Published Online: June 13, 2014
Glucocorticosteroids (GCS) are an important component of the treatment of the neutrophil-driven inflammation present in the airways and lungs of patients with COPD. However, the benefits of GCS treatment are at best modest, and it is uncertain which phase of the disease should be targeted and which sub-set of patients might benefit most. One of the explanations for why GCS are so limited in their efficacy is the concept of steroid-resistance, which for most patients appears to be acquired during the natural course of the disease. Understanding the molecular basis for this state and developing treatments that restore steroid sensitivity is therefore a major goal in COPD research.
In an editorial recently published in The Journal of Allergy and Clinical Immunology (JACI), Drs. Koenderman and Chilvers discuss the range of potential mechanisms underlying GCS un-responsiveness in COPD patients. Currently, it is uncertain which of the many GCS resistance mechanisms dominate. In addition, it is unclear whether such mechanisms operate equally in all patients, reflect just disease severity, or, like in asthma, might vary across the many different COPD phenotypes that exist. This editorial also highlights the capacity of GCS to impair bacterial killing and prime rather than reduce certain pro-inflammatory responses and hence the capacity for GCS to exacerbate immune-mediated damage and infection risk.
This editorial was triggered by an important paper by Milara and colleagues published concurrently in the JACI. This paper shows that Roflumilast N-oxide (RNO), the active metabolite of the phosphodiesterase-type -IV (PDE4) roflumilast, is able to reverse many of the biochemical markers of GCS resistance in neutrophils isolated from COPD patients and restore GCS sensitivity. The effects of this compound were remarkably broad ranging and included dampening abnormal PI3-kinase-δ, MIF and GRβ expression in neutrophils and restoring HDAC activity, which is important for chromatin re-modeling, all potent mediators of GSC resistance.
This is promising and important work, but many GCS have significant side effects even when used by inhalation and are not liked by patients. Hence, new treatments are urgently needed, which tackle the neutrophil-dominated chronic inflammation so evident in COPD. Fortunately many new agents are in advanced development and include more selective GCS compounds, with improved side-effect profiles. These agents include Roflumilast, which should allow significant sensitization of patients to GCS and hence allow improved efficacy and significant dose reduction, as well as a raft of entirely novel agents including PI3-kinase-δ, CXCR2, NRF2 and elastase inhibitors, to name but a few. However, fine tuning the neutrophil is tricky business and not without its perils. Showing the capacity of RNO to reverse GCS-resistance at the cellular level, this study provides new impetus to this ambition.
The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.