Glucocorticoids

The use of either high-dose inhaled corticosteroids and/or oral corticosteroids could have beneficial impact beyond the lungs, with an impact on systemic inflammation as well as local lung inflammation. Systemic inflammation has recently been identified as a risk for coronary artery disease. In the study by Sin and colleagues patients with mild to moderate COPD treated with high-dose inhaled or oral steroids lowered their C-reactive protein levels in blood by over 70%. The levels of C-reactive protein correlated with levels of IL-6, but IL-6 was not significantly impacted by corticosteroids. The mechanism for the systemic effects are not clear but are likely related to absorption of the inhaled steroids, leading to systemic effects similar to those observed on bone. Whether the use of inhaled corticosteroids in COPD can impact the high rate of coronary disease found in this population awaits large-scale trials.

To study the potential relevance of the interactions between COPD, use of inhaled corticosteroids, and osteoporosis, Scanlon and colleagues randomized over 400 subjects with mild to moderate (not severe) COPD to therapy with 600 µg of triamcinolone or placebo twice daily. Bone mineral density was analyzed at the femur and lumbar spine sequentially over 3 years. Over 3 years, there was a significant loss of bone mineral density at the femoral neck, but not the lumbar spine as compared with the placebo arm. There were also significantly more patients treated with inhaled corticosteroids who had a greater than 6% decline in bone mineral density as compared with the placebo group. Relationships were seen with female sex and the level of compliance with therapy.

Recent observational cohort studies suggest that inhaled glucocorticoids may decrease morbidity and mortality in patients with COPD after hospital discharge. To determine whether the conclusions are distorted by an immortal time bias, Suissa analyzed data from a population-based cohort of Saskatchewan residents, 55 years or older, who were first hospitalized for COPD between 1990 and 1997. Of 979 patients followed for 1 year after hospital discharge for COPD, 389 died or were rehospitalized for COPD. During the first 90 days after discharge, 383 patients received inhaled glucocorticoids. With time-fixed analysis, the rate of readmission or death (events per 100 per year) was 42 among glucocorticoid users and 63 among nonusers. With corrected, time-dependent analysis, the rate of readmission or death was 47 among glucocorticoid users and 59 among nonusers. The rate of readmission or death was affected markedly by the time available for receiving a glucocorticoid prescription in the time-fixed analysis; this effect was not observed with the corrected, time-dependent analysis. Use of inhaled glucocorticoids after hospitalization for COPD did not affect morbidity or mortality. The author concludes that an immortal time bias in previous observational studies has produced a misleading impression that inhaled glucocorticoids decrease morbidity and mortality after hospitalization for COPD. An editorial commentary by Samet accompanies this article.

Although observational studies in patients with COPD have revealed improved survival with use of inhaled glucocorticoids, the benefit has not been seen with randomized trials. One explanation for the discrepancy is the misclassification of users and nonusers because of immortal person–time bias; this bias arises because some patients will have died at the point of assessing glucocorticoid exposure, and thus patients who survive will have a longer opportunity for being exposed to glucocorticoids. To avoid the problem of immortal person–time bias, Fan and coworkers analyzed pharmacy refill records in 2,686 patients with COPD in a time-dependent manner. Mortality was not significantly decreased for average inhaled glucocorticoid use at either low dose (hazard ratio, 0.96) or medium/high dose (hazard ratio, 0.86). Likewise, mortality was not significantly decreased with recent inhaled glucocorticoid use at low dose (hazard ratio, 0.80) or medium/high dose (hazard ratio, 0.88). Use of inhaled glucocorticoids was not associated with hospitalizations or exacerbations secondary to COPD. The authors conclude that use of inhaled glucocorticoids, either in terms of dosage or length of use, is not associated with either exacerbations of COPD or mortality from COPD.

To determine the effect of glucocorticoids on cytokine release by alveolar macrophages, Culpitt and coworkers did bronchoalveolar lavage in 15 patients with COPD (FEV₁/FVC, 53%) and 15 cigarette smokers without airway obstruction. Basal release of interleukin-8 by macrophages was more than five times greater in the patients than in the smokers; release of granulocyte macrophage-colony stimulating factor was equivalent in the two groups. Both interleukin-1ß and cigarette smoke media increased the release of both interleukin-8 and granulocyte macrophage-colony stimulating factor from both the patients and the smokers. Dexamethasone did not inhibit the basal level or the stimulated release of interleukin-8 from the macrophages of the patients, although it inhibited release in the smokers. Dexamethasone inhibited both the basal release of granulocyte macrophage-colony stimulating factor and the release induced by interleukin-1ß, but it did not inhibit the release induced by cigarette smoke media. The authors conclude that the lack of efficacy of glucocorticoids in COPD might be secondary to relative insensitivity of macrophages in the respiratory tract to glucocorticoids.

The actions of glucocorticoids are determined in part by the type 2 isoform of 11ß-hydroxysteroid dehydrogenase. In a line of human bronchial epithelial cells (BEAS-2B), Suzuki and coworkers determined whether inhibition of this enzyme potentiates the inhibitory action of dexamethasone on release of interleukin-8 and whether the enzyme is upregulated during prolonged treatment with dexamethasone. Carbenoxolone, an inhibitor of 11ß-hydroxysteroid dehydrogenase, increased the potency of dexamethasone almost 10-fold. Incubation of the epithelial cells with increasing concentrations of dexamethasone for up to 72 hours led to considerable increases in messenger RNA and protein levels of the enzyme. Prolonged treatment with dexamethasone increased the activity of the enzyme in a dose- and time-dependent fashion. The authors conclude that bronchial epithelial cells autoregulate the bioactive levels of glucocorticoids by inducing expression of 11ß-hydroxysteroid dehydrogenase type 2 and that this enzyme may locally regulate the action of inhaled glucocorticoids.

In a state of the art review article on disorders of the respiratory muscles, Laghi and Tobin discuss the effect of COPD on the respiratory muscles.

Because glucocorticoids can affect matrix metalloproteinases, Choe and coworkers studied the effect of methylprednisolone on lung structure in adult rats. Daily methylprednisolone (2 mg per kg) for 1, 2, or 4 weeks produced an increase in mean linear intercept and a decrease in the surface–volume ratio. Animals also exhibited increased activity of matrix metalloproteinase-9. Rats treated with a broad-spectrum matrix metalloproteinase inhibitor (GM6001) did not develop emphysema. The authors conclude that methylprednisolone increases the activity of matrix metalloproteinases in rat lung and causes emphysema.

Citations 1-10 of 10 total displayed.

Loss of Bone Density with Inhaled Triamcinolone in Lung Health Study II

Paul D. Scanlon, John E. Connett, Robert A. Wise, Donald P. Tashkin, Thelma Madhok, Melissa Skeans, Paul C. Carpenter, William C. Bailey, A. Sonia Buist, Michael Eichenhorn, Richard E. Kanner, and Gail Weinmann the Lung Health Study Research Group
Am. J. Respir. Crit. Care Med. 170: 1302 -1309. First published online as doi:10.1164/rccm.200310-1349OC [Abstract] [Full text]  

Effects of Fluticasone on Systemic Markers of Inflammation in Chronic Obstructive Pulmonary Disease

Don D. Sin, Paige Lacy, Ernest York, and S. F. Paul Man
Am. J. Respir. Crit. Care Med. 170: 760 -765. First published online as doi:10.1164/rccm.200404-543OC [Abstract] [Full text]  

Fracture Risk Associated with Inhaled Corticosteroid Use in Chronic Obstructive Pulmonary Disease

Todd A. Lee and Kevin B. Weiss
Am. J. Respir. Crit. Care Med. 169: 855 -859. First published online as doi:10.1164/rccm.200307-926OC [Abstract] [Full text]  

Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease and Risk of Death and Hospitalization: Time-dependent Analysis

Vincent S. Fan, Chris L. Bryson, J. Randall Curtis, Stephan D. Fihn, Pierre-Olivier Bridevaux, Mary B. McDonell, and David H. Au
Am. J. Respir. Crit. Care Med. 168: 1488 -1494. First published online as doi:10.1164/rccm.200301-019OC [Abstract] [Full text]  

Measuring the Effectiveness of Inhaled Corticosteroids for COPD Is Not Easy!

Jonathan M. Samet
Am. J. Respir. Crit. Care Med. 168: 1-2. [Full text]  

Disorders of the Respiratory Muscles

Franco Laghi and Martin J. Tobin
Am. J. Respir. Crit. Care Med. 168: 10-48. [Abstract] [Full text]  

Effectiveness of Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease: Immortal Time Bias in Observational Studies

Samy Suissa
Am. J. Respir. Crit. Care Med. 168: 49 -53. First published online as doi:10.1164/rccm.200210-1231OC [Abstract] [Full text]  

Methylprednisolone Causes Matrix Metalloproteinase–dependent Emphysema in Adult Rats

Kang-Hyeon Choe, Laimute Taraseviciene-Stewart, Robertas Scerbavicius, Lajos Gera, Rubin M. Tuder, and Norbert F. Voelkel
Am. J. Respir. Crit. Care Med. 167: 1516 -1521. First published online as doi:10.1164/rccm.200210-1207OC [Abstract] [Full text]  

Dexamethasone Upregulates 11ß-Hydroxysteroid Dehydrogenase Type 2 in BEAS-2B Cells

Satoshi Suzuki, Kaori Koyama, Andrew Darnel, Hironori Ishibashi, Seiichi Kobayashi, Hiroshi Kubo, Takashi Suzuki, Hironobu Sasano, and Zygmund S. Krozowski
Am. J. Respir. Crit. Care Med. 167: 1244 -1249. First published online as doi:10.1164/rccm.200210-1139OC [Abstract] [Full text]  

Impaired Inhibition by Dexamethasone of Cytokine Release by Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary Disease

Sarah V. Culpitt, Duncan F. Rogers, Pallav Shah, Carmen De Matos, Richard E. K. Russell, Louise E. Donnelly, and Peter J. Barnes
Am. J. Respir. Crit. Care Med. 167: 24 -31. First published online as doi:10.1164/rccm.200204-298OC [Abstract] [Full text]