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ABSTRACT |
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INTRODUCTION
METHODS
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DISCUSSION
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An imbalance between proteases and antiproteases may play a role
in emphysema, which is characterized by increased degradation of
extracellular matrix, and in airway remodeling in chronic bronchitis and asthma, in which there is increased collagen deposition. We assessed the effect of smoking on release of matrix metalloprotease-9 (MMP-9) and of its inhibitor, tissue inhibitor of metalloprotease-1 (TIMP-1), from alveolar macrophages, and determined
the effects of proinflammatory (interleukin [IL]-1
and lipopolysaccharide [LPS]) and antiinflammatory (IL-10) stimuli on the release
of MMP-9 and TIMP-1. We performed bronchoalveolar lavage in
11 smokers and 11 nonsmokers, and cultured airway macrophages
in the presence of control medium, IL-1, and LPS. Airway macrophages from smokers released greater amounts of MMP-9 and
TIMP-1 at baseline and in response to IL-1 and LPS than did
those of nonsmokers. Airway macrophages from smokers produced more TNF-
and IL-10. IL-10 increased TIMP-1 release without modifying that of MMP-9, leading to a decrease in the MMP-9
to TIMP-1 ratio. Anti-IL-10 antibody had no effect on MMP-9 production induced by LPS. We conclude that the release of proteases
and antiproteases by airway macrophages is increased in cigarette
smokers, and can be regulated by exogenous IL-10.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The balance between proteases and antiproteases is thought
to play a key role in cigarette smoke-induced chronic lung disease. An increase in collagen deposition in the bronchial wall
is observed in chronic bronchitis, whereas histopathologic evidence of extracellular matrix (ECM) degradation is one of the
hallmarks of emphysema, which can be induced in rodents by
the intratracheal instillation of elastases (1). Moreover, deficiency of 1-antiproteinase is a known genetic cause of emphysema (1). The two main elastase-producing cell types in the
airways of smokers are neutrophils and macrophages, but
macrophages are by far the most abundant cell type in bronchoalveolar spaces, particularly in cigarette smokers (1).
Macrophage-derived elastolytic enzymes include matrix metalloprotease (MMP)-2 (gelatinase A, or 72-kD gelatinase), MMP-7 (matrilysin), MMP-9 (gelatinase B, or 92-kD gelatinase), and MMP-12 (macrophage metalloelastase) (1), all of which are capable of degrading type IV collagen (6). In general, MMPs are secreted as inactive proenzymes that are subsequently activated by several mechanisms including enzymatic cleavage (9). MMP-9 and MMP-12 account for most of the macrophage-derived elastase activity in smokers (1), and release of MMP-9 is under the influence of several inflammatory mediators, cytokines, and surface molecules (2, 5, 10).
Macrophages also produce tissue inhibitors of metalloproteinases (TIMPs), which bind to the active forms of MMPs (9). In addition, TIMP-1 binds to pro-MMP-9, whereas TIMP-2 inhibits pro-MMP-2. TIMP-1 release is also regulated by several cytokines, whereas TIMP-2 and MMP-2 are constitutively expressed (9, 14). Several studies suggest that the balance between regulated macrophage MMP and TIMP (i.e., MMP-9 and TIMP-1) may be an important determinant of the clinical expression of chronic obstructive pulmonary disease (COPD) (1, 8, 18). On one hand, this ratio is decreased in the sputum of patients with chronic bronchitis (18), which may contribute to the subepithelial fibrosis observed in this disease, and on the other hand, immunohistochemical studies of emphysematous lungs have shown an increase in the expression of MMP-9 but not of TIMP-1 (8).
Airway macrophages also produce IL-10 (19), an antiinflammatory cytokine that decreases MMP-9 release and increases TIMP-1 production by alveolar macrophages (AM)
from healthy subjects (23). The role of IL-10 in the pathogenesis of the extracellular matrix abnormalities that are observed
in chronic cigarette smoke-induced lung diseases has not been
investigated. We hypothesized that IL-10 plays a role in the
airway remodeling observed in COPD through its effects on
the balance of macrophage protease and antiprotease enzymes, either directly or indirectly through the regulation of
release of cytokines such as tumor necrosis factor (TNF)-, which is known to increase MMP-9 and TIMP-1 production
(11, 12, 16, 24). To address this issue, we compared the release of IL-10, TNF-, MMP-9, and TIMP-1 by unstimulated and
stimulated AM from asymptomatic smokers and nonsmokers,
and studied the role of IL-10 on MMP-9, TIMP-1, and TNF-
release. We also measured the levels of MMP-9 and TIMP-1
in bronchoalveolar lavage fluid (BALF).
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Volunteers
Twenty-two healthy subjects were recruited for the study. Eleven were current smokers with a cumulative smoking history of 5 to 10 pack-years, and 11 were never-smokers (Table 1). All subjects were free of any significant disease including asthma or recent (< 3 mo) acute respiratory tract infections. None was receiving any long-term treatment, especially with antiinflammatory agents. Smokers had to be free of chronic bronchitis (as defined according to criteria of the American Thoracic Society), and their spirometic data were within the normal range. All patients gave written informed consent before participating in the study, which was approved by the Royal Brompton Hospital Ethics Committee.
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Fiberoptic Bronchoscopy
Subjects were pretreated with atropine (0.6 mg intravenously) and midazolam (5 to 10 mg intravenously). Oxygen (3 L/min) was administered via nasal prongs throughout the procedure, and oxygen saturation was monitored with a digital oximeter. After induction of local anesthesia by application of lignocaine (4% [wt/vol]) to the upper airways and larynx, a fiberoptic bronchoscope was passed through the nasal passages into the trachea. Bronchoalveolar lavage (BAL) was performed from the right middle lobe, using four successive aliquots each of 60 ml of warmed 0.9% NaCl.
Isolation and Culture of AM
BALF was filtered through sterile gauze and centrifuged at 500 × g for 10 min. Cells were washed twice in Hanks' balanced salt solution (HBSS), counted, and plated in 12-well plates at a concentration of 1 × 106 cells/ml in complete culture medium. Cytospin preparations were also made for differential cell counts.
After culture for 24 h, the medium in which BAL cells were cultured was replaced by 1 ml of fresh complete medium. Adherent cells
(i.e., macrophages) from each subject were then cultured for a further
24 h in the presence of medium alone, medium + IL-1 (10 ng/ml), or
medium + LPS (10 µg/ml). In a subset of six subjects (three smokers
and three controls), the effect of IL-10 was studied by culturing macrophages in the presence of medium alone or of medium + IL-10 at
concentrations of 0.1, 1, and 10 ng/ml; LPS (10 µg/ml) was added 30 min later. The effect of an anti-IL-10 blocking antibody (10 ng/ml)
was studied in LPS-stimulated macrophages from three smokers.
BALF was concentrated 10-fold by using a microconcentrator filter, and was stored at 
70° C for later analysis.
Materials
Complete culture medium was RPMI-1640 (ICN-Flow, Ltd., High
Wycombe, UK) containing 10% heat-inactivated fetal calf serum (FCS;
Sera Laboratories, Crawley, UK), 2 mM L-glutamine (ICN-Flow), and
penicillin-streptomycin (100 U/ml-100 ml; ICN-Flow). Culture plates
were from Falcon (London, UK). LPS (Escherichia coli) was from
Sigma (Poole, UK). Recombinant human IL-1 and IL-10 were purchased from R&D Laboratories (Oxford, UK). Recombinant anti-IL-10 neutralizing antibody (MAB217) was obtained from R&D Laboratories. A preparation of 0.01 to 0.03 µg/ml of this antibody will neutralize 50% of the bioactivity of 5 ng/ml of recombinant human IL-10.
Enzyme-Linked Immunosorbent Assays for
MMP-9, TIMP-1, IL-10, and TNF-
The secretory products were assayed in macrophage supernatants and
concentrated BALF, using previously described quantitative sandwich-type enzyme-linked immunoassay techniques. Commercially available
kits were used (MMP-9 and TIMP-1: Biotrak; Amersham Pharmacia
Biotech Ltd., Little Chalfont, UK; IL-10: Quantikine; R&D Systems,
Abingdon, Oxon, UK; TNF-: Genzyme, Cambridge, MA). Briefly,
monoclonal primary antibodies were coated onto a microtiter plate.
After washing with PBS/Tween, the antibody was blocked with PBS/
10% FCS (200 µl). Standards and samples were then added, followed
by the appropriate conjugated secondary antibody, to sandwich-immobilize the measured product. For MMP-9 and TIMP-1 assays, the secondary antibodies were conjugated to horseradish peroxidase (HRP).
Addition of 5,5'-tetramethyl benzidine and hydrogen peroxide, followed 10 min later by addition of sulfuric acid (1.0 M) to stop the reaction, allowed color development in proportion to the amount of the
product. For TNF- and IL-10, secondary antibodies were biotinylated and color was developed through the addition of streptavidin-
HRP. For all assays, optical density was measured with a spectrophotometer set to 450 nm. Quantification was performed by interpolation from a standard curve. The lower limits of detection were 0.6 pg/
ml (MMP-9), 1.25 pg/ml (TIMP-1), 1.5 pg/ml (IL-10), and 15.6 ng/ml
(TNF-), respectively.
Albumin levels in BALF were quantified (in mg/L) by rocket immunoelectrophoresis, using specific antisera and standard human serum containing albumin at known concentrations.
Statistical Analysis
Since the studied variables could not be considered as normally distributed according to the Shapiro-Wilks test, nonparametric tests
were used for their evaluation. Comparisons of smokers versus controls were done with the Mann-Whitney U test, and correlations between levels of macrophage secretory products were analyzed with
Spearman's rank correlation test. The effects of IL-1, LPS, and IL-10
were studied with Wilcoxon's signed-ranks test. A value of p < 0.05 was considered statistically significant. All statistics were calculated
with SPSS software version 7.5 (SPSS Inc., Chicago, IL). Results are
expressed as mean ± SEM unless otherwise specified.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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BALF Cell Content and Levels of MMP-9 and TIMP-1
Table 1 shows total and differential cell counts in BALF from smokers and never-smokers, with greater macrophage recovery from BALF of smokers. Cells were > 85% viable as assessed by trypan blue exclusion. There was no difference in the BALF albumin concentrations of smokers (median: 26 mg/L; range: 20 to 31 mg/L) and nonsmokers (median: 27 mg/L; range: 19 to 49 mg/L). Although there was no difference in MMP-9 levels, TIMP-1 levels were significantly higher in smokers than in nonsmokers (p < 0.05). However, the molar ratios of MMP-9 to TIMP-1 were not different in the two groups (Figure 1). Immunoreactive IL-10 was undetectable in BALF.
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Release of MMP-9 and TIMP-1 by AM
The levels of both MMP-9 and TIMP-1 in supernatants from
centrifugation of AM were greater in smokers than in controls, both under basal conditions and after stimulation by
IL-1 (10 ng/ml) or LPS (10 µg/ml) (Figure 2). Overall, the
molar ratio of MMP-9 to TIMP-1 was less than 1.0, and tended
to be higher in smokers (Figure 3). LPS tended to increase the
release of MMP-9 by AM from smokers and of TIMP-1 by
AM from both smokers and nonsmokers, but these differences
did not reach significance (Figure 2). IL-1 significantly increased the release of MMP-9 but did not affect TIMP-1 in
smokers (Figure 2), and did not significantly alter the levels of
these two products in nonsmokers. There was a trend toward
an increase in MMP-9-to-TIMP-1 ratios under control conditions and after IL-1 and LPS stimulation in smokers (Figure 3).
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Release of TNF- and IL-10 by AM
Release of both TNF- and IL-10 by AM was increased in
smokers as compared with nonsmokers, both under baseline
conditions and after stimulation by LPS and IL-1 (Figure 4).
In smokers and in controls, LPS increased the release of both
TNF- and IL-10 (Figure 4), with the increase in TNF- being
greater than the increase in IL-10. IL-1 had no effect on
TNF- and IL-10 levels in smokers, whereas in nonsmokers
this cytokine increased the production of TNF- but not that
of IL-10, although TNF- levels remained very low.
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Cytokine Production by AM and MMP-9 and TIMP-1 Release and Levels in BALF
In both smokers and nonsmokers, the release of MMP-9 did
not correlate with that of TNF- and IL-10. By contrast, the
release of TIMP-1 did correlate with that of IL-10 in unstimulated macrophages from smokers (r = 0.89, p < 0.01) and in
LPS-stimulated macrophages from nonsmokers (r = 0.66, p < 0.05). The molar ratio of MMP-9 to TIMP-1 did not correlate
with levels of either TNF- or IL-10. Additionally, release of
MMP-9 and TIMP-1 did not correlate with that of the other,
and neither did release of TNF- and IL-10.
There was also no correlation between MMP-9 and TIMP-1
levels in BALF and the corresponding release of these substances from macrophages ex vivo under either control conditions or with IL-1 or LPS stimulation.
Effect of IL-10 and of Anti-IL-10 Antibody
IL-10 induced a dose-dependent increase in the level of
TIMP-1 released by AM without affecting the release of
MMP-9 by these cells (Figure 5). Accordingly, the MMP-9-to-TIMP-1 molar ratio was reduced in macrophages cultured in
the presence of IL-10, but this did not reach statistical significance. This cytokine also significantly reduced the production
of TNF- in a dose-dependent manner (Figure 5). Anti-IL-10
antibody (10 ng/ml) did not change the release of MMP-9
from LPS-stimulated AM of smokers (144 ± 121 pg/ml, compared with 113 ± 89 ng/ml in the absence of IL-10; n = 3).
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The main finding of this study was that AM from smokers release greater amounts of both MMP-9 and TIMP-1 than do
AM from nonsmokers, with a trend toward a higher molar ratio of MMP-9 to TIMP-1. In contrast, levels of TIMP-1 but not
MMP-9 in BALF were higher in smokers than in nonsmokers,
with no significant difference in molar ratios of MMP-9 to
TIMP-1. AM of smokers also produced more TNF- and IL-10
than did those from nonsmokers. Exogenous IL-10 increased
the release of TIMP-1 without modifying that of MMP-9. However, there was no regulation of MMP-9 by endogenous IL-10.
We studied asymptomatic smokers first, rather than patients with established cigarette smoke-induced lung disease, because we wanted to find out whether the biochemical abnormalities described in patients with chronic bronchitis or emphysema preceded the onset of disease. We also wanted to identify the earliest detectable biochemical changes in such disease. In smokers with established emphysema, levels of MMPs, including MMP-9, were found to be increased in BALF (25), and expression of MMP-9 was increased in AM (26). In the study by Betsuyaku and colleagues (27), asymptomatic smokers were studied, and increased levels of MMP-9 in BALF was observed only in those who had radiologic evidence of emphysema; thus, an increase in MMP-9 appears to be an early feature of emphysema in susceptible smokers. By contrast, our data indicate that in BALF, there is an increase in TIMP-1 levels in the presence of unchanged MMP-9 levels.
A decrease in the molar ratio of MMP-9 to TIMP-1 in induced sputum of patients with chronic bronchitis and chronic obstructive airways disease has also been reported (18), and this ratio correlated with FEV1, suggesting that this imbalance in protease/antiprotease enzymes may be a determinant of airflow limitation. However, in a study of BALF from patients with chronic bronchitis, MMP-9 levels were found to be increased, whereas MMP-9 and TIMP-1 release from AM was not enhanced, and the ratio of MMP-9 to TIMP-1 remained unchanged (24). On the other hand, an increase in MMP-9 but not in TIMP-1 activity has been reported in emphysematous lung tissues from smokers (8). Our data show that increased release of MMP-9 and TIMP-1 from AM occurs early in smokers, before any major changes in MMP-9 levels in BALF, and certainly before the onset of symptoms or disease. The marked increase in the release of TIMP-1 and to a lesser extent of MMP-9 by AM that we observed in asymptomatic smokers may disappear in some established lung diseases, since no increase in either of these products has been reported in patients with chronic bronchitis (24, 28). This may be due to the modulation of release of both MMP-9 and TIMP-1 by mediators involved in inflammatory processes (11, 12, 15, 17, 29), and it is possible that the release of various mediators may be affected by the onset of disease, thus resulting in the modulation of release of MMP-9 and TIMP-1.
We found that exogenous IL-10 can regulate the balance
between release of MMP-9 and TIMP-1 by AM of smokers.
IL-10 release was increased in smokers, and was correlated
with TIMP-1 levels. Moreover, in vitro treatment of macrophages with IL-10 increased TIMP-1 release in a dose-dependent manner without affecting MMP-9 release, resulting in a
decreased protease-to-antiprotease ratio. IL-10 is known to
increase gene transcription for TIMP-1 and decrease that for
MMP-9 in AM from healthy subjects (23). Regulation of the
macrophage protease/antiprotease balance by IL-10 is likely to be a complex phenomenon resulting from both direct and
indirect effects, since we and others (30) demonstrated that
this cytokine also decreases the release of proinflammatory
mediators such as TNF-, which can itself upregulate the production of both MMP-9 and TIMP-1 by macrophages (11, 13,
16). In addition, since MMP-9 increases TNF- levels by
cleaving the membrane-bound form of this cytokine (31), the
increased release of TNF- by AM of smokers may at least be
partly due to these subjects' increased MMP-9 secretion.
However, IL-10 dramatically reduced TNF- production by
macrophages without affecting MMP-9 levels, which suggests that IL-10 directly regulates TNF- expression. IL-10 may therefore regulate the MMP-9/TIMP-1 balance in AM by modulating these cells' production of MMP-9 and TIMP-1 both directly and indirectly (through the modulation of other cytokines,
such as TNF-) at the transcriptional level, and also at the
protein level through effects on the release of MMP-9 activators, such as other proteases or reactive oxygen species (ROS).
Another mechanism by which IL-10 may regulate the balance
between MMP-9 and TIMP-1 may involve its effect in influencing the phenotype of monocyte-derived macrophages (32).
Among its numerous anti-inflammatory effects, IL-10 inhibits the release of ROS by macrophages (30), which may occur under the action of cigarette smoke, since the latter has
powerful oxidant properties. This is of interest, since ROS
have been shown to activate MMP-9 through transformation
of the proenzyme into the active enzyme (33). These data are
in accordance with the other known antiinflammatory and
protective functions of IL-10, which include its inhibition of
the production of several proinflammatory cytokines and
chemokines by AM, including TNF-, IL-1, IL-6, macrophage inflammatory protein-1, and IL-8 (20, 30). IL-10 also
reduces the expression of major histocompatibility complex class II, B7.1/B7.2 antigens and clonal designator (CD)23 by
these cells, thereby decreasing their accessory cell function
(30). In contrast, IL-10 upregulates the release of another antiinflammatory cytokine, IL-1 receptor antagonist (30). IL-10
has already been shown to participate in the pathogenesis of
asthma, since its release by AM is decreased in this disease
(20), and patients with more severe asthma are more likely to
exhibit polymorphisms in the promoter region of the gene for
IL-10 that are associated with lower production of this cytokine (34, 35).
In our study, blocking the effects of endogenous IL-10 with a blocking antibody had no effects on MMP-9 release. This indicates that either IL-10 production was not sufficiently high to induce this release, as supported by the undetectable levels of IL-10 in BALF of smokers and nonsmokers, or that the effects of endogenous IL-10 may not be as potent in vivo as the effects observed in vitro.
In conclusion, we found that the release of MMP-9 and TIMP-1 by AM was increased in asymptomatic smokers, in the presence of an increased BALF concentration of TIMP-1 but not of MMP-9. We also found that exogenous IL-10 can increase the release of TIMP-1, but that neither exogenous nor endogenous IL-10 has any effect on MMP-9 release from AM.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Prof. K. F. Chung, Imperial College of Science, Technology and Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK. E-mail: f.chung{at}ic.ac.uk
(Received in original form October 25, 1999 and in revised form May 2, 2000).
Dr. Lim was supported by Astra Draco, Lund, Sweden, and Dr. Roche was supported by grants from the European Respiratory Society and Société de Pneumologie de Langue Française.S. L. and N. R. contributed equally to this work.
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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