Aktuelle Abstracts 06.07.01

Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD).

Takizawa H, Tanaka M, Takami K, Ohtoshi T, Ito K, Satoh M, Okada Y, Yamasawa F, Nakahara K, Umeda A
Department of Laboratory Medicine and Respiratory Medicine, Tokyo University, School of Medicine, 7-3-1Hongo, Bunkyo-ku, Tokyo 113, Japan. TAKIZAWA-PHY@h.u-tokyo.ac.jp

Tobacco smoke is believed to cause small airway disease and then chronic obstructive pulmonary disease (COPD), but the molecular mechanisms by which small airway obstruction occurs remain unknown. To study the gene expression levels of transforming growth factor (TGF)-beta1, a potent fibrogenic factor, in small airway epithelium from smokers and patients with COPD, we harvested highly pure samples of epithelial cells from small airways under direct vision by using an ultrathin bronchofiberscope BF-2.7T (outer diameter 2.7 mm with a biopsy channel of 0.8 mm in diameter). The expression levels of TGF-beta1 were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The mRNA levels of TGF-beta1 corrected by beta-actin transcripts were significantly higher in the smoking group and patients with COPD than those in nonsmokers (p < 0.01). Furthermore, among smokers and patients with COPD, TGF-beta1 mRNA levels correlated positively with the extent of smoking history (pack-years) and the degree of small airway obstruction as assessed by measurements of flow-volume curves. Immunocytochemistry of the cells demonstrated more intense stainings for TGF-beta1 in samples from smokers and patients with COPD than from nonsmokers. Spontaneously released immunoreactive TGF-beta1 levels from cultured epithelial cells were more elevated in subjects with a history of smoking and patients with COPD than in nonsmokers. Our study showed a close link between smoking and expression of TGF-beta1 in small airways. Our results also suggested that small airway epithelial cells might be involved in obstructive changes found in smokers and patients with COPD.

PMID: 11371421, UI: 21264009

Am J Respir Crit Care Med 2001 May;163(6):1395-9

Inspiratory capacity, dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute-walk test in chronic obstructive pulmonary disease.

Marin JM, Carrizo SJ, Gascon M, Sanchez A, Gallego B, Celli BR
Respiratory Service, Hospital Miguel Servet, University of Zaragoza School of Medicine, Zaragoza, Spain.

Patients with severe chronic obstructive pulmonary disease (COPD) develop dynamic lung hyperinflation (DH) during symptom-limited incremental and constant work exercise with cycle ergometer and treadmill. The increase in end-expiratory lung volume seems to be the best predictor of dyspnea. Quantification of DH is based on the relatively complex use of on-line measurement of inspiratory capacity (IC) from flow volume loops. We reasoned that DH could occur during daily activities such as walking, and that it could be simply measured using the spirometrically determined IC. We studied 72 men with COPD (FEV(1) = 45 +/- 13.3% predicted). IC was measured at rest and after a 6-min walk test. Exertional dyspnea was evaluated using the Borg scale and dyspnea during daily activities with the modified Medical Research Council (MRC) scale. IC decreased significantly from 28.9 +/- 6.7% TLC at rest to 24.1 +/- 6.8% TLC after exercise (p < 0.001). Exertional dyspnea correlated with DeltaIC (r = -0.49, p < 0.00001) and baseline MRC (r = 0.59, p < 0.00001). In many patients with COPD, walking leads to DH that can be easily determined with simple spirometric testing. DH helps explain exercise capacity limitation and breathlessness during simple daily activities.

Publication Types:
Validation studies

PMID: 11371407, UI: 21263995

Am J Respir Crit Care Med 2001 May;163(6):1365-70

Effect of imposed inflation time on respiratory frequency and hyperinflation in patients with chronic obstructive pulmonary disease.

Laghi F, Segal J, Choe WK, Tobin MJ
Division of Pulmonary and Critical Care Medicine, Edward Hines, Jr. Veterans Administration Hospital, 111N, 5th Avenue and Roosevelt Road, Hines, IL 60141, USA. flaghi@lumc.edu

Decreases in ventilator inflation time (TI,vent) can cause tachypnea, probably as a response to lung inflation. The response may differ in chronic obstructive pulmonary disease (COPD) because time-constant inhomogeneities could foster overdistention of some lung units during early inflation, causing neural inspiratory time to be shorter than in healthy subjects. We tested the hypothesis that a decrease in TI,vent causes tachypnea, prolongation of exhalation, and a decrease in intrinsic positive end-expiratory pressure (PEEP(i)). Ten patients with stable COPD received assist-control ventilation through a mouthpiece. Decreases in TI,vent, achieved through increases in flow from 30 to 90 L/min, increased frequency, from 16.1 +/- 1.0 (SE) to 20.8 +/- 1.5 breaths/min (p < 0.001), time for exhalation, from 2.1 +/- 0.2 to 2.3 +/- 0.2 s (p < 0.025), and decreased PEEP(i), from 7.0 +/- 1.3 to 6.4 +/- 1.1 cm H(2)O (p < 0.01). Decreases in TI,vent, achieved by decreasing inspiratory pause from 2 to 0 s, increased frequency, from 12.9 +/- 0.8 to 18.1 +/- 1.6 breaths/min (p < 0.001), time for exhalation, from 2.0 +/- 0.2 to 2.6 +/- 0.3 s (p < 0.001), and decreased PEEP(i), from 6.4 +/- 1.1 to 5.5 +/- 0.9 cm H(2)O (p < 0.01). In both experiments, decreases in TI,vent reduced inspiratory effort (p < 0.01). In conclusion, strategies to reduce TI,vent in patients with COPD caused tachypnea, yet prolonged the time for exhalation with consequent decrease in PEEP(i).

PMID: 11371402, UI: 21263990

Am J Respir Crit Care Med 2001 May;163(6):1320-5

Function of pulmonary neuronal M(2) muscarinic receptors in stable chronic obstructive pulmonary disease.

On LS, Boonyongsunchai P, Webb S, Davies L, Calverley PM, Costello RW
Department of Medicine, University Hospital Aintree, University of Liverpool, Liverpool L9 7AL, United Kingdom.

Anticholinergic drugs often cause a considerable degree of bronchodilation in patients with chronic obstructive pulmonary disease (COPD). Pulmonary neuronal M(2) muscarinic receptors function to limit the magnitude of vagally induced bronchoconstriction. We hypothesized that the effectiveness of anticholinergic agents in patients with COPD may reflect increased vagal reactivity due to dysfunction of M(2) muscarinic receptors. The function of M(2) receptors and the magnitude of vagally induced bronchoconstriction were assessed in subjects with normal lung function and in subjects with COPD. A nasal cold dry air challenge was used to induce a bronchoconstriction, measured as a change in airway resistance (Raw) at 5 Hz (R5) using impulse oscillometry. In subjects with COPD R5 rose from 0.68 +/- 0.06 to 0.74 +/- 0.07 kPa/L/s after the cold dry air challenge (p < 0.01) and in the control subjects R5 rose from 0.34 +/- 0.03 to 0.39 +/- 0.03 kPa/L/s (p < 0.01). The bronchoconstriction was inhibited by pretreatment with ipratropium bromide, indicating that it was vagally mediated. In both groups of subjects pretreatment with the selective M(2) muscarinic receptor agonist pilocarpine (5 mg/ml) prevented the cold air-induced bronchoconstriction, indicating normal function of M(2) receptors. These studies indicate that M(2) muscarinic receptors are functional in subjects with stable COPD.

PMID: 11371395, UI: 21263983

Am J Respir Crit Care Med 2001 May;163(6):1314-9

A novel pathophysiologic phenomenon in cachexic patients with chronic obstructive pulmonary disease: the relationship between the circadian rhythm of circulating leptin and the very low-frequency component of heart rate variability.

Takabatake N, Nakamura H, Minamihaba O, Inage M, Inoue S, Kagaya S, Yamaki M, Tomoike H
First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan.

Cachexic patients with chronic obstructive pulmonary disease (COPD) show abnormalities of the autonomic nervous system (ANS), neuroendocrine function, and energy expenditure. Leptin has been implicated in the regulation of ANS, neuroendocine function, and thermogenesis in humans. We assessed the physiologic significance of the circadian rhythm of circulating leptin using power spectrum analysis of heart rate variability (HRV) in nine cachexic male patients with COPD, eight noncachexic patients with COPD, and seven healthy control subjects. A diurnal pattern of 24-h leptin levels was present in both the control subjects (analysis of variance [ANOVA]; F = 7.80, p < 0.0001) and noncachexic COPD patients (F = 9.29, p < 0.0001), but was strikingly absent in the cachexic COPD patients (F = 2.09, p = NS). Analysis of HRV demonstrated that the diurnal rhythm of 24-h very low frequency (VLF; 0.003 to 0.04 Hz) showed significantly identical fluctuations with those of 24-h leptin levels, in all of the three groups (r = 0.388, p < 0.0001). Because VLF has been considered to reflect neuroendocrine and thermoregulatory influences, these data may suggest that the loss of circadian rhythm of circulating leptin has clinical importance in the pathophysiologic features in cachexic patients with COPD.

PMID: 11371394, UI: 21263982