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Circulating visfatin in chronic obstructive pulmonary disease
Nutrition 25 (2009) 373–378 www.nutritionjrnl.com
Applied nutritional investigation
Circulating visfatin in chronic obstructive pulmonary disease Xiaojing Liu, Ph.D., Yulin Ji, M.D., Jian Chen, M.D., Shuangqing Li, M.D., and Fengming Luo, M.D.* West China Hospital of Sichuan University, Chengdu, China Manuscript received November 11, 2007; accepted September 9, 2008.
Abstract
Objective: Malnutrition and continuous systemic inflammation occur frequently in patients with chronic obstructive pulmonary disease (COPD). Visfatin is a new adipokine, which increases in some inflammatory diseases. Its plasma level and relation with nutritional status and inflammation in COPD remain unknown. This study compared visfatin levels, nutritional status, and inflammation markers in patients with COPD and healthy controls. Methods: Plasma visfatin, tumor necrosis factor-␣ (TNF-␣) and C-reactive protein (CRP) were measured in 35 patients with COPD and 28 healthy controls. Body composition was assessed with bioelectrical impedance analysis. Results: Significantly lower body mass index and percentage of body fat were observed in patients with COPD compared with control subjects. The levels of plasma visfatin were higher in the COPD group compared with healthy controls (2.07 ⫾ 0.18 versus 1.88 ⫾ 0.15 ng/mL, P ⬍ 0.001). Levels of TNF-␣ and CRP were also significantly higher in patients with COPD compared with controls. Plasma CRP and TNF-␣ were positively correlated with visfatin in the COPD group. No significant correlations were found between visfatin and body mass index or percentage of body fat in both groups. Conclusion: Plasma visfatin levels increased in patients with COPD. This increased adipocytokine was significantly correlated with TNF-␣ and CRP. Visfatin may be a new proinflammatory adipocytokine in this disease. © 2009 Published by Elsevier Inc.
Keywords:
Visfatin; Systemic inflammation; Chronic obstructive pulmonary disease
Introduction Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease. It is often associated with clinically significant systemic alterations, including malnutrition and continuous systemic inflammation [1]. Patients with COPD with malnutrition always have a lower percentage of body fat (%fat) compared with normal controls. Adipokines, including leptin, ghrelin, resistin, and visfatin,
This work was supported by grant 30500222 from the National Natural Science Foundation of China (F.L.), grant 04GY029-083-1 from the Research Foundation of Science and Technology Bureau of Sichuan Province (F.L.), and grants 06GGYB514SF-030 (Y.J.) and 06GGYB918SF-030 (F.L.) from the Research Foundation of Science and Technology Bureau of Chengdu. Xiaojing Liu and Yulin Ji contributed equally to this study. * Corresponding author. Tel.: ⫹86-28-8181-2355; fax: ⫹86-28-85422788. E-mail address: [email protected] (F. Luo). 0899-9007/09/$ – see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.nut.2008.09.008
are peptides secreted from visceral adipose tissue. Under malnutrition and inflammatory stress, the production of these adipokines may be different from that in normal conditions [2]. Previous studies have indicated that adipose-derived hormones and cytokines play a role in the process of lung diseases [3]. Circulating ghrelin is found to be decreased in patients with COPD [4]. Repeated administration of ghrelin improves body composition, muscle wasting, and functional capacity in cachectic patients with COPD [5]. Visfatin, initially known as pre–B-cell colony– enhancing factor, is one adipokine and affects maturation of B-cell precursors. It also plays critical roles in some inflammation processes, including apoptosis of neutrophils [6] and secretion of interleukin (IL)-8 from human pulmonary artery endothelial cells [7]. Recent studies have shown that the visfatin level is significantly increased in bronchoalveolar lavage fluid and serum of acute lung injury in a mouse model. A few polymorphisms of visfatin gene are associated with increased
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odds of developing acute respiratory distress syndrome and an increased hazard of intensive care unit mortality among at-risk patients [8]. Whether visfatin relates to COPD inflammation is unknown at present. As an adipokine, visfatin correlates with nutritional status in some diseases. Circulating levels of visfatin are associated with parameters of metabolism [9]. Plasma levels of visfatin in patients with previously high visfatin levels have been found to be decreased after gastric banding [10]. In contrast, plasma levels of visfatin are increased in patients with weight loss induced by gastroplastic surgery [11]. Low weight is very common in patients with COPD. Until now, there has been no study on the visfatin level and its relation to nutritional status in patients with COPD. Therefore, this study compared the plasma level of visfatin and inflammation markers, body mass index (BMI), and percentage of body fat (%fat) in patients with COPD and controls.
Materials and methods Patients This study was approved by the medical ethics committee of the West China Hospital, Sichuan University. All subjects signed consent forms. The 35 patients (all men), diagnosed as having COPD according to criteria from the American Thoracic Society, had been clinically stable for at least 3 mo. Patients who had conditions known to affect plasma visfatin, including renal or liver insufficiency, metabolic diseases, and smoking (including current smokers or ex-smokers), were strictly excluded [12,13]. None of the patients were receiving nutritional support therapy or taking any medication at the time of evaluation. Twenty-eight age-matched healthy men who comprised the control group were non-smokers, had no medical illnesses, and had normal physical examinations and laboratory data. Both patient groups had visited the West China Hospital previously. Pulmonary function test Forced vital capacity and forced expiratory volume in 1 s were measured using standard spirometric techniques (MicroLoop; Micro Medical Ltd., Kent, United Kingdom). The reference values employed were those proposed by Zheng and Zhong [14]. Body composition Body composition was estimated using “foot-to-foot” bioelectrical impedance analysis technology (QuickMedical, Snoqualmie, WA, USA) as described previously [4]. While subjects were standing on blocks of solid metal on the machine, light weight, fat mass, fat-free mass, %fat, and BMI were automatically calculated by the machine after age, height,
and gender were entered. A standard calculation model was selected according to the instructions of the manufacturer. Collection of sample After overnight fasting (from 2100 h) blood was collected by venipuncture at 0700 h and centrifuged at 1600 ⫻ g for 15 min at 4°C. The plasma was collected and stored at ⫺70°C. Visfatin assay Visfatin was assayed with a sandwich enzyme-linked immunosorbent assay (ELISA) kit (AdipoGen Inc., Seoul, Korea) as described previously [15] using 100 L of sample. All samples were assayed in duplicate. Tumor necrosis factor-␣ and C-reactive protein assays Plasma tumor necrosis factor-␣ (TNF-␣) was measured using a high-sensitivity ELISA (R&D, Minneapolis, MN, USA) according to the manufacturer’s procedure. C-reactive protein (CRP) in plasma was measured using an ELISA kit (IBL, Hamburg, Germany). The minimum detectable concentrations for TNF-␣ and CRP were 4.4 pg/mL and 1 ng/mL, respectively. All assays were performed in duplicate. Statistical analysis Results are presented as mean ⫾ standard deviation. Differences between groups were statistically analyzed using an unpaired Student’s t test because all data were normally distributed. Correlations were performed using bivariate Pearson’s correlation test. Significance was determined at the 5% level. Data were analyzed with SPSS 10.0 for Windows (SPSS Inc., Chicago, IL, USA).
Results Clinical characteristics of patients with COPD and healthy controls are presented in Table 1. Significantly lower BMI and %fat were found in patients with COPD Table I Patient characteristics*
Age (y) BMI (kg/m2) FFM (kg) Body fat (%weight) FEV1 (%predicted) FVC (%predicted)
COPD (n ⫽ 35)
Control (n ⫽ 28)
P
70 ⫾ 7 18.4 ⫾ 2.3 38.3 ⫾ 4.6 20.0 ⫾ 4.8 59.5 ⫾ 14.9 72.0 ⫾ 16.6
70 ⫾ 7 22.3 ⫾ 3.5 46.2 ⫾ 5.8 28.7 ⫾ 8.3 75.1 ⫾ 8.0 86.1 ⫾ 8.1
0.758 ⬍0.001 ⬍0.001 0.011 ⬍0.001 0.001
BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; FFM, fat-free mass; FVC, forced vital capacity * Values are presented as mean ⫾ SD.
X. Liu et al. / Nutrition 25 (2009) 373–378
Fig. 1. Plasma visfatin, TNF-␣, and CRP in patients with COPD and healthy control subjects. **Significant differences between the control and COPD groups (P ⬍ 0.01). COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; TNF-␣, tumor necrosis factor-␣.
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(2.07 ⫾ 0.18 versus 1.88 ⫾ 0.15 ng/mL, P ⬍ 0.001; Fig. 1). Levels of TNF-␣ and CRP, which are markers of system inflammation, were significantly higher in patients with COPD compared with controls (TNF-␣ 24.35 ⫾ 9.99 versus 9.44 ⫾ 5.94 pg/mL, P ⬍ 0.001; CRP 17.46 ⫾ 5.76 versus 4.51 ⫾ 3.01 ng/mL, P ⬍ 0.001; Fig. 1). There was no significant correlation between visfatin and BMI in either group (control r ⫽ 0.083, P ⫽ 0.674; COPD r ⫽ 0.057, P ⫽ 0.744; Fig. 2a,b). Similarly, visfatin level and %fat did not exhibit a significant correlation in the COPD and control groups (control r ⫽ 0.034, P ⫽ 0.863; COPD r ⫽ 0.040, P ⫽ 0.819; Fig. 2c,d). In contrast, the marker of inflammation, plasma CRP, was positively correlated with visfatin level in the COPD group (r ⫽ 0.437, P ⫽ 0.009; Fig. 3b), but not in the control group (r ⫽ 0.018, P ⫽ 0.356; Fig. 3a). Plasma level of TNF-␣ also was positively correlated with visfatin in the COPD group (r ⫽ 0.392, P ⫽ 0.022; Fig. 3d), but not in the control group (r ⫽ 0.151, P ⫽ 0.443; Fig. 3c). Discussion
compared with control subjects. Moderate airflow limitation was found in patients with COPD. The levels of plasma visfatin were significantly higher in the COPD group compared with the healthy control group
In this study, plasma visfatin levels were found to be significantly increased in patients with COPD compared with healthy controls. Levels of TNF-␣ and CRP were
Fig. 2. Correlations of plasma visfatin levels and body mass index in (a) healthy control subjects and (b) patients with chronic obstructive pulmonary disease and percentage of body fat in (c) healthy control subjects and (d) patients with chronic obstructive pulmonary disease. CRP, C-reactive protein; TNF-␣, tumor necrosis factor-␣.
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Fig. 3. Correlations of plasma visfatin levels and C-reactive protein in (a) healthy control subjects and (b) patients with chronic obstructive pulmonary disease and tumor necrosis factor-␣ in (c) healthy control subjects and (d) patients with chronic obstructive pulmonary disease. BMI, body mass index.
higher in the COPD group compared with healthy controls. The levels of these two systemic inflammation markers were positively correlated with the level of plasma visfatin in patients with COPD. No significant correlation was found between plasma visfatin level and BMI or %fat in either group. Because TNF-␣ induces visfatin mRNA expression and visfatin inhibits neutrophil apoptosis, increased visfatin may be the result of COPD inflammation. In turn, it may play a critical role in the development and persistence of inflammation in COPD. There are conflicting results in plasma visfatin levels in patients with obesity or insulin resistance [16 –19]. The circulating visfatin levels were measured by different methods including enzyme immunoassays, radioimmunoassays, and ELISAs [16 –19]. However, Körner et al. [15] reported significant discrepancies between these assays and a very poor correlation. The conflicting results of vasfatin levels in obese or insulin-resistant patients [16 –19] may reflect values obtained using the different assay methods. Therefore, in our present study, we measured the circulating visfatin in patients with COPD with the most reliable method described [15], the ELISA. Evidence is accumulating that inflammation cytokines regulate the production of visfatin. Although Kralisch et al. [20] reported that TNF-␣ decreases visfatin in 3T3-L1 adi-
pocytes, in a more recent study, Hector et al. [21] showed that TNF-␣ stimulation significantly increased the mRNA level of visfatin in cultured human visceral adipose tissue isolated from patients without diabetes mellitus. In addition, other inflammation cytokines and mediators including lipopolysaccharide, IL-1, and IL-6 significantly increased the expression of visfatin 4 h after treatment of an amniotic epithelial cell line [22]. Furthermore, IL-1 induced the expression of visfatin in neutrophils [6]. Although visfatin is produced mainly by visceral adipose tissue, higher visfatin is also found in the serum of patients with lung injury compared with normal controls [23]. In addition to adipose tissue, macrophages, dendritic cells, and colonic epithelial cells of patients with inflammatory bowel disease produce visfatin [24]. As the number of inflammatory cells increases in COPD, the recruited macrophages and dendritic cells may produce visfatin, yielding higher levels in patients with COPD than normal. Consistent with our previous study [4], plasma levels of TNF-␣ and CRP were found to be significantly increased in patients with COPD with mild airflow limitation in this study. These results indicate that the increased level of visfatin in patients with COPD may be the potential result of local or systemic inflammation. Another possible cause of increased visfatin in COPD may be hypoxia. It has been demonstrated that visfatin, a
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new hypoxia-inducible gene, is stimulated by hypoxiainducible factor-1 by direct transcriptional regulation [25]. Hypoxia is very common in patients with COPD due to the airflow limitation and ventilation/perfusion mismatch. During hypoxia, the expression of hypoxia-inducible factor-1, a master regulator of oxygen homeostasis that controls transcriptional responses to hypoxia, increases significantly [26]. Thus, we hypothesize that hypoxia may contribute to the increased plasma visfatin level in patients with COPD. Increased visfatin levels were also found in other chronic diseases including rheumatoid arthritis [27] and chronic kidney diseases [12]. Although visfatin levels correlated with inflammation cytokines or mediators in those patients, the role of visfatin remains unclear. The physiologic role of increasing visfatin in COPD also remains unclear. Neutrophilic airway inflammation is a prominent feature of COPD. Increased neutrophil infiltration in the COPD lung may occur by the reduction of spontaneous neutrophil apoptosis and by the recruitment of neutrophils from the circulation [28]. Because visfatin inhibits the apoptosis of neutrophils, elevated visfatin levels may promote the survival of neutrophils in COPD. In addition, recombinant visfatin activates human leukocytes and induces the production of IL1, TNF-␣, and IL-6. Visfatin also increases the expression of intercellular adhesion molecules and other costimulatory molecules in neutrophils [24]. Therefore, systemic or local inflammation may increase visfatin expression. At the same time, increased visfatin may promote the inflammatory processes in COPD. Visfatin is not only a new inflammation marker but also a possibly important proinflammatory adipocytokine in COPD. Because visfatin expression has been found in several different tissues [29,30] and the expression of visfatin is determined by different factors [11,12], it is not surprising that no correlation was found between plasma visfatin and %fat in either group in our study. Further study should be performed to investigate the main source of circulating visfatin in patients with COPD.
Summary Plasma visfatin level was increased in patients with COPD. Visfatin may be a new proinflammatory adipocytokine in this disease. Increased visfatin does not correlate with BMI and %fat in patients with COPD.
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[23] Ye SQ, Simon BA, Maloney JP, Zambelli-Weiner A, Gao L, Grant A, et al. Pre–B-cell colony– enhancing factor as a potential novel biomarker in acute lung injury. Am J Respir Crit Care Med 2005;171: 361–70. [24] Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, Tilg H. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol 2007;178:1748 –58. [25] Bae SK, Kim SR, Kim JG, Kim JY, Koo TH, Jang HO, et al. Hypoxic induction of human visfatin gene is directly mediated by hypoxiainducible factor-1. FEBS Lett 2006;580:4105–13. [26] Semenza GL. Pulmonary vascular responses to chronic hypoxia mediated by hypoxia-inducible factor 1. Proc Am Thorac Soc 2005;2: 68 –70.
[27] Otero M, Lago R, Gomez R, Lago F, Dieguez C, Gomez-Reino JJ, Gualillo O. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:1198 –201. [28] Pletz MW, Lode H. Apoptosis of circulating neutrophils in COPD patients. Chest 2005;127:1464 –5. [29] Pilz S, Mangge H, Obermayer-Pietsch B, Marz W. Visfatin/pre–Bcell colony– enhancing factor: a protein with various suggested functions. J Endocrinol Invest 2007;30:138 – 44. [30] Krzysik-Walker SM, Ocon-Grove OM, Maddineni SR, Hendricks GL III, Ramachandran R. Is visfatin an adipokine or myokine? Evidence for greater visfatin expression in skeletal muscle than visceral fat in chickens. Endocrinology 2008;149:1543–50.
Applied nutritional investigation
Circulating visfatin in chronic obstructive pulmonary disease Xiaojing Liu, Ph.D., Yulin Ji, M.D., Jian Chen, M.D., Shuangqing Li, M.D., and Fengming Luo, M.D.* West China Hospital of Sichuan University, Chengdu, China Manuscript received November 11, 2007; accepted September 9, 2008.
Abstract
Objective: Malnutrition and continuous systemic inflammation occur frequently in patients with chronic obstructive pulmonary disease (COPD). Visfatin is a new adipokine, which increases in some inflammatory diseases. Its plasma level and relation with nutritional status and inflammation in COPD remain unknown. This study compared visfatin levels, nutritional status, and inflammation markers in patients with COPD and healthy controls. Methods: Plasma visfatin, tumor necrosis factor-␣ (TNF-␣) and C-reactive protein (CRP) were measured in 35 patients with COPD and 28 healthy controls. Body composition was assessed with bioelectrical impedance analysis. Results: Significantly lower body mass index and percentage of body fat were observed in patients with COPD compared with control subjects. The levels of plasma visfatin were higher in the COPD group compared with healthy controls (2.07 ⫾ 0.18 versus 1.88 ⫾ 0.15 ng/mL, P ⬍ 0.001). Levels of TNF-␣ and CRP were also significantly higher in patients with COPD compared with controls. Plasma CRP and TNF-␣ were positively correlated with visfatin in the COPD group. No significant correlations were found between visfatin and body mass index or percentage of body fat in both groups. Conclusion: Plasma visfatin levels increased in patients with COPD. This increased adipocytokine was significantly correlated with TNF-␣ and CRP. Visfatin may be a new proinflammatory adipocytokine in this disease. © 2009 Published by Elsevier Inc.
Keywords:
Visfatin; Systemic inflammation; Chronic obstructive pulmonary disease
Introduction Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease. It is often associated with clinically significant systemic alterations, including malnutrition and continuous systemic inflammation [1]. Patients with COPD with malnutrition always have a lower percentage of body fat (%fat) compared with normal controls. Adipokines, including leptin, ghrelin, resistin, and visfatin,
This work was supported by grant 30500222 from the National Natural Science Foundation of China (F.L.), grant 04GY029-083-1 from the Research Foundation of Science and Technology Bureau of Sichuan Province (F.L.), and grants 06GGYB514SF-030 (Y.J.) and 06GGYB918SF-030 (F.L.) from the Research Foundation of Science and Technology Bureau of Chengdu. Xiaojing Liu and Yulin Ji contributed equally to this study. * Corresponding author. Tel.: ⫹86-28-8181-2355; fax: ⫹86-28-85422788. E-mail address: [email protected] (F. Luo). 0899-9007/09/$ – see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.nut.2008.09.008
are peptides secreted from visceral adipose tissue. Under malnutrition and inflammatory stress, the production of these adipokines may be different from that in normal conditions [2]. Previous studies have indicated that adipose-derived hormones and cytokines play a role in the process of lung diseases [3]. Circulating ghrelin is found to be decreased in patients with COPD [4]. Repeated administration of ghrelin improves body composition, muscle wasting, and functional capacity in cachectic patients with COPD [5]. Visfatin, initially known as pre–B-cell colony– enhancing factor, is one adipokine and affects maturation of B-cell precursors. It also plays critical roles in some inflammation processes, including apoptosis of neutrophils [6] and secretion of interleukin (IL)-8 from human pulmonary artery endothelial cells [7]. Recent studies have shown that the visfatin level is significantly increased in bronchoalveolar lavage fluid and serum of acute lung injury in a mouse model. A few polymorphisms of visfatin gene are associated with increased
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odds of developing acute respiratory distress syndrome and an increased hazard of intensive care unit mortality among at-risk patients [8]. Whether visfatin relates to COPD inflammation is unknown at present. As an adipokine, visfatin correlates with nutritional status in some diseases. Circulating levels of visfatin are associated with parameters of metabolism [9]. Plasma levels of visfatin in patients with previously high visfatin levels have been found to be decreased after gastric banding [10]. In contrast, plasma levels of visfatin are increased in patients with weight loss induced by gastroplastic surgery [11]. Low weight is very common in patients with COPD. Until now, there has been no study on the visfatin level and its relation to nutritional status in patients with COPD. Therefore, this study compared the plasma level of visfatin and inflammation markers, body mass index (BMI), and percentage of body fat (%fat) in patients with COPD and controls.
Materials and methods Patients This study was approved by the medical ethics committee of the West China Hospital, Sichuan University. All subjects signed consent forms. The 35 patients (all men), diagnosed as having COPD according to criteria from the American Thoracic Society, had been clinically stable for at least 3 mo. Patients who had conditions known to affect plasma visfatin, including renal or liver insufficiency, metabolic diseases, and smoking (including current smokers or ex-smokers), were strictly excluded [12,13]. None of the patients were receiving nutritional support therapy or taking any medication at the time of evaluation. Twenty-eight age-matched healthy men who comprised the control group were non-smokers, had no medical illnesses, and had normal physical examinations and laboratory data. Both patient groups had visited the West China Hospital previously. Pulmonary function test Forced vital capacity and forced expiratory volume in 1 s were measured using standard spirometric techniques (MicroLoop; Micro Medical Ltd., Kent, United Kingdom). The reference values employed were those proposed by Zheng and Zhong [14]. Body composition Body composition was estimated using “foot-to-foot” bioelectrical impedance analysis technology (QuickMedical, Snoqualmie, WA, USA) as described previously [4]. While subjects were standing on blocks of solid metal on the machine, light weight, fat mass, fat-free mass, %fat, and BMI were automatically calculated by the machine after age, height,
and gender were entered. A standard calculation model was selected according to the instructions of the manufacturer. Collection of sample After overnight fasting (from 2100 h) blood was collected by venipuncture at 0700 h and centrifuged at 1600 ⫻ g for 15 min at 4°C. The plasma was collected and stored at ⫺70°C. Visfatin assay Visfatin was assayed with a sandwich enzyme-linked immunosorbent assay (ELISA) kit (AdipoGen Inc., Seoul, Korea) as described previously [15] using 100 L of sample. All samples were assayed in duplicate. Tumor necrosis factor-␣ and C-reactive protein assays Plasma tumor necrosis factor-␣ (TNF-␣) was measured using a high-sensitivity ELISA (R&D, Minneapolis, MN, USA) according to the manufacturer’s procedure. C-reactive protein (CRP) in plasma was measured using an ELISA kit (IBL, Hamburg, Germany). The minimum detectable concentrations for TNF-␣ and CRP were 4.4 pg/mL and 1 ng/mL, respectively. All assays were performed in duplicate. Statistical analysis Results are presented as mean ⫾ standard deviation. Differences between groups were statistically analyzed using an unpaired Student’s t test because all data were normally distributed. Correlations were performed using bivariate Pearson’s correlation test. Significance was determined at the 5% level. Data were analyzed with SPSS 10.0 for Windows (SPSS Inc., Chicago, IL, USA).
Results Clinical characteristics of patients with COPD and healthy controls are presented in Table 1. Significantly lower BMI and %fat were found in patients with COPD Table I Patient characteristics*
Age (y) BMI (kg/m2) FFM (kg) Body fat (%weight) FEV1 (%predicted) FVC (%predicted)
COPD (n ⫽ 35)
Control (n ⫽ 28)
P
70 ⫾ 7 18.4 ⫾ 2.3 38.3 ⫾ 4.6 20.0 ⫾ 4.8 59.5 ⫾ 14.9 72.0 ⫾ 16.6
70 ⫾ 7 22.3 ⫾ 3.5 46.2 ⫾ 5.8 28.7 ⫾ 8.3 75.1 ⫾ 8.0 86.1 ⫾ 8.1
0.758 ⬍0.001 ⬍0.001 0.011 ⬍0.001 0.001
BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; FFM, fat-free mass; FVC, forced vital capacity * Values are presented as mean ⫾ SD.
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Fig. 1. Plasma visfatin, TNF-␣, and CRP in patients with COPD and healthy control subjects. **Significant differences between the control and COPD groups (P ⬍ 0.01). COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; TNF-␣, tumor necrosis factor-␣.
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(2.07 ⫾ 0.18 versus 1.88 ⫾ 0.15 ng/mL, P ⬍ 0.001; Fig. 1). Levels of TNF-␣ and CRP, which are markers of system inflammation, were significantly higher in patients with COPD compared with controls (TNF-␣ 24.35 ⫾ 9.99 versus 9.44 ⫾ 5.94 pg/mL, P ⬍ 0.001; CRP 17.46 ⫾ 5.76 versus 4.51 ⫾ 3.01 ng/mL, P ⬍ 0.001; Fig. 1). There was no significant correlation between visfatin and BMI in either group (control r ⫽ 0.083, P ⫽ 0.674; COPD r ⫽ 0.057, P ⫽ 0.744; Fig. 2a,b). Similarly, visfatin level and %fat did not exhibit a significant correlation in the COPD and control groups (control r ⫽ 0.034, P ⫽ 0.863; COPD r ⫽ 0.040, P ⫽ 0.819; Fig. 2c,d). In contrast, the marker of inflammation, plasma CRP, was positively correlated with visfatin level in the COPD group (r ⫽ 0.437, P ⫽ 0.009; Fig. 3b), but not in the control group (r ⫽ 0.018, P ⫽ 0.356; Fig. 3a). Plasma level of TNF-␣ also was positively correlated with visfatin in the COPD group (r ⫽ 0.392, P ⫽ 0.022; Fig. 3d), but not in the control group (r ⫽ 0.151, P ⫽ 0.443; Fig. 3c). Discussion
compared with control subjects. Moderate airflow limitation was found in patients with COPD. The levels of plasma visfatin were significantly higher in the COPD group compared with the healthy control group
In this study, plasma visfatin levels were found to be significantly increased in patients with COPD compared with healthy controls. Levels of TNF-␣ and CRP were
Fig. 2. Correlations of plasma visfatin levels and body mass index in (a) healthy control subjects and (b) patients with chronic obstructive pulmonary disease and percentage of body fat in (c) healthy control subjects and (d) patients with chronic obstructive pulmonary disease. CRP, C-reactive protein; TNF-␣, tumor necrosis factor-␣.
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Fig. 3. Correlations of plasma visfatin levels and C-reactive protein in (a) healthy control subjects and (b) patients with chronic obstructive pulmonary disease and tumor necrosis factor-␣ in (c) healthy control subjects and (d) patients with chronic obstructive pulmonary disease. BMI, body mass index.
higher in the COPD group compared with healthy controls. The levels of these two systemic inflammation markers were positively correlated with the level of plasma visfatin in patients with COPD. No significant correlation was found between plasma visfatin level and BMI or %fat in either group. Because TNF-␣ induces visfatin mRNA expression and visfatin inhibits neutrophil apoptosis, increased visfatin may be the result of COPD inflammation. In turn, it may play a critical role in the development and persistence of inflammation in COPD. There are conflicting results in plasma visfatin levels in patients with obesity or insulin resistance [16 –19]. The circulating visfatin levels were measured by different methods including enzyme immunoassays, radioimmunoassays, and ELISAs [16 –19]. However, Körner et al. [15] reported significant discrepancies between these assays and a very poor correlation. The conflicting results of vasfatin levels in obese or insulin-resistant patients [16 –19] may reflect values obtained using the different assay methods. Therefore, in our present study, we measured the circulating visfatin in patients with COPD with the most reliable method described [15], the ELISA. Evidence is accumulating that inflammation cytokines regulate the production of visfatin. Although Kralisch et al. [20] reported that TNF-␣ decreases visfatin in 3T3-L1 adi-
pocytes, in a more recent study, Hector et al. [21] showed that TNF-␣ stimulation significantly increased the mRNA level of visfatin in cultured human visceral adipose tissue isolated from patients without diabetes mellitus. In addition, other inflammation cytokines and mediators including lipopolysaccharide, IL-1, and IL-6 significantly increased the expression of visfatin 4 h after treatment of an amniotic epithelial cell line [22]. Furthermore, IL-1 induced the expression of visfatin in neutrophils [6]. Although visfatin is produced mainly by visceral adipose tissue, higher visfatin is also found in the serum of patients with lung injury compared with normal controls [23]. In addition to adipose tissue, macrophages, dendritic cells, and colonic epithelial cells of patients with inflammatory bowel disease produce visfatin [24]. As the number of inflammatory cells increases in COPD, the recruited macrophages and dendritic cells may produce visfatin, yielding higher levels in patients with COPD than normal. Consistent with our previous study [4], plasma levels of TNF-␣ and CRP were found to be significantly increased in patients with COPD with mild airflow limitation in this study. These results indicate that the increased level of visfatin in patients with COPD may be the potential result of local or systemic inflammation. Another possible cause of increased visfatin in COPD may be hypoxia. It has been demonstrated that visfatin, a
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new hypoxia-inducible gene, is stimulated by hypoxiainducible factor-1 by direct transcriptional regulation [25]. Hypoxia is very common in patients with COPD due to the airflow limitation and ventilation/perfusion mismatch. During hypoxia, the expression of hypoxia-inducible factor-1, a master regulator of oxygen homeostasis that controls transcriptional responses to hypoxia, increases significantly [26]. Thus, we hypothesize that hypoxia may contribute to the increased plasma visfatin level in patients with COPD. Increased visfatin levels were also found in other chronic diseases including rheumatoid arthritis [27] and chronic kidney diseases [12]. Although visfatin levels correlated with inflammation cytokines or mediators in those patients, the role of visfatin remains unclear. The physiologic role of increasing visfatin in COPD also remains unclear. Neutrophilic airway inflammation is a prominent feature of COPD. Increased neutrophil infiltration in the COPD lung may occur by the reduction of spontaneous neutrophil apoptosis and by the recruitment of neutrophils from the circulation [28]. Because visfatin inhibits the apoptosis of neutrophils, elevated visfatin levels may promote the survival of neutrophils in COPD. In addition, recombinant visfatin activates human leukocytes and induces the production of IL1, TNF-␣, and IL-6. Visfatin also increases the expression of intercellular adhesion molecules and other costimulatory molecules in neutrophils [24]. Therefore, systemic or local inflammation may increase visfatin expression. At the same time, increased visfatin may promote the inflammatory processes in COPD. Visfatin is not only a new inflammation marker but also a possibly important proinflammatory adipocytokine in COPD. Because visfatin expression has been found in several different tissues [29,30] and the expression of visfatin is determined by different factors [11,12], it is not surprising that no correlation was found between plasma visfatin and %fat in either group in our study. Further study should be performed to investigate the main source of circulating visfatin in patients with COPD.
Summary Plasma visfatin level was increased in patients with COPD. Visfatin may be a new proinflammatory adipocytokine in this disease. Increased visfatin does not correlate with BMI and %fat in patients with COPD.
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