Yonago Acta medica 2002;45:49–57

Kinetics of the Levels of Pro- and Anti-Inflammatory Cytokines and
Vascular Endothelial Growth Factor in Serum and Pleural Fluid after
Major Lung Resection for Lung Cancer
Yuji Taniguchi
Division of Organ Regeneration Surgery, Department of Surgery, School of Medicine,
Tottori University, 683-8504 Japan
Some pro- and anti-inflammatory cytokines and angiogenesis-related factors play important roles in the inflammatory response after surgery. To study their kinetics andmutual relationships after major lung resection for lung cancer, concentrations ofinterleukin (IL)-6, -8 and -10 and vascular endothelial growth factor (VEGF) were
measured in serum and pleural fluid. Venous blood and pleural fluid samples werecollected before and up until 5 days after surgery from 10 patients with lung cancer,
treated by standard lobectomy at Tottori University Hospital between 1997 and 1999.
Cytokine levels after surgery were significantly higher than control levels before surgery
in serum and pleural fluid. In pleural fluid, cytokines and VEGF increased after surgery
10 to 100 times than in serum. IL-6 and -10 reached their peaks in pleural fluid later
than in serum, and then gradually decreased. Serum IL-8 reached its peak at 3 h,
decreased until day 2 and then remained stable. Serum VEGF decreased until 3 h, andthen showed little change. Pleural fluid IL-8 and VEGF reached their peaks at 3 or 6 h,
decreased until day 2 and then increased up to day 5. The amount of cytokines produced
per hour in drainage pleural fluid showed nearly the same kinetics as serum cytokines.
Serum cytokines and VEGF showed higher coefficient values to the hourly productionin pleural fluid than to the pleural fluid levels. During wound healing, IL-8 acted as apro-inflammatory cytokine in the early phase, but as an angiogenic factor like VEGF
in the late proliferative phase. The cytokine production per hour in pleural fluid isbelieved to be a useful marker of cytokine levels for evaluating surgical trauma after
major lung resection for lung cancer.
Key words: cytokine; cytokine production per hour (hourly production of cytokine); lung cancer;
vascular endothelial growth factor; wound healing

Interleukin (IL)-6 and IL-8 are known as proinflammatory cytokines, and IL-10 as an antiinflammatory cytokine. There have been many
reports about the kinetics of pro- and antiinflammatory cytokine levels after surgery, including thoracic procedures (Steinberg et al.,
1993; Sakamoto et al., 1994; Kawahito et al.,
1995; Waller et al., 1996; Atwell et al., 1998;
Liebold et al., 1999; Weissflog et al., 1999). However, most reports have described serum levelsof cytokines, and few have reported their pleu-

ral fluid levels (Sakamoto et al., 1994; Weissflog
et al., 1999). Thus, we thought it would be interesting to investigate the relationship of cytokine
levels between serum and pleural fluid. In addition, vascular endothelial growth factor (VEGF)
known as an important angiogenic factor(Fontanini et al., 1997; Inoue et al., 1997), hasrecently been demonstrated as acting together
with pro- and anti-inflammatory cytokines(Ishimura et al., 1998; Nissen et al., 1998; Sato etal., 1999). In the present study, to clarify whe-

Abbreviations: IL, interleukin; VEGF, vascular endothelial growth factor

49

Y. Taniguchi

ther IL-6, IL-8, IL-10 and VEGF are associatedafter surgery for lung cancer, the kinetics of thelevels of IL-6, IL-8, IL-10 and VEGF in both serum and pleural fluid were investigated.

mL. There were no severe postoperative complications such as respiratory failure, pneumonia, liver dysfunction or renal failure in thesepatients.
Blood and pleural fluid collection

Materials and Methods

Samples of venous blood were collected immediately after induction of anesthesia, and served
as controls. Samples of pleural fluid were collected by intrathoracic lavage with 50 mL ofphysiological saline just after thoracotomy, andused to determine the preoperative control dataof pleural fluid.
The other samples of serum and pleural
fluid were simultaneously collected at 3 and 6 h
and on days 1, 2, 3 and 5 after surgery. On days
1, 2, 3 and 5, the samples were collected 9:00 in
the morning. All samples were centrifuged immediately at 2,500 rpm for 15 min at 4˚C. Centrifuged samples were stored at –30˚C until the
assays were performed.

Patients
The subjects were recruited from non-small celllung cancer patients who underwent standard
lobectomy by posterolateral thoracotomy withmediastinal nodal dissection in Tottori University Hospital between October 1997 and June
1999. We applied the following exclusion criteria for patient selection: i) incomplete resection, because the residual tumor has the potential to affect the cytokine levels (Matsuguchi etal., 1991; Yamamoto et al., 1996); ii) extended
resection of the chest wall, diaphragm or mediastinum, because different degrees of surgicaltrauma have the potential to affect the cytokine
levels (Sakamoto et al., 1994); iii) administration of perioperative ulinastatin or corticosteroid, because these agents influence cytokine
release (Teoh et al., 1995; Kawamura et al.,1996) and iv) complication by pulmonary fibrosis, because this condition has the potential toaffect the IL-8 level (Keane et al., 1997).
A total of 10 patients were examined in thisstudy. They ranged in age from 49 to 76 years(mean, 64.3 years), consisting of 5 males and 5
females. Histologically, 3 patients sufferedwith squamous cell carcinomas, 6 patients withadenocarcinomas and 1 patient with mucoepidermoid carcinoma. Seven patients were inStage I, one was in Stage II and two were inStage III. All patients gave written informed
consent. After tracheal intubation (double
lumen endotracheal tube), general anesthesia
was applied in combination with a thoracic
epidural anesthesia in all patients. The thoracic
epidural catheter was used for postoperative
analgesia. Two thoracic tubes were indwelled
in all patients, and the pleural fluid was constantly aspirated with –10 cmH 2O pressure.
The duration of the surgery was 304.9 ± 13.3
min and the bleeding volume was 181.3 ± 57.3

Cytokine assays
IL-6, IL-8, IL-10 and VEGF concentrations
were measured using commercial enzymelinked immunosorbent assay kits (Genzyme,
Cambridge, MA for IL-6 and IL-10; Endogen,
Woburn, MA for IL-8; Techne, Minneapolis,
MN for VEGF).
Statistical analysis
Statistical analysis was performed with StatView 5.0 J software (Abacus, Concepts, Inc.,
Berkeley, CA). Differences in the kinetics ofcytokine and VEGF levels were analyzed using
Friedman’s test and Wilcoxon’s signed rank
test. Correlations between the serum and pleural fluid levels of cytokines and VEGF wereanalyzed using Spearman’s test. Results are expressed as mean ± SEM. P values of < 0.05
were considered significant.

50

Cytokines and VEGF after lung resection(pg/mL)IL-6 concentration in serum

800

**
600

A
**

400

**
**

200

**
0

Control

3h

6h

1

2

3

Results**
5 (day)Kinetics of serum cytokine and
VEGF levels

IL-8 concentration in serum(pg/mL)

**
50

B
**
**
**

25

0

Control

3h

6h

**

**

1

2

*

**

3

5 (day)IL-10 concentration in serum(pg/mL)

**
10

**

**
*

5

0

VEGF concentration in serum

C

15

Serum levels of cytokines after surgery(Figs. 1A–C) were significantly higher
than control levels throughout. IL-6 (Fig.
1A) and IL-10 (Fig. 1C) reached theirpeaks at 3 h (IL-6: 626.8 ± 63.0 pg/mL,
IL-10: 15.9 ± 1.6 pg/mL) and gradually
declined with time. Serum IL-8 (Fig.
1B) showed its peak at 3 h (47.5 ± 12.0
pg/mL), declined until day 2 and then remained stable. However, serum VEGF
levels (Fig. 1D) decreased until 3 h, followed by little change.

Control

3h

6h

1

2

3

5 (day)(pg/mL)400

D300

Figs. 1A–D. Kinetics of serum levels of cytokines and VEGF measured before and after
lung resection. *P < 0.05 and **P < 0.01
compared with the preoperative control level.
The data are presented as mean ± SEM. IL,
interleukin; VEGF, vascular endothelial
growth factor.

200

100

0

Control

3h

6h

1

2

3

5 (day)After surgery

51

Y. Taniguchi

IL-6 concentration inpleural fluid(× 103 pg/mL)
200

**

A

150

**
**

**

Kinetics of drainage fluid cytokine and VEGF levels

100

**
50

**
0
Control(× 103 pg/mL)
30

3h

6h

1

2

3

5

(day)

IL-8 concentration inpleural fluid

**

B

**

**
**

20

10

**
**

0
Control

3hIL-10 concentration inpleural fluid(× 103 pg/mL)
0.6

6h

**

1

2

3

5

(day)

Pleural fluid levels of cytokines and
VEGF (Figs. 2A–D) after surgery weresignificantly higher than control levels
throughout. IL-6 and IL-8 were about
100-fold and IL-10 and VEGF wereabout 10-fold higher in concentration
than in serum. Concerning level changes,
IL-6 (Fig. 2A) and IL-10 (Fig. 2C) reached their peaks (IL-6: 177,000 ± 30,600
pg/mL, IL-10: 481.0 ± 91.8 pg/mL) 6 h
or 1 day after surgery, later than in thepatterns seen in serum. In pleural fluid,
however, IL-8 (Fig. 2B) and VEGF
(Fig. 2D) levels showed their peaks inthe early phases, at 3 or 6 h (IL-8:
19,700 ± 5030 pg/mL, VEGF: 1838 ±

**

C
0.4

**
**

0.2

**
0

Control

3h

6h

1

2

3

**
5

(day)

(× 103 pg/mL)**
VEGF concentration inpleural fluid

2.0

**

D

**

**

1.5

**
**

1.0

0.5

0
Control

3h

6h

1

2

3

5

After surgery

52

(day)

Figs. 2A–D. Kinetics of pleural fluid levelsof cytokines and VEGF measured before
and after lung resection. *P < 0.05 and **P< 0.01 compared with the preoperative control level. The data are presented as mean ±SEM. IL, interleukin; VEGF, vascularendothelial growth factor.

Cytokines and VEGF after lung resection

Hourly IL-6 productionin pleural fluid(× 103 pg/h)
7500

A

**

**

5000

**
2500

**
**

0

**
Control

1500

6h

1

2

3

5

**

**

3

5

2

3

5

**

**

**

2

3

5

(day)

**

B

1000

**
500

**
0
Control(× 103 pg/h)

Hourly IL-10 productionin pleural fluid

182 pg/mL), decreased until day 2 (IL8: 2286 ± 787 pg/mL, VEGF: 980 ±223 pg/mL) and elevated again during
the late phase up to day 5 (IL-8: 14,900± 9580 pg/mL, VEGF: 1553 ± 261 pg/mL). When the amount of cytokines
produced per hour (hourly production)in pleural fluid was calculated by multiplying the concentration by drainage
volume per hour, the hourly cytokine
production in pleural fluid (Figs. 3A–C) showed nearly the same kinetics asserum concentration kinetics (Figs.
1A–C).

Hourly IL-8 productionin pleural fluid(× 103 pg/h)

3h

20

3h

6h

1

**
2

(day)

**

C
**

15

**

10
5

*
0

*
Control

3h

6h

1

(day)

(× 103 pg/h)Figs. 3A–D. Kinetics of hourly productionin pleural fluid of cytokines and VEGF
measured before and after lung resection.
*P < 0.05 and **P < 0.01 compared withthe preoperative control level. The data arepresented as mean ± SEM. IL, interleukin;
VEGF, vascular endothelial growth factor.

Hourly VEGF productionin pleural fluid

**
75

D
**

50

**
25

0

Control3h6h1After surgery

53

(day)

Y. Taniguchi

Relationships of cytokine and
VEGF levels between serumand pleural fluidA

IL-6 concentration in serum(pg/mL)n = 60r = 0.777
P < 0.0001

1000
750
500
250

(× 103 pg/h)
00BIL-8 concentration in serum(pg/mL)150

n = 60r = 0.550
P < 0.0001

100

Discussion

50(× 103 pg/h)00IL-10 concentration in serum(pg/mL)C

4000

n = 60r = 0.580
P < 0.0001

20

10(× 103 pg/h)
0(pg/mL)VEGF concentration in serum

2000

Hourly IL-8 production in pleural fluid

30

0

D

20,00010,000Hourly IL-6 production in pleural fluid

All factors showed significant correlations between serum levels andhourly productions in pleural fluid(IL-6: r = 0.777, IL-8: r = 0.550,
IL-10: r = 0.580, VEGF: r = 0.264)(Figs. 4A–D). These values of coefficients were higher than thosebetween serum levels and pleural
fluid levels for all factors (IL-6: r =0.517, IL-8: r = 0.494, IL-10: r =0.564, VEGF: r = 0.235).

25

50

Hourly IL-10 production in pleural fluidn = 60r = 0.264
P < 0.05

500

Various cytokines with a wide
range of biological activities play
the role of controlling inflammatory
and immunological reactions to surgical trauma. In the present study,
the concentrations of cytokines inpleural fluid were about 100-foldgreater than those in serum. Previous researchers also reported that
the IL-6 and IL-8 levels in thoracic
drainage fluid were about 100- to
1000-fold greater than those in peripheral blood (Sakamoto et al.,
1994; Krohn et al., 1998). Therefore, it is very clear that the cytokine
response is much stronger in the local pleural cavity than in the systemic blood.

250(× 103 pg/h)
0
0

50

100

150

Hourly VEGF production in pleural fluid

54

Figs. 4A–D. Relationships between
serum levels and hourly productions inpleural fluid studied for cytokines and
VEGF. IL, interleukin; VEGF, vascularendothelial growth factor.

Cytokines and VEGF after lung resection

In our present study, the kinetics of cytokine
levels in serum and pleural fluid showed significant correlations. In particular, the correlation between the hourly cytokine production inpleural fluid and the serum cytokine level was
higher than that between the pleural fluid
cytokine level and the serum cytokine level.
Sakamoto et al. (1994) reported that the messenger RNAs of cytokines could not be detectedin leukocytes from the peripheral blood but
could be demonstrated in leukocytes fromdrainage fluid: they suggested that cytokines
are induced and secreted mainly in the surgicalfield and simultaneously appear in the bloodstream. Asadullah et al. (1995) reported datafrom neurosurgery supporting this hypothesis.
Regarding the mechanism of this effect, weconsider it possible that pleural cytokines spillover into the peripheral blood through pleuralabsorption. Therefore, when the concentrationsof cytokines in pleural fluid are markedly higher than serum cytokine levels, such as after thoracic surgery, serum cytokine levels are strongly influenced by the amount of cytokines produced per hour in pleural fluid. Pleural fluid
can be collected because the thoracic tube is always indwelled after thoracic surgery. Thus,
the hourly production of cytokines in pleural
fluid appears to be a new useful marker of cytokine levels for evaluating the degree of trauma
caused by thoracic procedures.
IL-8 is a pro-inflammatory cytokine and has
a potent chemoattractant activity for neutrophils (Baggiolini et al., 1989). Recent studies
have shown that the serum IL-8 level peaked
within 24 h after surgery and decreased thereafter (Sakamoto et al., 1994; Atwell et al., 1998;
Liebold et al., 1999). However, few studies
have examined the kinetics of IL-8 later than 3days after surgery, particularly after major lungsurgery. In the present study, the kinetics of the
IL-8 level in pleural fluid showed 2 significant
peaks postoperatively, at 3 or 6 h and again on
day 5. Until day 2 after surgery, IL-8 functioned as a pro-inflammatory cytokine. However, re-elevation of IL-8 later than day 3 did
not necessarily indicate its function as a proinflammatory cytokine at that time. Koch et al.
(1992) reported that IL-8 has another function;

it induces neovascularization without inflammation. During wound healing, the period until
day 3 after surgery corresponds to an inflammatory phase, while the period later than day 3
corresponds to a proliferative phase (Fine andMustoe, 1997) during which angiogenesis occurs
at the wound site (Adzick, 1997). Grad et al.
(1998) reported that, in multiple trauma patients, serum VEGF was elevated from day 3
after injury. Angiogenesis-related factors suchas VEGF are induced in hypoxia (Shweiki et al.,
1992; Steinbrech et al., 1999). Hangai (1996)
reported that the tissue oxygen tension at theanastomosis site reached its lowest level on day
3 after tracheoplasty. Therefore, this condition
may re-elevate VEGF levels after day 3. Because both IL-8 and VEGF showed the same kinetics in pleural fluid, we figured that the function of IL-8 later than day 3 after surgery could
act as an angiogenic factor rather than as a proinflammatory cytokine.
In the present study, IL-8 and VEGF were
produced at high levels in pleural fluid after
lung surgery. Angiogenesis is required for thegrowth and metastasis of solid tumors (Folkman
et al., 1989; Bicknell and Harris, 1991; Imoto etal., 1998), and anti-IL-8 and anti-VEGF therapy
can inhibit both primary tumor growth andmetastasis (Asano et al., 1995; Warren et al.,
1995; Arenberg et al., 1996; Rowe et al., 2000).
Moreover, the inflammatory cytokine level inserum was reported to be higher after lobectomy of the lung than by gastrectomy and colorectal resection (Sakamoto et al., 1994). Proinflammatory cytokines such as IL-6 and IL-8
stimulate VEGF expression (Hanahan and
Folkman, 1996; Risau, 1997). It has been reported that excess surgical stress from thoracotomy facilitates metastasis (Hattori et al., 1980;
Hirai et al., 1997). Furthermore, Gabrilovich etal. (1996) recently reported that in vivo VEGF
can inhibit the functional maturation of dendritic cells which play a critical role in antitumor
immune responses. Based on the above, lobectomy by standard thoracotomy for lung cancer
may likely induce proliferation and metastasisof the tumor not only due to angiogenesis but
also to tumor immunity because VEGF wasproduced at high levels after lung resection.
55

Y. Taniguchi

Liebenthal C, Wauer H, Kox W, et al. Immunodepression following neurosurgical procedures.
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Kuwahara M, Toge T. Enhancing effect ofthoraco-laparotomy on liver metastasis and the

Our study examined only a small number ofpatients who underwent elective surgery forlung cancer. Also, because none of our patients
had severe postoperative complications, ourfindings only reflected normal cytokine kinetics
after major lung resection for lung cancer.
Therefore, further studies are needed to investigate whether our findings are applicable towedge resection, to lobectomy under videoassisted thoracic surgery regarded as minimallyinvasive for lung cancer, to extended procedures such as pneumonectomy and combined
resection of other involved organs for primarylung cancer, and to lung surgery for conditions
other than malignancy. If the cytokine cascade
producing the pro- and anti-inflammatory andangiogenic reactions were balanced, normal
healing after surgical trauma could be achieved.
However, overexpression of angiogenic factors
such as IL-8 and VEGF might promote recurrence or metastasis of cancer cells. Therefore,studies of cytokine kinetics will facilitate understanding of the normal biological response
and provide reference information for optimal
perioperative patient management.

Acknowledgments: The author would like to thankProfessor Yasuaki Kawai of the Division of Adaptation
Physiology, Department of Functional, Morphological and Regulation Science, Professor Shigetsugu
Ohgi of the Division of Organ Regeneration Surgery,
Department of Surgery and Professor Eiji Shimizu
of the Division of Internal Medicine and Molecular
Therapeutics, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University for their kind advice and valuable suggestions
concerning this study.
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Received April 19, 2002; accepted May 13, 2002
Corresponding author: Dr. Yuji Taniguchi

57