Glucocorticoid insensitivity as a future target of therapy for chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal and chronic inflammatory response in the lung that underlies the chronic airflow obstruction of the small airways, the inexorable decline of lung function, and the severity of the disease. The control of this inflammation remains a key strategy for treating the disease; however, there are no current anti-inflammatory treatments that are effective. Although glucocorticoids (GCs) effectively control inflammation in many diseases such as asthma, they are less effective in COPD. The molecular mechanisms that contribute to the development of this relative GC-insensitive inflammation in the lung of patients with COPD remain unclear. However, recent studies have indicated novel mechanisms and possible therapeutic strategies. One of the major mechanisms proposed is an oxidant-mediated alteration in the signaling pathways in the inflammatory cells in the lung, which may result in the impairment of repressor proteins used by the GC receptor to inhibit the transcription of proinflammatory genes. Although these studies have described mechanisms and targets by which GC function can be restored in cells from patients with COPD, more work is needed to completely elucidate these and other pathways that may be involved in order to allow for more confident therapeutic targeting. Given the relative GC-insensitive nature of the inflammation in COPD, a combination of therapies in addition to a restoration of GC function, including effective alternative anti-inflammatory targets, antioxidants, and proresolving therapeutic strategies, is likely to provide better targeting and improvement in the management of the disease.

Keywords: histone deacetylase; inflammation; oxidative stress; p38 mitogen-activated protein kinase; phosphoinositol 3-kinase.

Figure 1

Simplified diagrammatic representation of the mechanisms involved in an oxidant-mediated relative reduction of GC sensitivity. Oxidative stress generated by both exogenous and endogenous sources can directly (nitration and aldehyde adduct formation) and indirectly (PI3Kδ/Akt signaling) impair key transcriptional repressor proteins utilizing the GRα including HDAC-2, thus preventing GC-mediated repression of proinflammatory mediators. If the antioxidant defense response is impaired, this oxidant imbalance results in elevated inflammatory mediator expression, which GC is unable to repress. Abbreviations: GC, glucocorticoid; PI3K, phosphoinositide 3-kinase; GR, glucocorticoid receptor; HDAC, histone deacetylase; Nrf2, NF-E2-related factor 2 (a major regulator of antioxidant gene expression).

Figure 2

Possible therapeutic strategies for alternative effective anti-inflammatory drugs or for the additional restoration of GC function for an oxidant-mediated reduction in GC sensitivity. An effective antioxidant would combat one of the major contributing factors to the chronic and relatively GC unresponsive inflammation in COPD. Current therapies such as theophylline may be able to restore the effectiveness of GCs, thus allowing GC to be more effective in COPD. Oxidant-driven alterations in kinase signaling are likely to contribute to the impaired GRα function in COPD and selective targeting of these pathways, such as PI3Kδ and p38 MAPK, which could also restore the effectives of GC in COPD. In addition, alternative anti-inflammatory inhibitors, such as PI3Kδ/γ or p38 MAPK, may also provide effective alternative or combinatorial anti-inflammatory strategy to GCs in the oxidant-driven inflammation in COPD. Abbreviations: GC, glucocorticoid; COPD, chronic obstructive pulmonary disease; GR, glucocorticoid receptor; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; GSK, glycogen synthase kinase; ERK, extracellular signal-regulated kinase; HDAC, histone deacetylase.