflammation leads to more inflammation (the central process is histone acetylation which releases the DNA for pro-inflammatory protein synthesis. That’s it).

What does corticosteroid do?

First, It binds to its receptor, then goes to nucleus (correct term is translocation, because that’s where it will do its works) and does two things:

  1. Turn off pro-inflammatory proteins synthesis.
  2. Turn on anti-inflammatory proteins synthesis

So it works on both ways. Let’s see how does it work in details:

  1. When there is histone acetylation, there is histone deacetylation (opposite process). So there’s this enzyme called HDAC (histone deacetylation) which deacetylates histone, so DNA remains wrapped around histone. Corticosteroids increase HDAC activity which prevent DNA from unwrapping. End result? No pro-inflammatory proteins synthesis.
  2. Note that histone has many many residues (let’s think of histone as a machine with many buttons). Acetylation of specific residues causes the release of certain regions of DNA which leads to synthesis of a specific protein (like a machine with specific button with a specific function that it can perform). So, corticosteroids lead to acetylation of different residues in histone which release regions of DNA responsible for anti-inflammatory proteins synthesis.

So a problem in one of these 3 steps may cause corticosteroids resistance:

  1. Receptor translocation to nucleus
  2. Histone residues acetylation
  3. HDAC activity

So far so good….

Corticoisteroids resistance in COPD

  • Studies have shown that corticosteroids may not have the same efficacy as in asthma. Why?
  • Smoking may decrease HDAC activity. Thats why corticosteroids have 1 less target to work on.
  • Inflammation causes oxidative stress which also decreases HDAC activity.

Note, in asthma, a different process happens. Generally it involves the early processes (translocation of receptor and acetylation of histone residues).

Interestingly enough, theophylline may increase HDAC activity. So it is proposed that maybe a low dose of theophylline may result in better corticosteroids effect in COPD.

Let’s switch gear. Efficacy of corticosteroids in COPD.

  • So far, trials have shown that they reduce exacerbations and improve QOL but not sure about mortality and decline of lung functions.
  • Corticosteroids upregulate beta-2 adrenoreceptors so there maybe addictive benefits of using together with LABA.

ICS vs oral corticosteroids

  • Systemic oral corticosteroids may have better effects as COPD is small airway disease (and it’s difficult for ICS to reach small airways) and may also work systematically by suppressing eosinophils production by bone marrow.
  • However, patients requiring steroids treatment are often older patients. The side effects need to be considered.
  • ICS maybe less effective, but it is better than no steroids at all with minimal systemic side effects.

In conclusion,

  1. Exacerbation: we want efficacy -> short courses (2 weeks or less) of systemic corticosteroids 
    – Has been shown to improve dyspnea, shorten hospitalization and decrease relapse rate if used in AECOPD
  2. Stable COPD: we want lesser side effects -> ICS with or without  LABA

COPD with eosinophilia

  • During exacerbations, eosinophils in sputum and bronchial biopsies increase, suggesting their role in causing AECOPD.
  • Targetting blood eosinophils and identify those at risk of exacerbations and therefore treating them with long term ICS maybe the future.

References:

  1. Inhaled and systemic corticosteroids in chronic obstructive pulmonary disease.
    Falk JA1, Minai OA, Mosenifar Z. Proc Am Thorac Soc. 2008 May 1;5(4):506-12.
  2. Histone acetylation and deacetylation: importance in inflammatory lung diseases.
    Barnes PJ1, Adcock IM, Ito K. Eur Respir J. 2005 Mar;25(3):552-63
  3. Eosinophilic airway inflammation in COPD
    Shironjit Saha and Christopher E Brightling Int J Chron Obstruct Pulmon Dis. 2006 Mar; 1(1): 39–47.
  4. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials
  5. Dr Steven Pascoe, MBBS, Nicholas Locantore, PhD, Prof Mark T Dransfield, MD, Prof Neil C Barnes, FRCP, Prof Ian D Pavord, DM 12 April 2015
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