Serum vascular endothelial growth factor and angiopoietin-2 are associated with the severity of systemic inflammation rather than the presence of hemoptysis in patients with inflammatory lung disease.

Abstract

Vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) are major mediators of angiogenesis and are induced by tissue inflammation and hypoxia. The purpose of this study was to investigate whether serum VEGF and Ang-2 are associated with the presence of hemoptysis and the extent of systemic inflammation in patients with inflammatory lung diseases.
We prospectively enrolled 52 patients with inflammatory lung disease between June 2008 and October 2009.
The median values of VEGF and Ang-2 were 436 pg/mL and 2383 pg/mL, respectively. There was a significant positive correlation between serum Ang-2 and VEGF levels. VEGF levels were not significantly different according to the presence of hemoptysis. C-reactive protein (CRP) and Ang-2 level were significantly higher in patients without hemoptysis (n=26) than in those with hemoptysis (n=26; p<0.001 and p<0.001, respectively). CRP and arterial oxygen tension (PaO₂) were significantly correlated with both serum VEGF (p=0.032 and p=0.016, respectively) and Ang-2 levels (p<0.001 and p=0.041, respectively), after adjusting for other factors. Age and the absence of hemoptysis were factors correlated with serum Ang-2 levels.
Our study suggests that serum VEGF and Ang-2 levels are associated with PaO₂ and the severity of inflammation rather than the presence of hemoptysis in patients with inflammatory lung diseases. Thus, hemoptysis may not be mediated by increased serum levels of VEGF and Ang-2 in patients with inflammatory lung diseases, and further studies are required to determine the mechanisms of hemoptysis.

Full text

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Yonsei Med J http://www.eymj.org Volume 53 Number 2 March 2012
369
Original Article
http://dx.doi.org/10.3349/ymj.2012.53.2.369
pISSN: 0513-5796, eISSN: 1976-2437
Yonsei Med J 53(2):369-376, 2012
Serum Vascular Endothelial Growth Factor and Angiopoietin-2
Are Associated with the Severity of Systemic Inflammation
Rather than the Presence of Hemoptysis in Patients with
Inflammatory Lung Disease
Hye Yun Park, Cho Rom Hahm, Kyeongman Jeon, Won-Jung Koh, Gee Young Suh,
Man Pyo Chung, Hojoong Kim, O Jung Kwon, and Sang-Won Um
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Korea.
Received: April 25, 2011
Revised: June 3, 2011
Accepted: June 9, 2011
Corresponding author: Dr. Sang-Won Um,
Division of Pulmonary and Critical Care
Medicine, Department of Medicine,
Samsung Medical Center, Sungkyunkwan
University School of Medicine,
50 Irwon-Dong, Gangnam-gu,
Seoul 135-710, Korea.
Tel: 82-2-3410-3429, Fax: 82-2-3410-6956
E-mail: sangwonum@skku.edu
∙ The authors have no financial conflicts of
interest.
© Copyright:
Yonsei University College of Medicine 2012
This is an Open Access article distributed under the
terms of the Creative Commons Attribution Non-
Commercial License (http://creativecommons.org/
licenses/by-nc/3.0) which permits unrestricted non-
commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Purpose: Vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2)
are major mediators of angiogenesis and are induced by tissue inflammation and
hypoxia. The purpose of this study was to investigate whether serum VEGF and
Ang-2 are associated with the presence of hemoptysis and the extent of systemic
inflammation in patients with inflammatory lung diseases. Materials and Meth-
ods: We prospectively enrolled 52 patients with inflammatory lung disease be-
tween June 2008 and October 2009. Results: The median values of VEGF and
Ang-2 were 436 pg/mL and 2383 pg/mL, respectively. There was a significant
positive correlation between serum Ang-2 and VEGF levels. VEGF levels were
not significantly different according to the presence of hemoptysis. C-reactive pro-
tein (CRP) and Ang-2 level were significantly higher in patients without hemopty-
sis (n=26) than in those with hemoptysis (n=26; p<0.001 and p<0.001, respective-
ly). CRP and arterial oxygen tension (PaO2) were significantly correlated with both
serum VEGF (p=0.032 and p=0.016, respectively) and Ang-2 levels (p<0.001 and
p=0.041, respectively), after adjusting for other factors. Age and the absence of he-
moptysis were factors correlated with serum Ang-2 levels. Conclusion: Our study
suggests that serum VEGF and Ang-2 levels are associated with PaO2 and the se-
verity of inflammation rather than the presence of hemoptysis in patients with in-
flammatory lung diseases. Thus, hemoptysis may not be mediated by increased se-
rum levels of VEGF and Ang-2 in patients with inflammatory lung diseases, and
further studies are required to determine the mechanisms of hemoptysis.
Key Words: Angiogenesis, angiopoietin-2, hemoptysis, inflammation, vascular
endothelial growth factor
INTRODUCTION
Angiogenesis is characterized by the formation of new microvessels from preex-

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Patients with hemoptysis (hemoptysis group) were enrolled
if they had hemoptysis within 2 weeks before study enroll-
ment, and the patients without hemoptysis (no hemoptysis
group) were enrolled if they did not have any hemoptysis
more than 2 years before study enrollment. All study pa-
tients except one were admitted to general ward or emer-
gency department for the management of symptomatic be-
nign lung diseases. We excluded patients with neoplastic
conditions, including lung cancer, vasculitis, and lung dis-
ease associated with collagen vascular disease. Serum sam-
ples for VEGF and Ang-2, clinical data, such as age, gen-
der, smoking status, clinical symptoms, and laboratory data,
including peripheral white blood cell (WBC) count, hemo-
globin (Hb), prothrombin time (PT), C-reactive protein
(CRP), and arterial oxygen tension (PaO2), were obtained at
study enrollment.
Determination of sample size
The required sample size was calculated based on VEGF
levels according to the presence of hemoptysis in patients
with asperilloma.6 Assuming 437±164 pg/mL of VEGF in
the hemoptysis group and 162±102 pg/mL in the no he-
moptysis group, a sample size of 42 patients (21 per group)
was required to detect a 120 pg/mL difference between the
two groups with a power of 90% and α error of 0.05 using a
two-tailed test.17 Anticipating a potential 20% drop-out rate,
we planned to include 52 subjects (26 per group).
Measurement of VEGF and Ang-2
Serum samples from each individual were obtained at the
time of study enrollment. Sera were stored at -80°C. Serum
VEGF and Ang-2 concentrations were measured in tripli-
cate for each sample using a commercial enzyme-linked
immunosorbent assay (ELISA) kit (R&D Systems, Minne-
apolis, MN, USA). The detection ranges of ELISA kits for
VEGF and Ang-2 were 31.2-2000 pg/mL and 46.9-3000
pg/mL, respectively. Therefore, serum was diluted to mea-
sure serum Ang-2 levels.
Statistical analysis
Data presented are expressed as either the median and in-
terquartile range (IQR, 25th and 75th percentiles) or the
number (percentage) of patients. For univariate analysis or
relation with hemoptysis, categorical variables were ana-
lyzed using a Pearson χ2 test or Fisher’s exact test; continu-
ous variables were analyzed using a Mann-Whitney U test.
VEGF and Ang-2 levels did not fit normality assumptions;
isting vasculature and is associated with numerous inflam-
matory conditions, such as atherosclerosis, arthritis, reti-
nopathy, and tumor growth.1 Previous studies provided
evidence that inflammation exists in a mutually dependent
association with angiogenesis.2,3
Among the numerous angiogenic factors, vascular endo-
thelial growth factor (VEGF) is the most extensively stud-
ied and is significantly related to the severity of inflamma-
tory lung diseases, such as active tuberculosis, chronic
bronchitis, pulmonary aspergilloma, and pulmonary disease
caused by cystic fibrosis.4-7 Overexpression of VEGF is
also significantly correlated with lung cancer progression
and metastasis. Antiangiogenic agents have received wide-
spread attention as targets for lung cancer therapy.8,9 Recent
studies reported that VEGF elevation correlates significant-
ly with the presence of hemoptysis in patients with pulmo-
nary aspergilloma.6 Another major factor involved in angio-
genesis, angiopoietin-2 (Ang-2), is also induced by
hypoxemia10 and plays an important role in initiating vessel
sprouting in concert with VEGF.11,12 In contrast with angio-
poietin-1, which stabilizes blood vessels, Ang-2 destabiliz-
es blood vessels, initiating angiogenic changes instead of
regression, and promotes the neovascularization of tumor
cells.13-16
The purpose of this study was to investigate whether se-
rum VEGF and Ang-2 were associated with the presence of
hemoptysis and the level of systemic inflammation in pa-
tients with inflammatory lung diseases.
MATERIALS AND METHODS
　　　
Study population
The study was approved by the Institutional Review Board
of Samsung Medical Center (a 2600-bed University affiliat-
ed hospital in Seoul, Korea) and was registered with www.
clinicaltrials.gov (NCT01171768). Informed written con-
sent was obtained from all participants.
Patients presented to the Samsung Medical Center for the
treatment of benign inflammatory lung diseases, including
bronchiectasis, aspergilloma, pneumonia, and post-tubercu-
losis destroyed lung, between June 2008 and December
2009. Diagnosis of post-tuberculosis destroyed lung (inactive
tuberculosis) was considered when chest computed tomogra-
phy (CT) scan showed the findings compatible with fibrotic
sequelae of old tuberculosis and all mycobacterial examina-
tions of sputum or bronchial washing fluid were negative.

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Correlation between serum VEGF or angiopoietin-2
and other parameters
The median VEGF levels were 375 pg/mL in bronchiecta-
sis, 472 pg/mL in aspergilloma, 554 pg/mL in post-tubercu-
losis destroyed lung, and 451 pg/mL in pneumonia. The
median Ang-2 levels were 2444 pg/mL in bronchiectasis,
1689 pg/mL in aspergilloma, 3021 pg/mL in post-tubercu-
losis destroyed lung, and 4344 pg/mL in pneumonia.
Serum Ang-2 levels were significantly correlated with se-
rum VEGF levels (p=0.028) (Fig. 1). Serum VEGF levels
demonstrated a significant positive correlation with WBC
and a negative correlation with PaO2 levels (Table 3). Age,
gender, smoking status, presence of hemoptysis, and CRP
levels showed no significant correlation with VEGF levels
thus, log-transformed VEGF and Ang-2 (ln VEGF and ln
Ang-2) values were used in analyses. As the VEGF and
Ang-2 levels were measured in triplicate from single pa-
tient samples, a mixed model was used to analyze associa-
tions between parameters. Additionally, to take random ef-
fects between subjects into account, we used the ‘random
statement’ function in PROC MIXED. All p values are two-
sided with p<0.05 considered to indicate statistical signifi-
cance. Statistical analyses were performed using the SAS
software (ver. 9.1; SAS Institute, Cary, NC, USA).

RESULTS

Baseline clinical and laboratory features
Characteristics of the enrolled patients are listed in Table 1.
In this study, 52 study patients underwent extensive evalua-
tions for underlying disease including chest CT scan (n=
46), bronchoscopy (n=21), and sputum bacterial and myco-
bacterial examinations (n=44). There were 25 men and 27
women, with a median age of 58 years (range, 47-66). Of
the 52 patients, 14 patients (27%) had a history of smoking,
and 22 (42%) had a history of tuberculosis treatment. The
most common disease in enrolled patients was bronchiecta-
sis (62%); 14% had an aspergilloma, and 14% had post-tu-
berculosis destroyed lung. Median VEGF and Ang-2 levels
were 436 pg/mL (257-724) and 2383 pg/mL (1807-3209),
respectively. In total, 5 patients received oxygen therapy
(1-2 L/min) on arterial blood gas analysis.
Comparison of clinical laboratory features depending
on the presence of hemoptysis
In patients with hemoptysis (n=26), bronchiectasis (54%),
aspergilloma (27%), and post-tuberculosis destroyed lung
(19%) were observed. In those without hemoptysis (n=26),
bronchiectasis (69%), post-tuberculosis destroyed lung
(8%), pneumonia (19%), and pulmonary tuberculosis (4%)
were observed. Patients with hemoptysis had more signifi-
cant history of tuberculosis treatment compared with those
without hemoptysis. However, the median CRP and Ang-2
levels were significantly higher in patients without hemop-
tysis than in those with hemoptysis (CRP; 0.34 vs. 3.29
mg/dL; p<0.001, and Ang-2; 2017 vs. 2946 pg/mL;
p<0.001). There was no significant difference in age, gen-
der, smoking history, presenting symptoms, or laboratory
findings (including WBC, Hb, PT, PaO2, serum VEGF lev-
els) (Table 2).
Table 1. Baseline Characteristics of Enrolled Patients (n=52)
Median (IQR) or No. (%)
58 (47-66)Age
Sex
Female
Male
Smoking status
Current smoker
Ex-smoker
Non-smoker
Comorbidities
Hypertension
Diabetes mellitus
Prior therapy for tuberculosis
Lung Diseases
Bronchiectasis
Aspergilloma
Post-tuberculosis destroyed lung
Pneumonia without bronchiectasis
Pulmonary tuberculosis
Presenting symptoms
Cough
Dyspnea
Fever
Laboratory findings
WBC (#/μL)
Hemoglobin (g/dL)
PT (INR)
CRP (mg/dL)
PaO2 (mm Hg)
VEGF (pg/mL)
Ang-2 (pg/mL)
WBC, white blood cell; PT, prothrombin time; CRP, C-reactive protein;
VEGF, vascular endothelial growth factor; Ang-2, angiopoietin-2; IQR, in-
terquartile range; INR, international normalized ratio; PaO2, arterial oxygen
tension.
25 (48%)
27 (52%)
2 (4%)
12 (23%)
38 (73%)
8 (15%)
2 (4%)
22 (42%)
32 (62%)
7 (14%)
7 (14%)
5 (10%)
1 (2%)
36 (69%)
15 (29%)
7 (13%)
8035 (6257-10533)
12.5 (11.3-14.0)
1.05 (0.99-1.13)
1.13 (0.24-4.13)
81.7 (66.1-90.5)
436 (257-724)
2383 (1807-3209)

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of hemoptysis were significantly correlated with serum
Ang-2 levels (Table 4).
DISCUSSION
In the present study, serum VEGF levels did not differ ac-
cording to the presence of hemoptysis. However, we dem-
onstrated that serum VEGF and Ang-2 levels in patients
with inflammatory lung diseases correlated significantly
with elevations in serum CRP and reduction of PaO2.
(Table 3). Ang-2 levels showed significantly positive corre-
lations with age, WBC, and CRP levels, while demonstrat-
ing a negative correlation with PaO2 levels (Table 3).
Multivariate analysis using PROC MIXED for repeated
measures data was performed to identify factors significant-
ly correlated with serum VEGF or Ang-2 levels. CRP lev-
els and PaO2 were found to be significant correlated with
both serum VEGF (p=0.032 and p=0.016, respectively) and
Ang-2 levels (p<0.001 and p=0.041, respectively) after ad-
justing for other factors (age, gender, smoking history, and
the presence of hemoptysis) (Table 4). Age and the absence
Table 2. Comparison of Clinical Laboratory Features according to the Presence of Hemoptysis
With hemoptysis (n=26)
Age 56 (47-65)
Sex
Female 11 (42%)
Male 15 (58%)
Smoking status
Current smoker 2 (8%)
Ex-smoker 7 (27%)
Non-smoker 17 (65%)
Comorbidities
Hypertension 6 (23%)
Diabetes mellitus 1 (4%)
Prior therapy for tuberculosis 15 (58%)
Lung diseases
Bronchiectasis 14 (54%)
Aspergilloma 7 (27%)
Post-tuberculosis destroyed lung 5 (19%)
Pneumonia 0
Pulmonary tuberculosis 0
Severity of diseases
No. of involved lobes 2 (1-3)
Presenting Symptoms
Cough 16 (62%)
Dyspnea 6 (23%)
Fever 2 (8%)
Laboratory findings
WBC (#/μL) 7645 (6353-9695)
Hemoglobin (g/dL) 13 (11-14)
Platelet (×103/μL) 216 (186-260)
PT (INR) 1.06 (1.01-1.14)
aPTT (sec) 36 (31-38)
CRP (mg/dL) 0.34 (0.13-2.09)
PaO2 (mm Hg) 83.5 (75.1-94.2)
VEGF* 389 (270-684)
Ang-2* 2017 (1633-2597)
WBC, white blood cell; PT, prothrombin time; aPTT, activated partial thromboplastin time; CRP, C-reactive protein; VEGF, vascular endothelial growth factor;
Ang-2, angiopoietin-2; INR, international normalized ratio; PaO2, arterial oxygen tension.
*The analysis used a mixed model, accounting for the random effect between subjects (logarithmic transformed VEGF and Ang-2 values were used).
Without hemoptysis (n=26)
60 (48-66)
p value
0.826
0.405
14 (54%)
12 (46%)
0.252
0
5 (19%)
21 (81%)
2 (8%)
1 (4%)
7 (27%)
0.248
1.000
0.025
0.005
18 (69%)
0
2 (8%)
5 (19%)
1 (4%)
3 (2-4) 0.390
20 (77%)
9 (35%)
5 (19%)
0.229
0.358
0.419
8285 (5973-10638)
12.4 (11.8-13.9)
250 (195 - 317)
1.04 (0.98-1.12)
38 (34-41)
3.29 (0.60-7.19)
74.7 (64.7-87.6)
449 (224-776)
2946 (2101-4698)
0.742
0.615
0.359
0.359
0.039
0.001
0.142
0.934
<0.001

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sults also demonstrated that VEGF levels were increased in
inflammatory lung diseases, such as bronchiectasis, asper-
gilloma, post-tuberculosis destroyed lung, and pneumonia,
when compared with published normal values.20,21 Addi-
tionally, elevated VEGF levels correlated with severity of
inflammation. Significant change in the serum VEGF levels
Angiogenesis, the growth of new capillary blood vessels
from pre-existing vasculature, is an important contributor to
tissue inflammation and abnormal remodeling in inflamma-
tory diseases. Consistent with previous data that levels of
VEGF are significantly elevated in inflammatory disorders,
including lung inflammatory disease,6,7,18,19 our present re-
0
500
1000
1500
2000
VEGF (pg/mL)
020004000
Ang-2 (pg/mL)
6000800010000
0
500
1000
1500
2000
0 20004000
Ang-2 (pg/mL)
60008000 10000
0
500
1000
1500
2000
0 20004000
Ang-2 (pg/mL)
60008000 10000
Fig. 1. Correlation between serum VEGF and Ang-2 levels. VEGF, vascular endothelial growth factor; Ang-2, angiopoietin-2. p=0.028.
Table 3. Univariate Analysis of Associations between Serum VEGF or Angiopoietin-2 levels and Other Measured Parameters
Ln [VEGF]
Coefficient SE
Age -0.003 0.005
Sex (female*) 0.114 0.128
Smoking status† (non-smoker*) 0.1160.144
Comorbidities
Hypertension (No*)-0.159 0.177
Diabetes mellitus (No*)-0.0500.333
Prior therapy for tuberculosis (No*) 0.0890.130
Presenting symptoms
Cough (No*) 0.2470.137
Dyspnea (No*) 0.3550.139
Fever (No*)-0.1990.187
Hemoptysis (No*) 0.0110.128
Amount of hemoptysis (cc) -0.0001 0.0003
Laboratory findings
WBC (#/μL) 0.00006 0.00002
Hemoglobin (g/dL)0.0160.017
PT (INR)1.0850.733
CRP (mg/dL)0.0220.02
PaO2 (mm Hg)-0.0060.003
Ln, natural logarithm; WBC, white blood cell; PT, prothrombin time; CRP, C-reactive protein; VEGF, Vascular endothelial growth factor; Ang-2, angiopoietin-2;
SE, standard error; PaO2, arterial oxygen tension.
Analysis using a mixed model to account for the random effect between subjects (logarithmic transformed VEGF and Ang-2 values were used).
*Reference category.
†Smoking status: smokers (current smoker or ex-smoker) and non-smoker.
Variables
Ln [Ang-2]
SE
0.003
0.081
0.092
p value
0.524
0.375
0.423
Coefficient
0.013
0.144
0.092
p value
<0.001
0.077
0.317
0.370
0.880
0.493
-0.020
0.260
-0.154
0.113
0.211
0.082
0.862
0.220
0.061
0.074
0.011
0.288
0.934
0.672
0.196
0.286
0.030
-0.420
0.0003
0.087
0.087
0.120
0.074
0.0002
0.026
0.001
0.801
<0.001
0.121
0.005
0.358
0.141
0.160
0.055
0.000064
-0.004
1.0961
0.059
-0.004
0.00001
0.011
0.462
0.009
0.002
<0.001
0.745
0.019
<0.001
0.027
VEGF (pg/mL)VEGF (pg/mL)

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374
ting of various cancers.15,28 To our best knowledge, this is the
first reported study to evaluate Ang-2 levels in inflammato-
ry lung diseases, including bronchiectasis, post-tuberculosis
destroyed lung, and aspergilloma.
During development of inflammatory tissue, hypoxic
conditions can promote angiogenesis, leading to induced
VEGF and Ang-2 production. Expression of Ang-2 was el-
evated in cultured endothelial cells exposed to hypoxia,29-31
while VEGF mRNA expression was increased.32,33 In the
present study, PaO2 levels were correlated inversely with
VEGF and Ang-2 levels; suggesting that angiogenesis me-
diators may be released in response to low PaO2 in patients
with inflammatory lung diseases.
Significant associations between VEGF and Ang-2 levels
have been noted in earlier studies in patients with various tu-
mors,28 diabetes mellitus,34 and asthma.35 The present study
demonstrated that serum VEGF and Ang-2 levels had a sig-
nificant positive correlation in inflammatory lung diseases.
However, in contrast to a previous study,6 our study did
not find a significant association between the presence of
hemoptysis and VEGF levels. This lack of an association
may be explained by differences in the distribution of dis-
ease between the hemoptysis and the no hemoptysis groups.
As shown in Table 2, the prevalence of bronchiectasis (54%),
aspergilloma (27%), and post-tuberculosis destroyed lung
(19%) in the hemoptysis group differed from the no hemop-
tysis group where bronchiectasis (69%), pneumonia (19%),
and post-tuberculosis destroyed lung (8%) were prevalent.
with the treatment of inflammatory lung diseases have been
reported.4,6 To our best knowledge, however, our present
study is the first to demonstrate that serum VEGF levels are
positively correlated with serum CRP levels and WBCs. In
a previous study on patients undergoing major surgery,
there was no significant correlation between increases in se-
rum VEGF levels and serum IL-6 or CRP levels.22
Recently, several clinical studies have shown that circu-
lating levels of Ang-2 are increased in septic shock patients,
as well as non-septic patients with, or at risk of, acute lung
injury/acute respiratory distress syndrome; this is related to
vascular permeability and pulmonary dysfunction.23-26 In
these studies, serum Ang-2 levels were positively correlated
with serum CRP levels. In the present study, Ang-2 levels
were positively correlated with CRP levels and WBCs, both
representing markers of inflammation. Compared with the
levels of Ang-2 in previous studies,23,25,27 the median level
of Ang-2 in septic shock patients was greater than 4000 pg/
mL; this is significantly higher than the levels seen in the
current study (median Ang-2 level of 2383 pg/mL). How-
ever, the levels of Ang-2 in the current study are similar to
data measured in cancer patients, including lung, breast,
and prostate,15,28 and were greater than the levels of Ang-2
in the healthy volunteers without lung disease (1000-1500
pg/mL).28 Our findings suggest that high Ang-2 levels are
associated with the severity of inflammatory lung disease in
patients without sepsis, and that the Ang-2 levels in inflam-
matory diseases are similar to the levels reported in the set-
Table 4. Multivariate Correlations between Serum VEGF or Angiopoietin-2 Levels and Other Measured Parameters
Coefficient
Ln [VEGF]
Age-0.007
Sex (female*)-0.142
Smoking status† (non-smoker*)0.121
The presence of hemoptysis 0.188
CRP (mg/dL) 0.042
PaO2 (mm Hg) -0.007
Ln [Ang-2]
Age0.012
Sex (female*)0.127
Smoking status† (non-smoker*)0.025
The presence of hemoptysis-0.275
CRP (mg/dL)0.038
PaO2 (mm Hg)-0.003
Ln, natural logarithm; T, t statistic value; VEGF, vascular endothelial growth factor; Ang-2, angiopoietin-2; CRP, C-reactive protein; SE, standard error; PaO2,
arterial oxygen tension.
Analysis using a mixed model to account for the random effect between subjects (logarithmic transformed VEGF and Ang-2 values were used).
*Reference category.
†Smoking status: smokers (current smoker or ex-smoker) and non-smoker.
SET p value
0.005
0.177
0.180
0.152
0.020
0.003
-1.26
-0.80
0.67
1.24
2.16
-2.45
0.211
0.424
0.503
0.218
0.032
0.016
0.003
0.090
0.091
0.077
0.010
0.002
4.43
1.42
0.28
-3.59
3.88
-2.06
<0.001
0.157
0.783
<0.001
<0.001
0.041

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375
This study was supported by the Samsung Medical Cen-
ter Clinical Research Development Program grant, #CRS-
109-10-1.
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When the VEGF levels were compared between patients
with aspergilloma, which were present only in the hemop-
tysis group, and those with pneumonia, which were present
only in the non-hemoptysis group, no significant difference
in VEGF levels was observed. Additionally, when compari-
son was restricted to patients with bronchiectasis from both
groups, VEGF levels were not significantly correlated with
the presence of hemoptysis. The lack of a significant differ-
ence in VEGF levels between the hemoptysis and no he-
moptysis groups can be partially explained by the different
disease distribution in the two groups. In previous reports
of associations between VEGF levels and hemoptysis in 21
pulmonary aspergilloma patients,6 the mean serum VEGF
levels in 6 patients with hemoptysis and 15 patients without
hemoptysis were 437 pg/mL and 162 pg/mL, respectively.
The reported serum VEGF levels were similar to the asper-
gilloma patients with hemoptysis in the current study.
The present study has several other limitations. The mea-
surements of VEGF and Ang-2 levels were made with se-
rum, not lung tissue; it is unclear whether serum VEGF or
Ang-2 levels reflect the levels in lung tissue. Also, because
the present study was conducted with multiple inflammato-
ry lung diseases, the sample size might have influenced the
statistical power; this limits the interpretation of the study
despite the fact that a formal sample size calculation was
performed. Finally, the timing of measurement of serum
angiogenesis markers in this study was not uniform in rela-
tion to stages of lung injury. Since the level of serum angio-
genesis markers could vary in different stages of lung inju-
ry, our data should be interpreted conservatively. A larger-
scale study in patients with bronchiectasis, aspergilloma,
and pneumonia is needed to further clarify the association
between hemoptysis and VEGF levels.
In conclusion, serum VEGF and Ang-2 levels were asso-
ciated with the PaO2 and the severity of inflammation, rather
than the presence of hemoptysis in patients with inflamma-
tory lung diseases. Hemoptysis in patients with inflammato-
ry lung diseases may not be mediated by increased serum
levels of VEGF and Ang-2. Further studies are required to
determine the mechanism(s) of hemoptysis in patients with
inflammatory lung disease.
ACKNOWLEDGEMENTS
This research was supported by the IN-SUNG Foundation
for Medical Research (CA98761).

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