|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
ABSTRACT |
|---|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Unexplained weight loss is common in patients with chronic obstructive pulmonary disease (COPD).
Since leptin, an obesity gene product, is known to play important roles in the control of body weight
and energy expenditure, we investigated serum leptin levels, along with circulating tumor necrosis
factor-
(TNF-) and soluble TNF receptor (sTNF-R55 and -R75) levels, in 31 patients with COPD and
15 age-matched healthy controls. The body mass index (BMI) and percent body fat (%fat) were significantly lower in the COPD patients than in the healthy controls (BMI = 18.1 ± 2.7 kg/m2 versus
22.8 ± 2.2 kg/m2 [mean ± SD]; p < 0.0001; %fat = 16.9 ± 5.8% versus 24.3 ± 4.9%; p < 0.001). Serum leptin levels were significantly lower in the COPD patients than in the healthy controls (1.14 ± 1.17 ng/ml versus 2.47 ± 2.01 ng/ml; p < 0.05). In contrast, serum TNF- levels (6.59 ± 1.92 pg/ml
versus 5.41 ± 1.60 pg/ml; p < 0.05), plasma sTNF-R55 (1.16 ± 0.47 ng/ml versus 0.67 ± 0.13 ng/ml;
p < 0.0001) and sTNF-R75 (3.65 ± 1.29 ng/ml versus 2.25 ± 0.43 ng/ml; p < 0.0001) levels were significantly higher in the COPD patients than in the healthy controls. Importantly, circulating leptin levels (log transformed) did correlate well with BMI and %fat, but not with TNF- or with sTNF-R levels in the COPD patients. These data suggest that circulating leptin is independent of the TNF- system and is regulated physiologically even in the presence of cachexia in patients with COPD.
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Unexplained weight loss commonly occurs in patients with chronic obstructive pulmonary disease (COPD) (1, 2). That these findings are clinically important is indicated by their adverse relation to physical performance and survival in COPD (3), independent of the severity of airflow obstruction. Although the increased work of breathing in COPD could be partly responsible for excessive energy expenditure (4), this hypothesis is still controversial (5, 6). In either case, it does not by itself explain weight loss, and other mechanisms have been considered.
Leptin, an adipocyte-derived hormone, plays an important role in an energy homeostasis by signaling the brain about the amount of adipose tissue stored in the body (7, 8). After interaction with specific receptors located in the central nervous system and in peripheral tissues, leptin induces a complex response, including control of body weight and energy expenditure (9). Improvements in lipid metabolism and glucose homoeostasis, and increased thermogenesis, are considered to be some of the important metabolic effects of leptin (7, 8). Administration of recombinant leptin to ob/ob mice, which have a genetic defect in leptin production, reduces food intake, increases energy expenditure, and decreases body weight (7, 8). Circulating leptin levels are reported to correlate with the body mass index (BMI) in humans (10, 11). In pathologic conditions such as chronic renal insufficiency (12) and bacterial endotoxemia (13), and with exposure to high-dose glucocorticoids (14), inappropriately increased levels of leptin are thought to induce excessive metabolic effects underlying anorexia and loss of body weight.
Recently, cytokine-mediated metabolic derangements have
begun to be considered as among the candidates responsible
for cachexia in COPD patients (15, 16). It has been suggested
that tumor necrosis factor- (TNF-), a pleiotropic cytokine
causing cachexia (17, 18), plays a part in metabolic changes associated with chronic wasting diseases such as cancer (19), cystic fibrosis (20), congestive heart failure (CHF) (21), and COPD
(15, 16). It was shown that both circulating levels of TNF-
and TNF- production by peripheral blood monocytes were
increased in weight-losing COPD patients (15, 16), suggesting
that activation of the TNF- system was associated with the
cachexia observed in COPD patients. Importantly, administration of endotoxin or cytokines including TNF- or IL-1
produced a prompt and dose-dependent increase in serum
leptin levels in both experimental animals (13, 22) and in humans (23). This suggests that increased levels of circulating
leptin may contribute to anorexia and weight loss in pathologic conditions including COPD.
Against this background, we conducted the present study
to elucidate two questions. First, whether circulating leptin
levels are inappropriately increased in patients with COPD.
Second, whether circulating levels of leptin are related to
those of TNF- or soluble TNF receptors (sTNF-Rs) in patients with COPD. Two kinds of soluble TNF receptor have
been shown to be sensitive markers of activation of the TNF-
system (24). We felt that answering these two questions might
provide new insights into the pathophysiology of cachexia in
COPD patients.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Study Population
Thirty-one patients with COPD (all male) were diagnosed according
to the criteria of the American Thoracic Society (25). Their irreversible chronic airflow obstructions were confirmed. The patients had
been clinically stable for at least 3 mo and lacked clinical signs of exacerbation, such as infection or heart failure. Patients who had conditions known to affect serum leptin or TNF- levels, such as corticosteroid use, cancer, collagen vascular disease, smoking, cardiac failure,
or infection were strictly excluded (13, 14, 19, 21, 22, 26, 27). The patients were not receiving nutritional support therapy.
Fifteen age-matched healthy males were also studied as control subjects. These control subjects had no medical illnesses, had normal physical examinations, blood counts, chemistries, and showed no symptoms or signs of infection at the time of study.
After an overnight fast, all subjects had anthropometric measurements and were tested for body composition with bioelectric impedance analysis (HBF-301; Omron Corp., Tokyo, Japan). Percent of normal body weight (% normal BW) was calculated using the 1995 National Nutritional Assessment by the Japanese Ministry of Health and Welfare. Informed consent was obtained from all subjects in the study.
Measurement of Body Composition by Bioelectric Impedance Analysis
The basic principles of bioelectric impedance analysis were described by Lukaski and colleagues (28). Using the HBF-301 instrument, we calculated fat-free tissue mass (FFM) as follows:
|
where Ht is height (in centimeters), weight is in kilograms, age is in
years, and bioelectric impedance, Z, in ohms (
) measured between
both palms. This equation was applied for male subjects in the standing position.
Pulmonary Function Test
FVC and FEV1 were measured with standard spirometric techniques (CHESTAC-25 part II EX; Chest Corp., Tokyo, Japan). The highest value from at least three spirometric maneuvers was used. Reference values were those proposed by Quanjer and coworkers (29). Arterial blood gas was analyzed with the subject in the sitting position and breathing air (280 Blood Gas System; Ciba Corning Diagnostics Corp., Medfield, MA).
Determination of Serum Leptin and TNF Levels
Blood samples were drawn between 8:00 and 9:00 A.M. from subjects
who had been fasting since 8:00 P.M. the previous night. Both serum and
plasma were separated from blood cells by centrifugation at 1,000 × g
for 5 min. All samples were stored at 
70° C until analyzed.
Serum leptin concentrations were measured in duplicate with a highly sensitive radioimmunoassay (RIA) (Linco Res, Inc., St. Louis, MO) (30). The antibody used in the RIA was a polyclonal antibody raised in rabbits against a highly purified recombinant human leptin. Both the calibrators (0.5, 1, 2, 5, 10, 20, 50, and 100 µg/L) and 125I-labeled tracer for the RIA were prepared with a recombinant human leptin. Calibrators or specimens (100 µl) in duplicate were mixed with 125I- labeled leptin and incubated overnight at 4° C with the leptin antibody. Antirabbit IgG was added to all samples, which were then incubated for 20 min at 4° C to precipitate the antibody-antigen complex. After then centrifuging the samples for 15 min at 2,000 × g and 4° C, the supernates were decanted and the radioactivity in the pellets was counted to determine bound radioactivity. The log values of the calibrators were plotted against the unknown bound counts/zero calibrator bound counts (B/B0) to generate a curve for the calculation of unknowns.
Serum TNF- and plasma sTNF-R55 and sTNF-R75 concentrations were measured in duplicate with enzyme-linked immunosorbent
assay (ELISA) kits (Quantikine; R&D Systems, Minneapolis, MN)
(31). Briefly, a microtiter plate was coated with a murine monoclonal antibody specific for TNF-, sTNF-R55, or sTNF-R75. Standards and
samples were added to individual wells. After several washes to remove unbound proteins, an enzyme-linked (conjugated to alkaline phosphatase for TNF- and to horseradish peroxidase for sTNF-Rs) polyclonal antibody specific for TNF-, sTNF-R55, or sTNF-R75 was
added to the wells. Following another several washes to remove unbound antibody-enzyme reagent, a substrate solution (lyophilized nicotinamide adenine dinucleotide phosphate [NADPH] for TNF-, hydrogen peroxide and tetramethylbenzidine for sTNF-Rs) was added. For the measurement of TNF-, amplifier solution (lyophilized amplifier enzymes) was added (high-sensitivity kit). The reaction was
stopped with 2N sulfuric acid. The color generated was determined with a spectrophotometric microtiter plate reader (Model 450; Bio-Rad, Richmond, CA) by measuring the optical density at 490 nm and
450 nm for TNF- and the sTNF-Rs, respectively.
Statistical Analysis
Because the normality hypothesis was not always fulfilled for most of the variables except for height, statistical analysis was performed with the Mann-Whitney U test for nonparametric data to analyze differences between the two groups. The relations between continuous variables were evaluated with Spearman's rank correlation technique. Results were expressed as mean ± SD. Significance was determined at the 5% level. Statistical analysis was done with the Statview Statistical Package (Statview, Inc., Berkeley, CA).
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Clinical characteristics of both the COPD patients and the healthy controls are shown in Table 1. Patients with COPD had significantly lower BW, BMI, and percent body fat (%fat) than did the control subjects. The COPD patients had severe airflow limitation, decreased arterial PO2, and increased arterial PCO2 values. The control subjects had normal %FVC and %FEV1 on spirograms.
|
We first analyzed serum leptin levels in patients with COPD and then in the healthy controls. The levels of leptin (Table 2) in the COPD patients were significantly lower than in the healthy controls (1.14 ± 1.17 ng/ml versus 2.47 ± 2.01 ng/ml; p < 0.05). We found significant correlations between serum leptin levels (log transformed) and BMI (r = 0.706; p = 0.0001; Figure 1) as well as %fat (r = 0.554; p < 0.005; Figure 2) in COPD patients. Similar results were achieved for the control subjects (BMI: r = 0.874; p < 0.005; Figure 1; %fat: r = 0.713; p < 0.01; Figure 2).
|
|
|
In light of the ability of TNF- to increase leptin levels in
humans (23), we next examined serum TNF- and plasma
sTNF-R55 and -R75 levels in both the COPD patients and
healthy controls. We found that serum TNF- and plasma
sTNF-R55 and sTNF-R75 concentrations in COPD patients
were significantly higher than those in the healthy controls.
This was in contrast to decreased leptin levels in the COPD
patients as compared with the healthy controls (Table 2). Importantly, serum leptin levels did not correlate with either serum TNF- or with plasma sTNF-R levels in either the COPD
patients or the healthy controls.
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
This study was done to evaluate circulating leptin levels and
the possible association between leptin and the TNF- system in the regulation of energy expenditure, body composition,
and metabolic effect in COPD patients. Against expectation,
we found that serum leptin levels in COPD patients were not
elevated over those in healthy controls, although serum TNF-
levels were significantly increased in the COPD patients. Furthermore, we were unable to find any relationship between
circulating leptin and TNF- levels. These observations suggest that leptin is not primarily under the control of the TNF-
system, and it seems not to play an important role in weight
loss in patients with COPD. The positive correlation between
serum leptin levels and BMI in patients with COPD confirms that circulating leptin levels remain regulated even in patients in the cachexic status seen in COPD. Similar physiologic regulation of leptin is also noted in other malnutritional states such
as anorexia nervosa (32) and acquired immune deficiency syndrome (AIDS) (33).
The physiologic relevance of the slightly but significantly
increased TNF- levels in the COPD patients in the present
study is difficult to explain, but several speculations warrant
further discussion. First, inflammation is not the only source
of activation of the TNF- system; hypoxia, for example, can
induce TNF- and sTNF-R release in a human macrophage
cell line, THP-1 (34). Hypoxemia observed in COPD patients
might contribute to the activation of the TNF- system independently of airways inflammation. Second, although TNF-
exerts its effect at least partly in a paracrine/autocrine fashion
in each tissue, there is no significant correlation between TNF-
levels at local sites and in the systemic circulation (35). It may
be possible that circulating TNF- is spilled from the lung tissue of COPD patients (36, 37). Third, we have previously reported that circulating TNF-, sTNF-R55, and sTNF-R75
were increased in patients with CHF (21) to levels similar to
those observed in our COPD patients. Since the levels of both
sTNF-R55 and sTNF-R75 were affected in close proportion to
the disease severity and hemodynamic variables in patients
with CHF (21), the increased levels of circulating TNF- and
sTNF-Rs found in our study would be related to the pathophysiology of right-sided heart failure associated with COPD.
Additionally, as shown by Francia and colleagues (15), serum
levels of TNF- were much higher in weight-losing COPD patients than in COPD patients of normal weight. Less marked but persistent elevation of circulating levels of TNF- may
have unknown effects on metabolic abnormalities, independent of leptin, in patients with COPD.
Our data showed significantly increased levels of circulating sTNF-R55 and -R75 in clinically stable patients with
COPD. Two kinds of TNF--binding proteins are known as
extracellular fragments of TNF-R55 and -R75 (38). The endogenous formation of TNF- and other inflammatory stimuli
leads to the shedding of TNF-Rs, which interfere with the
binding of TNF- to TNF-Rs on the cell surface, and sTNF-Rs
therefore act as regulatory components of the TNF- system
(24). The increased levels of circulating sTNF-Rs in COPD
patients may reflect activation of the TNF- system or other
pathophysiologic activities (24).
The lower levels of circulating leptin in the COPD patients in our study may have some clinical significance for the following reasons. First, hypoxemic COPD patients were found to have impaired glucose tolerance, which cannot be readily explained by changes in known glucoregulatory hormones (39). Lower leptin levels, such as those observed in our study, might contribute to this phenomenon, since leptin is known to improve glucose homeostasis (7, 8). Second, sexual impotence and atrophy of the testes associated with reduced serum testosterone levels have been found in hypoxemic male patients with COPD (40). Although there is a negative correlation between serum leptin and testosterone in healthy men (27), this relationship may not exist in patients with COPD, because serum leptin levels in our study were extremely low. However, reduced levels of circulating leptin, independently of testosterone, might contribute to the sexual disturbances seen in patients with COPD, since leptin has an important function in stimulating the reproductive system (7, 8). Third, although growth hormone (GH) levels are normal in COPD patients (39, 43), administration of recombinant human growth hormone (rhGH) has been attempted in an effort to improve nitrogen balance and increase muscle strength in patients with COPD (44, 45). Since serum GH levels are inversely correlated with circulating levels of leptin (27), this rhGH treatment for COPD patients may aggravate the lower levels of leptin. Additionally, leptin has recently been reported to have been involved in T-cell-mediated immunity (46). Since administration of leptin to mice reverses the immunosuppressive state in starvation, the lower leptin levels in patients with COPD might contribute to a higher frequency of pulmonary infection in COPD patients.
In summary, we evaluated serum levels of leptin, TNF-,
and sTNF-Rs in patients with COPD and in age-matched
healthy controls. We found that circulating levels of leptin
were significantly lower in patients with COPD than in the
healthy controls. In addition, there was no relationship between circulating leptin levels and the activated TNF- system
in patients with COPD. However, circulating leptin levels correlated well with BMI and %fat in COPD patients, as also
demonstrated in the healthy controls. We conclude that the
physiologic regulation of leptin is maintained despite weight loss in patients with COPD, and that circulating levels of leptin are not controlled by the TNF- system. However, decreased levels of circulating leptin may have some pathophysiologic roles in patients with COPD.
| |
Footnotes |
|---|
Correspondence and requests for reprints should be addressed to Noriaki Takabatake, M.D., c/o Hidenori Nakamura, M.D., First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan.
(Received in original form June 23, 1998 and in revised form October 22, 1998).
Acknowledgments: The authors thank the Cosmic Corporation (Tokyo, Japan) for technical assistance and critical discussion.
| |
References |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1. Schols, A. M. W. J., P. B. Soeters, R. Mostert, W. H. M. Saris, and E. F. M. Wouters. 1991. Energy balance in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 143: 1248-1252 [Medline].
2. Schols, A. M. W. J., P. B. Soeters, A. M. C. Dingemans, R. Mostert, P. J. Frantzen, and E. F. M. Wouters. 1993. Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am. Rev. Respir. Dis. 147: 1151-1156 [Medline].
3. Wilson, D. O., R. M. Rogers, E. Wright, and N. R. Anthonisen. 1989. Body weight in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 139: 1435-1438 [Medline].
4. Donahoe, M., R. M. Rogers, D. O. Wilson, and B. E. Pennock. 1989. Oxygen consumption of the respiratory muscles in normal and malnourished patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 140: 385-391 [Medline].
5.
Sridhar, M. K.,
R. Carter,
M. E. J. Lean, and
S. W. Banham.
1994.
Resting energy expenditure and nutritional state of patients with increased
oxygen cost of breathing due to emphysema, scoliosis and thoracoplasty.
Thorax
49:
781-785
6. Hugli, O., Y. Schutz, and J. W. Fitting. 1995. The cost of breathing in stable chronic obstructive pulmonary disease. Clin. Sci. 89: 625-632 [Medline].
7. Auwerx, J., and B. Staels. 1998. Leptin. Lancet 351: 737-742 [Medline].
8.
Flier, J. S..
1997.
Leptin expression and action: new experimental paradigms.
Proc. Natl. Acad. Sci. U.S.A.
94:
4242-4245
9.
Tartaglia, L. A..
1997.
The leptin receptor.
J. Biol. Chem.
272:
6093-6096
10. Maffei, M., J. Halaas, E. Ravussin, R. E. Pratley, G. H. Lee, Y. Zhang, H. Fei, S. Kim, R. Lallone, S. Ranganathan, P. A. Kern, and J. M. Friedman. 1995. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med. 1: 1155-1161 [Medline].
11.
Considine, R. V.,
M. K. Sinha,
M. L. Heiman,
A. Kriauciunas,
T. W. Stephens,
M. R. Nyce,
J. P. Ohannesian,
C. C. Marco,
L. J. McKee,
T. L. Bauer, and
J. F. Caro.
1996.
Serum immunoreactive leptin concentrations in normal-weight and obese humans.
N. Engl. J. Med.
334:
292-295
12.
Merabet, E.,
S. Dagogo-Jack,
D. W. Coyne,
S. Klein,
J. V. Santiago,
S. P. Hmiel, and
M. Landt.
1997.
Increased plasma leptin concentration in
end-stage renal disease.
J. Clin. Endocrinol. Metab.
82:
847-850
13. Grunfeld, C., C. Zhao, J. Fuller, A. Pollock, A. Moser, J. Friedman, and K. R. Feingold. 1996. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters: a role for leptin in the anorexia of infection. J. Clin. Invest. 97: 2152-2157 [Medline].
14.
De Vos, P.,
R. Saladin,
J. Auwerx, and
B. Staels.
1995.
Induction of ob
gene expression by corticosteroids is accompanied by body weight loss
and reduced food intake.
J. Biol. Chem.
270:
15958-15961
15. Di Francia, M., D. Barbier, J. L. Mege, and J. Orehek. 1994. Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 150: 1453-1455 [Abstract].
16.
de Godoy, I.,
M. Donahoe,
W. J. Calhoun,
J. Mancino, and
R. M. Rogers.
1996.
Elevated TNF- production by peripheral blood monocytes
of weight-losing COPD patients.
Am. J. Respir. Crit. Care Med.
153:
633-637
[Abstract].
17.
Tracey, K. J.,
H. Wei,
K. R. Manogue,
Y. Fong,
D. G. Hesse,
H. T. Nguyen,
G. C. Kuo,
B. Beutler,
R. S. Cotran, and
A. Cerami.
1988.
Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation.
J. Exp. Med.
167:
1211-1227
18. Argiles, J. M., J. Lopez-Soriano, S. Busquets, and F. J. Lopez-Soriano. 1997. Journey from cachexia to obesity by TNF. FASEB J. 11: 743-751 [Abstract].
19. Balkwill, F., R. Osborne, F. Burke, S. Naylor, D. Talbot, H. Durbin, J. Tavernier, and W. Fiers. 1987. Evidence for tumor necrosis factor/ cachectin production in cancer. Lancet 2: 1229-1232 [Medline].
20.
Norman, D.,
J. S. Elborn,
S. M. Cordon,
R. J. Rayner,
M. S. Wiseman,
E. J. Hiller, and
D. J. Shale.
1991.
Plasma tumour necrosis factor-alpha in
cystic fibrosis.
Thorax
46:
91-95
21. Nozaki, N., S. Yamaguchi, M. Shirakabe, H. Nakamura, and H. Tomoike. 1997. Soluble tumor necrosis factor receptors are elevated in relation to severity of congestive heart failure. Jpn. Circ. J. 61: 657-664 [Medline].
22.
Sarraf, P.,
R. C. Frederick,
E. M. Turner,
G. Ma,
N. T. Jaskowiak,
D. J. Rivet III,
J. S. Flier,
B. B. Lowell,
D. L. Fraker, and
H. R. Alexander.
1997.
Multiple cytokines and acute inflammation raise mouse leptin
levels: potential role in inflammatory anorexia.
J. Exp. Med.
185:
171-175
23.
Zumbach, M. S.,
M. W. J. Boehme,
P. Wahl,
W. Stremmel,
R. Ziegler, and
P. P. Nawroth.
1997.
Tumor necrosis factor increases serum leptin
levels in humans.
J. Clin. Endocrinol. Metab.
82:
4080-4082
24. Diez-Ruiz, A., G. P. Tilz, R. Zangerle, G. Baier-Bitterlich, H. Wachter, and D. Fuchs. 1995. Soluble receptors for tumor necrosis factor in clinical laboratory diagnosis. Eur. J. Haematol. 54: 1-8 [Medline].
25. American Thoracic Society. 1987. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am. Rev. Respir. Dis. 136: 225-243 [Medline].
26. Maury, C. P. J., and A. M. Teppo. 1989. Tumor necrosis factor in the serum of patients with systemic lupus erythematosus. Arthritis Rheum. 32: 146-150 [Medline].
27. Nyström, F., B. Ekman, M. Österlund, T. Lindström, K. P. Öhman, and H. J. Arnqvist. 1997. Serum leptin concentrations in a normal population and in GH deficiency: negative correlation with testosterone in men and effects of GH treatment. Clin. Endocrinol. 47: 191-198 [Medline].
28.
Lukaski, H. C.,
P. E. Johnson,
W. W. Bolonchuk, and
G. I. Lykken.
1985.
Assessment of fat-free mass using bioelectrical impedance measurements of the human body.
Am. J. Clin. Nutr.
41:
810-817
29. Quanjer, P. H., editor. 1983. Standardized lung function testing. Bull. Eur. Physiopathol. Respir. 19:7-44.
30.
Ma, Z.,
R. L. Gingerich,
J. V. Santiago,
S. Klein,
C. H. Smith, and
M. Landt.
1996.
Radioimmunoassay of leptin in human plasma.
Clin.
Chem.
42:
942-946
31. Hino, T., H. Nakamura, Y. Shibata, S. Abe, S. Kato, and H. Tomoike. 1997. Elevated levels of type II soluble tumor necrosis factor receptors in the bronchoalveolar lavage fluids of patients with sarcoidosis. Lung 175: 187-193 [Medline].
32.
Grinspoon, S.,
T. Gulick,
H. Askari,
M. Landt,
K. Lee,
E. Anderson,
Z. Ma,
L. Vignati,
R. Bowsher,
D. Herzog, and
A. Klibanski.
1996.
Serum leptin levels in woman with anorexia nervosa.
J. Clin. Endocrinol.
Metab.
81:
3861-3863
33. Grunfeld, C., M. Pang, J. K. Shigenaga, P. Jensen, R. Lallone, J. Friedman, and K. R. Feingold. 1996. Serum leptin levels in the acquired immunodeficiency syndrome. J. Clin. Endocrinol. Metab. 81: 4342-4346 [Abstract].
34. Scannell, G., K. Waxman, G. J. Kaml, G. Ioli, T. Gatanaga, R. Yamamoto, and G. A. Granger. 1993. Hypoxia induces a human macrophage cell line to release tumor necrosis factor-alpha and its soluble receptors in vitro. J. Surg. Res. 54: 281-285 [Medline].
35.
Torre-Amione, G.,
S. Kapadia,
J. Lee,
J. B. Durand,
R. D. Bies,
J. B. Young, and
D. L. Mann.
1995.
Tumor necrosis factor- and tumor necrosis factor receptors in the failing human heart.
Circulation
93:
704-711
36. Nakamura, H., T. Hino, S. Kato, Y. Shibata, H. Takahashi, and H. Tomoike. 1996. Tumor necrosis factor receptor gene expression and shedding in human whole lung tissue and pulmonary epithelium. Eur. Respir. J. 9: 1643-1647 [Abstract].
37. Rich, E. A., J. R. Panuska, R. S. Wallis, C. B. Wolf, M. L. Leonard, and J. J. Ellner. 1989. Dyscoordinate expression of tumor necrosis factor-alpha by human blood monocytes and alveolar macrophages. Am. Rev. Respir. Dis. 139: 1010-1016 [Medline].
38. Lantz, M., U. Gullberg, E. Nilsson, and I. Olsson. 1990. Characterization in vitro of a human tumor necrosis factor-binding protein: a soluble form of a tumor necrosis factor receptor. J. Clin. Invest. 86: 1396-1402 .
39. Hjalmarsen, A., U. Aasebo, K. Birkeland, G. Sager, and R. Jorde. 1996. Impaired glucose tolerance in patients with chronic hypoxic pulmonary disease. Diabete Metabol. 22: 37-42 .
40. Semple, Pd'A., G. H. Beastall, W. S. Watson, and R. Hume. 1980. Serum testosterone depression associated with hypoxia in respiratory failure. Clin. Sci. 58: 105-106 [Medline].
41. Aasebo, U., A. Gyltnes, R. Bremnes, A. Aakvaag, and L. Slordal. 1993. Reversal of sexual impotence in male patients with chronic obstructive pulmonary disease and hypoxaemia with long-term oxygen therapy. J. Steroid Biochem. Mol. Biol. 46: 799-803 [Medline].
42.
Gossney, R..
1987.
Atrophy of Leydig cells in the testes of men with longstanding chronic bronchitis and emphysema.
Thorax
42:
615-619
43.
Semple, Pd'A.,
G. H. Beastall,
W. S. Watson, and
R. Hume.
1981.
Hypothalamic-pituitary dysfunction in respiratory hypoxia.
Thorax
36:
605-609
44.
Pape, G. S.,
M. Friedman,
L. E. Underwood, and
D. R. Clemmons.
1991.
The effect of growth hormone on weight gain and pulmonary function
in patients with chronic obstructive lung disease.
Chest
99:
1495-1500
45.
Burdet, L.,
B. de Muralt,
Y. Schutz,
C. Pichard, and
J. W. Fitting.
1997.
Administration of growth hormone to underweight patients with
chronic obstructive pulmonary disease: a prospective, randomized,
controlled study.
Am. J. Respir. Crit. Care. Med.
156:
1800-1806
46. Lord, G. M., G. Matarese, J. K. Howard, R. J. Baker, S. R. Bloom, and R. I. Lechler. 1998. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394: 897-901 [Medline].
This article has been cited by other articles:
 |
|
 |
|
  E. F. M. Wouters, N. L. Reynaert, M. A. Dentener, and J. H. J. Vernooy Systemic and Local Inflammation in Asthma and Chronic Obstructive Pulmonary Disease: Is There a Connection? Proceedings of the ATS, December 15, 2009; 6(8): 638 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. D. Wagner Possible mechanisms underlying the development of cachexia in COPD Eur. Respir. J., March 1, 2008; 31(3): 492 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Barreiro, A M W J Schols, M I Polkey, J B Galdiz, H R Gosker, E B Swallow, C Coronell, J Gea, and on behalf of the ENIGMA in COPD project Cytokine profile in quadriceps muscles of patients with severe COPD Thorax, February 1, 2008; 63(2): 100 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Takabatake, Y. Shibata, S. Abe, T. Wada, J.-i. Machiya, A. Igarashi, Y. Tokairin, G. Ji, H. Sato, M. Sata, et al. A Single Nucleotide Polymorphism in the CCL1 Gene Predicts Acute Exacerbations in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2006; 174(8): 875 - 885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Chen, M. J. Hansen, J. E. Jones, R. Vlahos, S. Bozinovski, G. P. Anderson, and M. J. Morris Cigarette Smoke Exposure Reprograms the Hypothalamic Neuropeptide Y Axis to Promote Weight Loss Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1248 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Takabatake, M. Sata, S. Inoue, Y. Shibata, S. Abe, T. Wada, J.-i. Machiya, G. Ji, T. Matsuura, Y. Takeishi, et al. A Novel Polymorphism in Secretory Phospholipase A2-IID Is Associated with Body Weight Loss in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., November 1, 2005; 172(9): 1097 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Huang, X. Zhang, Z.-W. Jiang, B.-Z. Liu, N. Li, and J.-S. Li Hypoleptinemia in Gastric Cancer Patients: Relation to Body Fat Mass, Insulin, and Growth Hormone JPEN J Parenter Enteral Nutr, July 1, 2005; 29(4): 229 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. F. M. Wouters Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 26 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. P. Man and D. D. Sin Effects of Corticosteroids on Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 78 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Casaburi, S. Bhasin, L. Cosentino, J. Porszasz, A. Somfay, M. I. Lewis, M. Fournier, and T. W. Storer Effects of Testosterone and Resistance Training in Men with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2004; 170(8): 870 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Mazan, E. F. Deveney, S. DeWitt, D. Bedenice, and A. Hoffman Energetic cost of breathing, body composition, and pulmonary function in horses with recurrent airway obstruction J Appl Physiol, July 1, 2004; 97(1): 91 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W Q Gan, S F P Man, A Senthilselvan, and D D Sin Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis Thorax, July 1, 2004; 59(7): 574 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Andreassen and J. Vestbo Chronic obstructive pulmonary disease as a systemic disease: an epidemiological perspective Eur. Respir. J., November 2, 2003; 22(46_suppl): 2s - 4s. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Arao, N. Takabatake, M. Sata, S. Abe, Y. Shibata, T. Honma, K. Takahashi, A. Okada, Y. Takeishi, and I. Kubota In Vivo Evidence of Endothelial Injury in Chronic Obstructive Pulmonary Disease by Lung Scintigraphic Assessment of 123I-Metaiodobenzylguanidine J. Nucl. Med., November 1, 2003; 44(11): 1747 - 1754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. I. Cohen, K. Marzouk, P. Berkoski, C. P. O'Donnell, V. Y. Polotsky, and S. M. Scharf Body Composition and Resting Energy Expenditure in Clinically Stable, Non-Weight-Losing Patients With Severe Emphysema Chest, October 1, 2003; 124(4): 1365 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E F M Wouters Eat well to get well Thorax, September 1, 2003; 58(9): 739 - 740. [Full Text] [PDF]
|
|
|
|
|
|
D D Sin and S F P Man Impaired lung function and serum leptin in men and women with normal body weight: a population based study Thorax, August 1, 2003; 58(8): 695 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.A. Rabinovich, M. Figueras, E. Ardite, N. Carbo, T. Troosters, X. Filella, J.A. Barbera, J.C. Fernandez-Checa, J.M. Argiles, and J. Roca Increased tumour necrosis factor-{alpha} plasma levels during moderate-intensity exercise in COPD patients Eur. Respir. J., May 1, 2003; 21(5): 789 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumura, M. Nakayama, H. Satoh, A. Naito, K. Kamahara, and K. Sekizawa Plasma Orexin-A Levels and Body Composition in COPD Chest, April 1, 2003; 123(4): 1060 - 1065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.G.N. Agusti, A. Noguera, J. Sauleda, E. Sala, J. Pons, and X. Busquets Systemic effects of chronic obstructive pulmonary disease Eur. Respir. J., February 1, 2003; 21(2): 347 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Santolaria, A. Perez-Cejas, M.-R. Aleman, E. Gonzalez-Reimers, A. Milena, M.-J. De La Vega, A. Martinez-Riera, and M.-A. Gomez-Rodriguez LOW SERUM LEPTIN LEVELS AND MALNUTRITION IN CHRONIC ALCOHOL MISUSERS HOSPITALIZED BY SOMATIC COMPLICATIONS Alcohol Alcohol., January 1, 2003; 38(1): 60 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E F M Wouters Chronic obstructive pulmonary disease * 5: Systemic effects of COPD Thorax, December 1, 2002; 57(12): 1067 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Vernooy, M. Kucukaycan, J. A. Jacobs, N. H. Chavannes, W. A. Buurman, M. A. Dentener, and E. F. Wouters Local and Systemic Inflammation in Patients with Chronic Obstructive Pulmonary Disease: Soluble Tumor Necrosis Factor Receptors Are Increased in Sputum Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1218 - 1224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. F. M. Wouters, E. C. Creutzberg, and A. M. W. J. Schols Systemic Effects in COPD* Chest, May 1, 2002; 121 (2009): 127S - 130S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Barazzone-Argiroffo, P. Muzzin, Y. R. Donati, C.-D. Kan, M. L. Aubert, and P.-F. Piguet Hyperoxia increases leptin production: a mechanism mediated through endogenous elevation of corticosterone Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1150 - L1156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Goldberger Heartbeats, Hormones, and Health . Is Variability the Spice of Life? Am. J. Respir. Crit. Care Med., May 1, 2001; 163(6): 1289 - 1290. [Full Text]
|
|
|
|
|
|
N. TAKABATAKE, H. NAKAMURA, O. MINAMIHABA, M. INAGE, S. INOUE, S. KAGAYA, M. YAMAKI, and H. TOMOIKE 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 Am. J. Respir. Crit. Care Med., May 1, 2001; 163(6): 1314 - 1319. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. P. Kotler Cachexia Ann Intern Med, October 17, 2000; 133(8): 622 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fantuzzi and R. Faggioni Leptin in the regulation of immunity, inflammation, and hematopoiesis J. Leukoc. Biol., October 1, 2000; 68(4): 437 - 446. [Abstract] [Full Text]
|
|
|
|
|
|
M. S. M. Ip, K. S. L. Lam, C.-m. Ho, K. W. T. Tsang, and W.-k. Lam Serum Leptin and Vascular Risk Factors in Obstructive Sleep Apnea Chest, September 1, 2000; 118(3): 580 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. F.M. Wouters Nutrition and Metabolism in COPD Chest, May 1, 2000; 117 (2009): 274S - 280S. [Full Text] [PDF]
|
|
|
|
|
|
N. TAKABATAKE, H. NAKAMURA, S. ABE, S. INOUE, T. HINO, H. SAITO, H. YUKI, S. KATO, and H. TOMOIKE The Relationship between Chronic Hypoxemia and Activation of the Tumor Necrosis Factor-alpha System in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1179 - 1184. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. Filippatos, K. Tsilias, G. Baltopoulos, and L. Anthopoulos Serum leptin concentration in heart failure patients: does the literature reflect reality? Eur. Heart J., February 2, 2000; 21(4): 334 - 334. [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |