ABSTRACT
BACKGROUND: Disease progression in COPD is associated with a decline in exercise performance over time. We assessed whether tiotropium might mitigate this by determining its effect on treadmill endurance time (ET) over 2 years. METHODS: This was a randomized, double-blind, placebo-controlled trial of tiotropium, 18 µg daily, in patients with COPD (FEV1/FVC < 70%; postbronchodilator FEV1 < 65%). The primary end point was ET at 90% of baseline maximum work rate at 96 weeks. Secondary end points were ET at other visits, ET by smoking status, spirometry, and St. George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 519 patients were randomized (tiotropium 260, placebo 259). Mean age was 65 years, 77% were men, 34% were continuing smokers, and mean FEV1 was 1.25 L (44% predicted). Significantly more patients discontinued placebo (hazard ratio [95% CI], 0.61 [0.44-0.83]). Baseline ET was 301 s (improvement tiotropium/placebo was 13% overall; P = .009; 18% at 48 weeks, P = .004; 13% at 96 weeks, P = .106). In patients with baseline ET between 2 and 10 min (n = 404), improvement at 96 weeks was 19% (P = .04). Current smokers had higher ET with tiotropium vs placebo (P = .018). FEV1/FVC improved with tiotropium (P < .01). SGRQ total score at 96 weeks improved with tiotropium vs placebo by 4.03 units (P = .007). CONCLUSIONS: Treadmill ET was numerically greater over 2 years with tiotropium vs placebo. However, the 96-week difference was not statistically significant. Spirometry and health status also improved with tiotropium over 2 years, attesting to the benefits of long-acting bronchodilator therapy. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00525512; URL: www.clinicaltrials.gov.
Subject(s)
Bronchodilator Agents/pharmacology , Exercise Test , Physical Endurance/physiology , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/physiopathology , Scopolamine Derivatives/pharmacology , Aged , Disease Progression , Double-Blind Method , Endpoint Determination , Female , Health Status Indicators , Humans , Male , Middle Aged , Placebos , Respiratory Function Tests , Smoking/adverse effects , Tiotropium BromideABSTRACT
Benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are potent ligands for the aryl hydrocarbon receptor (AHR). High-density oligonucleotide microarrays were used to generate global gene expression profiles of wild-type and Ahr(-/-) vascular smooth muscle cells (SMCs) from mouse aorta. To determine whether there are signaling pathways other than the AHR involved in B[a]P metabolism, wild-type and AHR knockout (Ahr(-/-) SMCs were exposed to B[a]P. Two signaling pathways, represented by TGF-beta2 and IGF-1, were identified as potential candidates of an AHR alternate pathway for cells to respond to B[a]P. The wild-type SMCs responded similarly to B[a]P and TCDD in the regulation of a small set of common genes known to respond to the activated AHR (e.g., glutamine S-transferase). However, wild-type SMCs responded in a way that involves many additional genes, suggesting that a very divergent cellular response may be involved when SMCs are exposed to the two classic inducers of the AHR. In contrast, many more genes in the Ahr(-/-) cells responded similarly to B[a]P and TCDD, including Cyp1b1, than responded differently, which indicates that eliminating the AHR is effective for investigating potential alternate cellular mechanisms that respond to B[a]P and TCDD.
Subject(s)
Benzo(a)pyrene/toxicity , Carcinogens/toxicity , Dioxins/toxicity , Environmental Pollutants/toxicity , Gene Expression Regulation/drug effects , Muscle, Smooth, Vascular/drug effects , Receptors, Aryl Hydrocarbon/physiology , Animals , Aorta/drug effects , Cells, Cultured , Mice , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Polychlorinated Dibenzodioxins/toxicity , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Messenger/isolation & purification , Receptors, Aryl Hydrocarbon/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The molecular basis for the adverse biological effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), a pervasive environmental toxin, is largely unknown. TCDD is a ligand for the cytosolic aromatic hydrocarbon receptor (AHR) which mediates the transcriptional induction of the xenobiotic metabolizing genes in the CYP1 family of cytochromes P450. Previous studies have suggested that the AHR may carry out important functions in the cell in addition to metabolizing toxins. We present gene expression profiles of smooth muscle cells from wild type and Ahr(-/-) mice that show significant changes in the RNA levels of the transforming growth factor-beta3 (Tgfb3) gene and genes involved in the modulation and processing of TGF-beta. The RNA expression profiles support a hypothesis that in the wild type, the AHR represses Tgfb gene expression and affects the gene expression of several TGF-beta-modulating and processing genes. We also observed that RNA levels increased for TGF-beta2, CYP1b1, and TGF-beta-related genes in Ahr(-/-) smooth muscle cells exposed to TCDD. These data are consistent with a hypothesis that TCDD stimulates the TGF-beta2 signaling pathway in the absence of the AHR to activate the Cyp1b1 gene. The above results provide a possible explanation for some of the multiple biological effects of TCDD and the physiological role played by the AHR in the absence of environmental agents.
