ORIGINAL ARTICLE

Serum levels of matrix metalloproteinase-9, tissue inhibitors of

metalloproteinase-1 and their ratio are associated with impaired
lung function in the elderly: A population-based study resp_1718 530..535

INGA S. ÓLAFSDÓTTIR,1 CHRISTER JANSON,1 LARS LIND,2 JOHANNES HULTHE,3

MARÍA GUNNBJÖRNSDÓTTIR4 AND JOHAN SUNDSTRÖM2

1
Department of Medical Sciences: Respiratory Medicine & Allergology, 2Department of Medical Sciences,
Uppsala University Hospital, Uppsala, 3Wallenberg Laboratory for Cardiovascular Research, Salgrenska
University Hospital, Gothenburg, Sweden, and 4Department of Allergy, Respiratory Medicine and Sleep,
Landspitali University Hospital, Reykjavík, Iceland

ABSTRACT SUMMARY AT A GLANCE

Background and objective: Matrix metalloprotein-
ases (MMP) and their inhibitors, tissue inhibitors of
metalloproteinases (TIMP), regulate homeostasis and
turnover of the extra cellular matrix. The aim of this
study was to investigate the associations of serum
MMP-9 and TIMP-1 with lung function.
Methods: Spirometry was performed in a nificant in men but not in women.
population-based sample of 888 subjects aged
70 years. Serum MMP-9 and TIMP-1 concentrations
were measured by ELISA.
Results: Lower FEV1 values were associated with
higher serum levels of MMP-9 (P = 0.001) and TIMP-1
(P < 0.001), and a higher ratio of MMP-9 to TIMP-1
(P = 0.02). These associations were significant after
adjustment for gender, weight, height, BMI, current
smoking, pack years of smoking and the time for which
samples were frozen. After stratification for gender, the
associations between FEV1 and MMP-9, TIMP-1, and
their ratio, were significant in men but not in women.
Conclusions: Lower FEV1 was significantly but weakly
associated with higher serum levels of MMP-9, TIMP-1
and a higher MMP-9/TIMP-1 ratio.This association was
stronger in men than in women, suggesting a possible
role for extracellular matrix remodelling in the devel-
opment of impaired lung function. These associations
may also partly explain the association between low
FEV1 and cardiovascular disease.
Correspondence: Inga Sif Ólafsdóttir, Department of Medical
Sciences: Respiratory Medicine & Allergology, Uppsala Univer-
sity Hospital, SE 751 85 Uppsala, Sweden. Email:
inga_sif.olafsdottir@medsci.uu.se
Conflict of Interest Statement: Astra Zenica R&D supported the
study with an unrestricted grant and was not involved in the
design, analysis, reporting/writing of the study. The authors
report no conflicts of interest.
Received 5 May 2009; invited to revise 5 June 2009, 30 July
2009, 14 September 2009; revised 6 July 2009, 20 August 2009, 24
November 2009; accepted 24 November 2009 (Associate Editor:
Chi Chiu Leung).
© 2010 The Authors
Journal compilation © 2010 Asian Pacific Society of Respirology
To investigate their association with lung function,
serum levels of MMP-9 and TIMP-1 were measured
in 888 elderly subjects. Low FEV1 was associated
with higher levels of MMP-9 and TIMP-1. After
stratification for gender, associations between
FEV1 and MMP-9, TIMP-1, and their ratio, were sig-
Key words: age, gender, lung function, matrix
metalloproteinase-9, tissue inhibitor of
metalloproteinase-1.
INTRODUCTION
Matrix metalloproteinases (MMP) are crucial for the
homeostasis and turnover of extracellular matrix in
health and disease. The protease–antiprotease
hypothesis states that an imbalance between pro-
teolytic enzymes and their inhibitors could result in
tissue proteolysis, which may be of importance in the
development of impaired lung function.1
Matrix metalloproteinases are a family of pro-
teolytic enzymes that degrade all types of extracellu-
lar matrix components.2,3 MMP-9 is a major elastolytic
enzyme and is produced by a range of stromal cells, as
well as alveolar macrophages and neutrophils, which
play a major role in lung diseases such as COPD.4–6
MMP activity is regulated by proteolytic activation of
the inactive proenzymes and through inhibition of
the active enzyme by tissue inhibitors of metallopro-
teinases (TIMP). TIMP-1 binds to both the active and
precursor forms of MMP-9 in a 1 : 1 ratio and selec-
tively inhibits its enzymatic activity.7 The ratio of
MMP-9/TIMP-1 in both serum8 and sputum9 corre-
lated with clinical parameters and lung function, and
Respirology (2010) 15, 530–535
doi: 10.1111/j.1440-1843.2010.01718.x
Association of MMP-9 and TIMP-1 with FEV1
other studies have shown that FEV1 correlated posi-
tively with the MMP-9/TIMP-1 ratio.10,11 However,
these were all relatively small, case–control studies
that were not population-based.
We hypothesized that MMP may have an important
role in the pathogenesis of impaired lung function,
and that the extracellular matrix remodelling process
may be reflected in the relationship of serum MMP-9
and TIMP-1 levels to lung function at the population
level. Therefore, the relationship of serum MMP-9 and
TIMP-1 levels to lung function was investigated in a
large elderly population.
METHODS
Study population
The Prospective Investigation of the Vasculature in
Uppsala Seniors (PIVUS; see http://www.medsci.
uu.se/pivus/pivus.htm) study was conducted
between 2001 and 2004. The design of the PIVUS
study has been published in detail.12 All subjects aged
70 years and living in the municipality of Uppsala,
Sweden, were eligible to participate in the study. Par-
ticipants were chosen from the civil registry, and
between April 2001 and June 2004, eligible subjects
(n = 2025) were randomly invited to participate in the
study, through postal invitation within 2 months of
their 70th birthday. A total of 1016 subjects agreed to
participate. As the participation rate was only 50.1%,
cardiovascular disorders and medications were evalu-
ated for 100 consecutive non-participants. The preva-
lence of cardiovascular drug use, history of
myocardial infarction, coronary revascularization,
use of antihypertensive medications, statins and
insulin treatment were similar to those in the partici-
pants; however, the prevalence of diabetes, conges-
tive heart failure and stroke was higher among
non-participants.12
The study was approved by the Ethics Committee at
the University of Uppsala, and all participants gave
informed consent.
Clinical investigations
Participants completed a questionnaire concerning
their medical history, regular medication use and
smoking habits. All subjects were examined the
morning after an overnight fast: no medication or
smoking was permitted after midnight before the
examination. Height, weight and abdominal and hip
dimensions were recorded, and blood samples were
taken for analysis by standard laboratory techniques.
BMI was calculated as weight in kilograms divided
by the square of height in metres. Subjects were cat-
egorized as never-smokers, ex-smokers or current
smokers. Pack-years of smoking were calculated
from the available data on number of cigarettes
smoked per week and the duration of smoking in
years.
© 2010 The Authors
Journal compilation © 2010 Asian Pacific Society of Respirology
531
Lung function tests
The spirometric evaluations performed in the PIVUS
study have been described previously.13 FEV1 was
measured with a Vitalograph Alpha spirometer
(Vitalograph Ltd, Buckingham, England), in accor-
dance with the American Thoracic Society recom-
mendations.14 The best of three values recorded was
used in the analysis. FEV1 values were expressed as
percent of predicted values, adjusted for age, gender
and height. Predicted values for FEV1 were based on
the European Coal and Steel Union reference values.15
Serum matrix metalloproteinase-9
and tissue inhibitors of
metalloproteinase-1 measurements
Serum MMP-9 and TIMP-1 levels were analysed using
commercial ELISA from R&D Systems Europe Ltd.
(Abingdon, UK). Blood samples were placed in glass
test tubes without additives, then centrifuged 1 h
after sampling, and the serum frozen at -70°C until
analysed. Samples were thawed for analysis an
average of 776 days (range 456–1124) after sampling.
Analysis of samples from 20 subjects, twice on the
same plate, gave coefficients of variation of 5.4% for
MMP-9 and 4.8% for TIMP-1. The ratio of MMP-9 to
TIMP-1 in serum was calculated.
Statistical analysis
The distribution of MMP-9 and TIMP-1 values was
examined and natural logarithmic transformation
was performed in order to normalize the distribu-
tions. Simple linear regression was used to assess the
association of matrix factors (serum levels of MMP-9,
TIMP-1 and the MMP-9/TIMP-1 ratio) with FEV1%.
The independent association between FEV1
(expressed in millilitres) and the matrix factors were
analysed by multiple linear regression with adjust-
ment for gender, age, height, BMI, pack-years of
smoking, current smoking and time for which the
sample was frozen, as confounding variables. The
matrix factors were standardized to one SD in all
regression models. Potential interactions between the
matrix factors and gender, BMI, pack-years of
smoking and current smoking were investigated in all
models. All models were investigated in gender-
pooled and gender-specific strata, and gender was
included as a covariate in all gender-pooled analyses,
in addition to the covariates listed previously. The
STATA 9 programme was used for all analyses and
P-values < 0.05 were considered significant.
RESULTS
Characteristics of the study population
The study included 888 subjects with acceptable
spirometry results and data for serum MMP-9 and
Respirology (2010) 15, 530–535
532
Table 1 Clinical characteristics of the participants
Women n = 456 (51%)
MMP-9, ng/mL (95% CI) 182 (174,190)
TIMP-1, ng/mL (95% CI) 174 (171,176)
MMP-9/TIMP-1 ratio, mean ⫾ SD 1.17 ⫾ 0.58
Smoking (%)
Current smokers 11%
Ex-smokers 34%
Never-smokers 54%
Pack-years
Geometric mean (95% CI) 5.5 (4.3–6.9)
Spirometry
FEV1 % predicted mean ⫾ SD 101 ⫾ 19
MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.
TIMP-1 levels. The characteristics of these partici-
pants are presented in Table 1.
Characteristics of the non-participants
The 128 subjects who did not participate in the evalu-
ation of spirometry were more likely to be men than
women (14.8% vs 10.4%, P = 0.04) and the men had
slightly higher TIMP-1 values than women (185 ng/
mL, 95% CI: 177–194 vs 175 ng/mL, 95% CI: 173–177;
P = 0.01). There were no differences for BMI, MMP-9
levels or smoking history.
Univariate associations
There were inverse associations between FEV1% and
serum MMP-9 and TIMP-1 levels, and MMP-9/
TIMP-1 ratio (Fig. 1). Higher MMP-9 and TIMP-1
levels were associated with increased BMI (P-value for
trend < 0.0001), as was the MMP-9/TIMP-1 ratio
(P-value for trend 0.005). MMP-9 and TIMP-1 levels
were also associated with smoking status, being
lowest in never-smokers and highest in current
smokers.
Multivariate regression models
The associations between the matrix factors and FEV1
remained significant after adjustment for gender, age,
height, BMI, current smoking, pack-years of smoking
and the time for which the sample was frozen
(Table 2). A significant gender interaction was identi-
fied in the associations between MMP-9, TIMP-1 and
FEV1 (P = 0.002), and between MMP-9/TIMP-1 ratio
and FEV1 (P = 0.02). After stratification for gender, the
associations between the matrix factors and FEV1
were statistically significant for men but not for
women (Table 2). There was no interaction between
smoking and BMI.
DISCUSSION
In this population-based study, weak but significant
inverse associations were identified between the
Respirology (2010) 15, 530–535
IS Ólafsdóttir et al.
Men n = 432 (49%) All subjects n = 888
191 (182,200) 186 (180,193)
177 (173,180) 175 (173,177)
1.22 ⫾ 0.62 1.19 ⫾ 0.6
9% 10%
48% 41%
42% 48%
8.2 (6.8–9.9) 6.9 (5.9–7.9)
96 ⫾ 20 99 ⫾ 20
matrix factors and FEV1 in elderly subjects. After
stratification for gender, these associations were sig-
nificant for men but not for women.
Consistent with previous studies, higher serum
levels of MMP-9 were associated with lower FEV1.16,17
Studies in animals,18 and on BAL, tissue samples and
sputum from humans,4,19–23 indicate that MMP-9 and
TIMP-1 are candidate proteinases in the pathogenesis
of COPD. In this study, both MMP-9 and TIMP-1 were
elevated in participants with impaired lung function,
suggesting an underlying proteolytic environment in
subjects with poor lung function in general, and not
just in subjects with COPD. Impairment of lung func-
tion correlated with MMP-9/TIMP-1 ratio, indicating
that a chronic imbalance in MMP-9 and TIMP-1 may
be an important factor in the development of poor
lung function in this elderly population.
Impaired lung function was inversely correlated
with MMP-9, TIMP-1 and their ratio in men, whereas
no such association was identified for women. A
gender difference in the association of CRP levels with
FEV1 decline, with a stronger inverse association
between CRP and FEV1 in men than in women, has
been reported.24,25 Furthermore, there was an associa-
tion between a faster rate of decline in FEV1 and
higher CRP levels in men but not in women.24 Hor-
monal changes in women affect low-grade inflamma-
tion,26 and an increase in inflammatory mediators,
paralleling a rise in cardiovascular risk has been
observed after menopause.27 A large retrospective
study of 1053 patients with severe emphysema
revealed gender differences, with women having
more dyspnoea, anatomically smaller airway lumens,
disproportionately thicker airway walls and less
extensive emphysema, characterized by smaller
emphysematous lesions and less peripheral involve-
ment, compared with men.28 It is possible that
gender-specific hormonal or anatomical differences
may be related to differences in inflammatory activity,
which may, in turn, influence the pathogenesis of
airflow limitation.
The prevalence of smoking in the present study
population was similar to that reported for other
elderly populations.29 Increased levels of MMP-9
and TIMP-1 are associated with high BMI, and an
© 2010 The Authors
Journal compilation © 2010 Asian Pacific Society of Respirology
Association of MMP-9 and TIMP-1 with FEV1 533

FEV1 (% predicted) FEV1 (% predicted)

r = −0.11, P = 0.001 r = −0.15, P < 0.0001
150 150

100 100

50 50

0 0
10 30 100 320 1000 100 160 250 400 630
MMP-9 (ng/mL) TIMP-1
1 (ng/mL)
FEV1 (% predicted)

150 r = −0.08, P = 0.02

100

50

0
0 1 2 3 4 5
MMP-9 / TIMP-1

Figure 1 Correlations between FEV1% and serum levels of matrix metalloproteinase (MMP)-9, tissue inhibitor of
metalloproteinase (TIMP)-1 and the ratio of MMP-9 to TIMP-1.

Table 2 Multivariate adjusted models for the association of MMP-9 and TIMP-1 levels with FEV1

Models adjusted for gender, BMI,

pack years and current smoking
MMP-9 TIMP-1 MMP-9/TIMP-1 ratio

FEV1, b-coefficient (95% CI) in mL per 1 SD All† -40 (-72, -8) -44 (-76, -11) -37 (-69, -4)
change in matrix marker Men‡ -81 (-134, -28) -55 (-104, -6) -67 (-119, -14)
Women‡ 2 (-35, 40) -27 (-68, 14) -2 (-40, 36)

†
Adjusted for gender, age, height, BMI, current smoking, pack-years and time for which the sample was frozen.
‡
Adjusted for age, height, BMI, current smoking, pack-years and time for which the sample was frozen.
MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.

imbalance in the MMP-9/TIMP-1 ratio is postulated
to be a pathophysiological background for many of the
diseases associated with obesity, such as cardiovascu-
lar disease.30,31 Reduced lung function is associated
with cardiovascular morbidity and mortality, and even
a modest decline in FEV1 has been associated with a
fivefold increase in death due to ischaemic heart
disease, independently of age, gender and smoking
history.32,33 Circulating MMP-9 and TIMP-1 are associ-
ated with cardiovascular diseases and may reflect
© 2010 The Authors
Journal compilation © 2010 Asian Pacific Society of Respirology
extracellular matrix degradation consequent to car-
diovascular remodelling.34–36 Thus, it is possible that
MMP-9, TIMP-1 and the balance between these two
enzymes are key to the association between impair-
ment of lung function and cardiovascular disease.
One of the strengths of this study is that the data
were collected from a general population, and
assessed using high-quality, standardized methods.
However, the limitations of the study merit some dis-
cussion. First, the ELISA used to measure MMP and
Respirology (2010) 15, 530–535
534
TIMP in serum detect both total enzyme and pro-
enzyme; ideally, a correlation should be established
between tissue activity and circulating levels of
MMP-9 and TIMP-1. Second, it has been suggested
that MMP-9 levels do not reflect overall MMP activity
in the airways, as COPD is associated with higher
levels of MMP-9 but not with increased MMP activ-
ity.37 Third, post-bronchodilator measurements of
FEV1 were not performed. Fourth, it has been sug-
gested that MMP-9 in plasma may degrade over time
when stored at -80°C, although TIMP-1 levels appear
to remain stable.38 The pattern and cause of this deg-
radation is uncertain and studies on samples from
this study indicated a small, but statistically signifi-
cant, increase in TIMP-1 levels but no definite change
in MMP-9 levels over time. Although the participa-
tion rate was only 50.1%, there were no major
differences between non-participants and partici-
pants, as indicated by an analysis of a subsample of
the population.12
In conclusion, this study has shown that lower FEV1
is weakly associated with higher levels of MMP-9,
TIMP-1 and a higher MMP-9/TIMP-1 ratio. These
matrix factors account for a very small proportion of
the observed variance in lung function parameters.
The association was stronger in men than in women,
and may indicate a role for extracellular matrix
remodelling in the development of impaired lung
function. These associations may also partly explain
the link between low FEV1 and cardiovascular disease.
ACKNOWLEDGEMENTS
This study was a collaboration between the Depart-
ment of Medicine, University Hospital, Uppsala and
AstraZeneca R&D Mölndal, Sweden. This analysis of
the PIVUS data was financially supported by Bror
Hjerpestedt Association, Uppsala Heart and Lung
Association, and the Swedish Heart and Lung
Foundation.
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