Steroid Resistance in COPD

COPD is a chronic inflammatory disease of the lungs, which is progressive, leading to progressive symptoms and decline in lung function. This suggests that we need to develop anti-inflammatory treatments to deal with this underlying inflammatory process. The most widely used anti-inflammatory treatments for chronic diseases are corticosteroids or steroids. These treatments are highly effective in many inflammatory diseases, such as asthma, which also is associated with inflammation of the airways.

Steroids are highly effective in asthma, and we give them by inhalation in order to reduce any systemic side effects. This leads to control of asthma with reduced symptoms and prevention of exacerbations, and reduced mortality. People naturally expected that steroids might be a useful therapy for COPD, and so many studies were done looking at the effects of inhaled steroids in COPD, often given over several years to see whether they reduced progression. But, sadly, inhaled steroids turned out to be a little clinical value: they don’t reduce the symptoms, they reduce exacerbations a little, but they completely fail to reduce disease progression and they don’t reduce the mortality of COPD. So they’ve largely failed in terms of any clinical efficacy, and we now know that this is because the inflammation that affects COPD is largely steroid resistant. So even high doses of steroids are not able to reduce the inflammatory process. There is one exception which is the COPD patients that have some features of asthma, and they have the eosinophilic type of inflammation like asthma. That does show some response to steroids, although nothing like the degree of improvement with steroids that we see in asthma.

The majority of COPD is resistant to steroids, and a lot of our research is focused on trying to understand why the inflammation of asthma is sensitive to steroids, but the inflammation in the same parts of the lung, in COPD, is resistant to steroids. That involves understanding how steroids work to control inflammation. We’ve looked at the molecular pathways of steroids, and when steroids enter cells, they bind to glucocorticoid receptors that are found in a cytoplasm of cells, and these receptors then move into the nucleus, where they seek out activated inflammatory genes and switch them off leading to reduced secretion of inflammatory proteins, and this results in reduced inflammation.

What we’ve worked out is the mechanism whereby glucocorticoid receptors switch off inflammatory genes. This is linked to the fact that when you activate inflammatory genes, you get acetylation of core histones, around which DNA is wound, and the chromosome structure. When genes are inactive, the chromatin structure is tightly packed. But when the genes become activated, this opens up the chromatin structure, because the basic histone molecules, around which DNA is wound, become acetylated by histone acetyltransferases. This means that gene transcription can proceed leading to the expression of inflammatory genes. What we’ve found is that steroids work by reversing histone acetylation by the recruitment of an enzyme called histone deacetylase 2, and this by reversing histone acetylation causes the open chromatin structure to be compacted again, which therefore switches off transcription of the inflammatory genes.

This is how steroids work in asthma to switch off inflammatory genes, but in COPD the histone deacetylase 2, or HDAC2, is inactivated, and it becomes inactivated by oxidative stress, which activates a pathway called PI 3-kinase delta. PI 3-kinase delta is able to result in the inactivation of the HDAC2 protein, which leads to its reduction. So it means that it’s not available for when steroids are trying to switch off inflammation because the protein has been lost. This is interesting because it tells us why COPD is steroid resistant. But I think what’s really interesting is the potential for reversing this resistance.

Now we understand the molecular pathway that leads to steroid resistance. What we found is theophylline, which is a very old treatment that was previously used as a bronchodilator, in very low concentrations is able to increase the histone deacetylase 2 and therefore reverse the steroid resistance that is found in COPD. A theophylline is a very cheap drug that’s been very widely used, and to achieve this reversal of steroid resistance you only require very low doses. Previously, high doses of theophylline were needed for bronchodilation and it fell out of favor because this was associated with side effects. But now we are talking about much lower doses of theophylline that are pretty much free of any side effects. We think there’s a potential for drugs to reverse steroid resistance and that theophylline could be repurposed in order to do this. But because theophylline is very cheap, it’s very difficult to get funding to look at clinical trials that are needed to show that theophylline would be effective, although two such studies are currently underway. It’s been very difficult to get them funded.

But there are other drugs that could potentially reverse steroid resistance. Nortriptyline is an antidepressant that we found is able to do this, working through the same mechanism as theophylline, which is inhibiting PI 3-kinase delta, that is responsible for the reduced HDAC2. But there are also selective PI 3-kinase delta inhibitors that have now been developed. We know that these drugs may have side effects if they are given systemically and, in fact, have hematological side effects. But inhaled drugs that inhibit PI 3-kinase delta have now been developed, and these drugs can potentially be used to reverse steroid resistance in COPD.

Incidentally, people with severe asthma also lose the responsiveness to steroids, and that’s through the same mechanism. We think the common cause is reduced HDAC2 and that this is triggered by increased oxidative stress that is found in COPD and in severe asthma. This opens up the possibility for new treatments.

The other approach, of course, is to find alternative anti-inflammatory treatments. Many pharmaceutical companies have been looking for new types of anti-inflammatory drug. The only anti-inflammatory treatments for COPD that have so far gone into the clinic is a phosphodiesterase-4 inhibitor called roflumilast. Roflumilast is effective in animal models of COPD, for example, but has a rather poor clinical effect because it has a lot of side effects when it’s given as a tablet. This means that the dose is really limited by these side effects, and at the low doses that can be tolerated the clinical benefit is really quite small. So this means we need to look further for other anti-inflammatory treatments, and there are several new classes of drug, particularly kinase inhibitors that are being looked at as potential anti-inflammatory treatments in COPD. I think that more studies are needed to discover the most useful drugs, and, probably, to avoid side effects these drugs will need to be given by inhalation.

I think there’s a lot of work that is needed to develop new treatments and then to go into clinical trials in suitably selected patients to demonstrate clinical benefit. But we certainly do need drugs that will reduce the progression of COPD, reduce its major impact and reduce its high mortality.