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B and Matrix Metalloproteinase Production in Alveolar Macrophages via Oxidant-Sensitive Pathways1
Division of Pulmonary Biology, Children’s Hospital Medical Center, Cincinnati, OH 45229
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B was highly
expressed and translocated to the nucleus. Increased NF-B binding
was detected by EMSA in nuclear extracts of AMs isolated from
SP-D-/- mice. Antioxidants
N-acetylcysteine and pyrrolidine dithiocarbamate
inhibited MMP production by AMs from SP-D-/- mice. To
assess whether increased oxidant production influenced NF-B
activation and production of MMP-2 and -9, AMs from
SP-D-/- mice were treated with the NADPH oxidase
inhibitors diphenylene iodonium chloride and apocynin. Inhibition of
NADPH oxidase suppressed NF-B binding by nuclear extracts and
decreased production of MMP-2 and 9 in AMs from SP-D-/-
mice. SN-50, a synthetic NF-B-inhibitory peptide, decreased MMP
production by AMs from SP-D-/- mice. Oxidant production
and reactive oxygen species were increased in lungs of
SP-D-/- mice, in turn activating NF-B and MMP
expression. SP-D plays an unexpected inhibitory role in the regulation
of NF-B in AMs. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Reactive oxygen species (ROS), including superoxide anion
(O2-), hydroxyl radical
(OH·), and hydrogen peroxide
(H2O2) have been implicated
in the pathogenesis of several lung diseases associated with oxidative
stress, including emphysema, adult respiratory distress syndrome,
asthma, and lung fibrosis (6). Although ROS play a
critical role in host defense, increased ROS-generated during acute and
chronic inflammation can be cytotoxic, causing oxidative damage to
various macromolecules, lipid peroxidation, protein cross-linking,
protein fragmentation, DNA damage, and strand breaks (7).
Oxidative stress has been associated with activation of transcriptional
pathways mediating cellular responses to infection and injury. For
example, activity of NF-B and AP-1, were stimulated by
oxidative stress (8). Binding sitesfor NF-B and AP-1
were identified in the promoters of numerous genes, including
proinflammatory cytokines (9). Likewise,
cis-acting elements binding NF-B and/or AP-1 were present
in the promoter regions of the MMP-2, -9, and -12 genes
(10, 11, 12, 13). Therefore, we hypothesized that ROS,
generated by AMs in SP-D-/- mice, might
activate redox-sensitive transcription factors, causing increased
expression of the MMP. In the present study, increased ROS were
demonstrated in lungs of SP-D-/- mice. MMP-2
and -9 production by AMs from SP-D-/- mice was
stimulated by oxidant-sensitive pathways, including NF-B
activation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SP-D-/- mice were generated by targeted gene inactivation (3). SP-D-/- mice survive and breed normally in the vivarium under barrier containment facilities at Children’s Hospital Medical Center (Cincinnati, OH). Experimental procedures were reviewed and approved by the Children’s Hospital Institutional Animal Care and Use Committee. Swiss black SP-D-/- and age-matched Swiss black SP-D+/+ wild-type (WT) mice were mated separately to generate animals for this study. Evidence of viral and bacterial pathogens was not detected in sentinel mice in the colony.
Bronchoalveolar lavage (BAL) and isolation of AMs
BAL was performed by instilling 10 1-ml aliquots of PBS. BAL fluid from several animals was pooled to provide sufficient numbers of macrophages for each analysis. The lavage was centrifuged at 1200 rpm at 7 min, and pelleted cells were resuspended in serum-free RPMI 1640 medium containing 1% of Nutriodoma (Boehringer Mannheim, Indianapolis, IN), and counted with a hemocytometer. More than 90% of BAL cells were AM in both WT and SP-D-/- mice. For some experiments, AMs were isolated by differential attachment to tissue culture flasks at 37°C. Nonadherent cells then were removed, and fresh, serum-free medium was added. The adherent AMs were maintained in a humidified atmosphere containing 5% CO2 and 95% air until the end of experiments.
Lipid hydroperoxide (LPO) concentration
LPO was measured in whole lung from SP-D-/- and WT mice with the LPO-586 assay kit (Oxis International, Portland, OR). Lungs were isolated and homogenated with PBS containing 5 mM butylated hydroxytoluene and centrifuged 15,000 rpm for 15 min at 4°C. Supernatants were collected and the content of malonaldehyde and 4-hydroxyalkenals was measured colorimetrically following the manufacturer’s procedures.
Histochemical detection of lipid peroxidation-derived carbonyls
Lung sections (10 µm thick) obtained from frozen tissue specimens were exposed for 1 h at 60°C to a 0.1% 3-OH-2-naphthoic acid hydrazine (OHNAH) solution in 50% ethanol containing 5% acetic acid. After the reaction, the sections were washed thoroughly in 50% ethanol and stained for 5–10 min with a 0.1% fast blue B solution in an alcoholic buffer prepared by mixing equal volumes of 100 mM phosphate buffer, pH 7.4, and 95% ethanol. Carbonyls are converted to naphthoic hydrazones by reaction with OHNAH. Coupling with the diazonium salt then yields violet azo dyes (14).
Detection of intracellular ROS
Intracellular ROS accumulation was determined with the fluorescent probe 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate (CDCFH; Molecular Probes, Eugene, OR). AMs were incubated with 10 µM CDCFH for 30 min, rinsed with PBS, and fixed with 4% paraformaldehyde. Fluorescence was observed by fluoromicroscopy with excitation and emission wavelengths of 485 and 530, respectively.
Immunostaining for NF-B p65
BAL cells were isolated from WT and SP-D-/- mice, cytospun and fixed with cold methanol for 10 min, and washed in PBS. The slides then were incubated at 4°C overnight with a rabbit anti-p65 Ab (Santa Cruz Biotechnology, Santa Cruz, CA). After incubation, the slides were washed in PBS and incubated with FITC-conjugated goat anti-rabbit IgG (Santa Cruz Biotechnology) as a second Ab, and compared with samples prepared identically without primary Ab.
Treatment of AMs in vitro
AMs from SP-D-/- mice were pooled and
placed in culture at a concentration of 5 x
105 cells per well in serum-free RPMI 1640
medium. The AMs were treated with 20 mM N-acetylcysteine
(NAC), 200 µM pyrolidine dithiocarbamate (PDTC), 1 µM diphenylene
iodonium chloride (DPI; Sigma, St. Louis, MO), or 1 mM apocynin
(Aldrich, Milwaukee, WI). Cells also were incubated with a 10 µM
SN-50 (Calbiochem, La Jolla, CA), an inhibitor of NF-B
nuclear import. After 6 h of incubation, supernatants were removed
and the cells were washed and incubated with fresh medium including the
reagents for 24 h. At the concentrations used, these agents did
not alter macrophage viability, as determined by trypan blue exclusion
or lactate dehydrogenase measurement (Roche, Indianapolis, IN). RAW
264.7 murine macrophage cell line was obtained from the American Type
Culture Collection (Manassas, VA) and maintained in DMEM containing
10% FBS, 10 mM HEPES, 50 U/ml penicillin, and 50 µg/ml streptomycin.
Cells (2 x 105) cells in 24-well plates
were incubated with or without 10 µM menadione (Sigma) for
24 h.
Gelatin zymography
MMP activities were measured in macrophage-conditioned medium. Proteinases in the conditioned medium were concentrated by incubation with gelatin-agarose beads (Amersham Pharmacia, Arlington Heights, IL) for 2 h at 4°C. The beads were pelleted and washed, and proteinases were eluted by incubation in sample buffer for 45 min at 37°C. The samples then were electrophoresed into 10% Zymogram gelatin gels (NOVEX, San Diego, CA). After electrophoresis, gels were washed twice with 2.5% Triton X-100 (37°C, 30 min) and incubated for 16 h with 40 mM Tris-HCl (pH 7.5), 10 mM CaCl2, and 1 µM ZnCl2. Gels were stained with 0.5% (w/v) Coomassie blue in 50% methanol and 10% acetic acid for 30 min, then destained. MMP were detected as clear bands against a blue background.
Nuclear extract preparation
Nuclear extracts were obtained by using a modified method described previously (15). Lavaged cells were lysed with Buffer A (10 mM HEPES, 10 mM KCl, 0.1 mM EDTA, 1.5 mM MgCl2, 0.2% Nonidet P-40, 1 mM DTT, and 0.5 mM PMSF, followed by vortexing to shear the cytoplasmic membranes. Nuclei were pelleted by centrifugation at 3000 rpm for 3 min at 4°C in a microcentrifuge. Nuclear proteins were extracted with high-salt buffer C (20 mM HEPES, 25% glycerol, 1.5 mM MgCl2, 0.1 mM EDTA, 1.5 mM MgCl2, 420 mM NaCl, 1 mM DTT, and 0.5 mM PMSF) and stored at -80°C. Total nuclear protein concentrations were determined by the bicinchoninic acid method.
EMSA
Activation of transcription factors NF-B and AP-1 were
assessed by EMSA with consensus oligonucleotides of NF-B (AGT TGA
GGG GAC TTT CCC AGGC) and AP-1 (CGC TTG ATG AGT CAG CCG GAA; Promega,
Madison, WI), respectively. Probes were end-labeled with
T4 polynucleotide kinase in the presence of
[
-32P]ATP. Labeled probes were purified on a
Nick column (Pharmacia, Piscataway, NJ). Nuclear protein (5 µg) was
incubated with labeled probes for 15 min at room temperature. The
mixture was electrophoresed and the gel dried and subjected to
autoradiography. Band specificity was determined by competition
experiments with a molar excess of double-stranded nucleotide probes
consisting of an unlabeled NF-B or AP-1 consensus binding site that
was added to nuclear extracts before the addition of labeled probes.
Supershift assays for NF-B proteins also were done with polyclonal
Abs obtained from Santa Cruz Biotechnology. Specific Abs against p65,
p50, or c-Rel were incubated with the nuclear
extracts for 1 h at 4°C before the labeled probes were
added.
MMP-2 and -9 mRNA by RT-PCR
Total RNA from macrophages was extracted by TRIzol reagent (Life
Technologies, Gaithersburg, MD) according to the manufacturer’s
protocol. Reverse transcription was conducted for 45 min at 42°C with
oligo(dT) and Moloney murine leukemia virus reverse transcriptase (Life
Technologies). cDNA were amplified with various primers specific for
the cDNA sequences of the following molecules: MMP-2 (5'-TCT GCG GGT
TCT CTG CGT CCT GTG C-3', 5'-GTG CCC TGG AAG CGG AAC GGA AAC T-3'),
MMP-9 (5'-TTC TCT GGA CGT CAA ATG TGG-3', 5'-CAA AGA AGG AGC CCT AGT
TCA AGG-3'), 
-actin (5'-GTG GGC CGC TCT AGG CAC CAA-3', 5'-CTC TTT
GAT GTC ACG CAG GAT TTC-3'). The PCR products were electrophoresed in
1% agarose gels and stained with ethidium bromide-stained gels that
were imaged by using the Alpha-Imager 2000 Documentation and Analysis
Software (Alpha Innotech, San Leandro, CA).
Statistics
Results are presented as means ± SE. Comparison was made by Student’s t test. Statistical calculations were performed with the Statview II statistical package (Abacus Concepts, Berkeley, CA). A value of p < 0.05 was regarded as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether oxidant stress was increased in the lungs of
SP-D-/- mice, LPO concentrations were assessed.
LPO content of lung homogenates was increased significantly in lungs of
SP-D-/- compared with those from WT mice (Fig. 1
). Histochemical staining with OHNAH
tetrazolium, a reagent that detects reactive carbonyls, demonstrated
increased staining in lung sections from
SP-D-/- mice. The intensity of OHNAH staining
in SP-D-/- mice was not uniform, being most
prominent at the sites of foamy macrophage infiltration (Fig. 2). Intracellular ROS in AMs were
determined by CDCFH, an indicator of intracellular peroxides, including
H2O2 and lipid peroxides.
Increased CDCFH fluorescence was observed in AMs from
SP-D-/- compared with those from control mice
(Fig. 3). Taken together with previous
findings demonstrating increased hydrogen peroxide production by AMs
from SP-D-/- mice, the present data support the
concept that oxidative stress is increased in pulmonary tissues in the
absence of SP-D.
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B in SP-D-/- mice
ROS activate redox-sensitive transcription factors, including
NF-B and AP-1 (8). Immunofluorescence staining analysis
with anti-NF-B p65 Ab demonstrated that the p65 subunit of
NF-B was present in the cytoplasm of AM from both WT and
SP-D-/- mice (Fig. 4A). However, in AMs from
SP-D-/- mice, increased staining for NF-B
p65 was observed; furthermore, nuclear staining was markedly increased
in AMs from SP-D-/- mice and was almost never
detected in AMs from WT mice. NF-B activity was determined in
nuclear extracts from SP-D-/- mice by assessing
binding to a consensus NF-B oligonucleotide in EMSA (Fig. 4B). Increased NF-B binding was observed in nuclear
extracts from AMs of SP-D-/- mice. Binding of
the nuclear extract to the NF-B site was inhibited by coincubation
with the unlabeled NF-B oligonucleotide, supporting the specificity
of the EMSAs. Likewise, AP-1 binding activity was increased in nuclear
extracts from AMs of SP-D-/- mice. Supershift
assay for NF-B showed that the protein/DNA complex contained both
components of NF-B p50 and p65, but not c-Rel (Fig. 4C).
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To determine whether increased oxidant production mediated the
expression of MMP by AMs from SP-D-/- mice, the
cells were treated with NAC and PDTC, both antioxidant reagents
(7, 16). Gelatinolytic activity in the culture medium of
untreated and treated cells was analyzed by SDS-PAGE zymography (Fig. 5). Treatment of AMs from
SP-D-/- mice with NAC and PDTC reduced
gelatinolytic activity consistent with mobility of MMP-2 and -9.
Because NADPH oxidases are important sources of ROS in macrophages, we
assessed whether ROS generated by NADPH oxidases or other oxidases
mediated the increased MMP expression characteristic of
SP-D-/- mice. AMs from
SP-D-/- mice were incubated with NADPH oxidase
inhibitors DPI and apocynin. SDS-PAGE zymography demonstrated that both
of the NADPH oxidase inhibitors markedly suppressed MMP enzymatic
activity (Fig. 6A). Likewise,
apocynin reduced MMP-2 and -9 mRNA in cultured AMs from
SP-D-/- mice (Fig. 6B). Apocynin
reduced binding of nuclear extracts from AMs isolated from
SP-D-/- mice to a NF-B oligonucleotide (Fig. 6C). Apocynin also decreased DNA binding activity to an AP-1
oligonucleotide (data not shown). AMs were cultured with SN-50, a
synthetic inhibitory peptide that blocks nuclear import of NF-B
(17). SN-50 markedly suppressed MMP-2 and -9 production by
AM from SP-D-/- mice (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B
activity, and increased MMP production by AMs. Because NF-B is a
critical mediator of transcriptional responses during inflammation,
these findings support the concept that SP-D is required for
appropriate regulation of both oxidant production and inflammatory
responses by AMs. SP-D is required for suppression of steady-state
NF-B activation and MMP expression that may contribute to the
emphysema characteristic of SP-D-/- mice
(4). The increased nuclear translocation and activity of
NF-B seen in the AMs from SP-D-/- mice may
influence the heightened inflammatory responses of AMs from these mice
during pulmonary infections (5).
Increased oxidative stress in the lungs of
SP-D-/- mice was supported by the increased
production of ROS by AMs, increased content of oxidized lipid species,
reactive carbonyls, and CDCFH fluorescence. However, the mechanism
underlying the oxidative stress in the lungs of
SP-D-/- mice remains unclear and may relate
either to increased oxidant production (4), decreased
antioxidant activity, or failure to clear ROS (18). The
present studies support the concept that NF-B activation by AMs was
mediated, at least in part, by apocynin- and DPI-sensitive pathways,
supporting a role of NADPH oxidase or other oxidases in the process.
Recently, NF-B activation pathway by NADPH oxidase in alcoholic
liver injury also was reported (19). However, the
specificity of these inhibitors for various oxidases has not been
established. Indeed, DPI inhibits a wide range of flavoproteins
including NADPH oxidase and complex I within the mitochondrial electron
transport chain (20). Therefore, it is possible that
pathways other than NADPH oxidase are involved in this process. Recent
studies by Bridges et al. (18) also demonstrated that SP-A
and SP-D prevented oxidation of unsaturated phospholipids in vitro
supporting a direct antioxidant function for these proteins. This
activity may be particularly important in the lungs of
SP-D-/- mice, wherein concentrations of
alveolar lipids are markedly increased and concentrations of SP-A are
relatively low (3, 21). Large aggregate surfactant from
SP-D-/- mice contained increased lipid peroxide
species (M. Yoshida and J. Whitsett, unpublished observations), perhaps
reflecting increased oxidant production or decreased oxidant clearance
by the lung.
Foamy macrophages are a prominent feature of the lung pathology in
SP-D-/- mice (2, 3). The increased
oxidant production and foamy AM formation seen in
SP-D-/- mice are reminiscent of findings in
atheromas, wherein uptake of oxidized lipids by tissue macrophages
further induced ROS, and enhanced macrophage activation (22, 23). Although lung lipid concentrations are markedly increased
in SP-D-/- mice (3), it is not
likely that increased lipid content alone is a sufficient stimulus to
generate the activated foamy macrophages. Indeed, similarly increased
surfactant lipid concentrations and foamy macrophages were observed in
GM-CSF and common -chain receptor-deficient mice without the
increased oxidant production or AM activation seen in the
SP-D-/- mice (24, 25). Taken
together, the present findings support the concept that SP-D signaling
is required for the regulation of oxidant production or clearance of
ROS by AMs in the lung. Recent findings that SP-D binds to CD14 via its
carbohydrate recognition domain, inhibiting CD14 LPS interactions
(26), suggesting a mechanism by which AM activity may be
modulated by SP-D. Because LPS-CD14 interactions may also influence
NADPH oxidase and NF-B (19, 27), these pathways may
mediate the increased inflammatory responses seen during pulmonary
infections in the SP-D-/- mice
(5). We also observed that the addition of mouse SP-D (5
µg/ml) in vitro did not reduce MMP production by AMs from
SP-D-/- mice (M. Yoshida and J. A.
Whitsett, unpublished observations). This finding suggests that direct
signaling via SP-D was not sufficient to inhibit MMP production by AMs
from SP-D-/- mice in vitro and that activation
of AMs may be mediated indirectly by chemical messengers generated in
the lungs of SP-D-deficient mice.
SP-D plays an important role in the modulation of pulmonary infection, caused by numerous pathogens (1). SP-D binds to various microorganisms and their products, including Gram-negative and Gram-positive bacteria, respiratory viruses, fungi, and endotoxin. In vitro studies support the role of SP-D in the binding and aggregation of pathogens, enhancing their phagocytosis and killing properties. Paradoxically, in the presence of some pathogens, oxidant production and killing by AMs in vitro was increased by SP-D, findings that contrast with the marked activation of endogenous oxidant production seen in AMs from the SP-D-deficient mice (4). Thus, SP-D actions on effector cells may be mediated by complex interactions among various receptors that may uniquely recognize the pathogen, SP-D-pathogen complexes, or SP-D. Because SP-D also binds to various lipid components, including phosphatidylinositol and glucosylceramide (28, 29), known second messengers involved in inflammatory responses, SP-D also may indirectly influence cell signaling by interacting with such molecules.
The present work demonstrates that the excess ROS generated in the
absence of SP-D, activate the redox-sensitive transcription factor,
NF-B. Thus, SP-D appears to play a central role in the regulation of
NF-B activity in AMs. Because NF-B regulates numerous
proinflammatory response genes expressed by AMs, including IL-1,
TNF-
, IL-6, and MMP-2, and -9 (9),
SP-D-dependent pathways may be important modulators of the general
response of the AM to infection and inflammation. Indeed, in recent
studies, increased production of the cytokines TNF-, IL-6, and
IL-1 was observed after pulmonary infection by bacterial pathogens
in SP-D-/- mice (5), supporting
the concept that SP-D orchestrates both steady-state and
infection-induced proinflammatory cytokine production by AMs.
In the present studies, SN-50, a selective NF-B inhibitor,
suppressed MMP-2 and -9 production. SN-50 is known to inhibit nuclear
import of NF-B, thereby inhibiting its transcriptional activity
(17). An NF-B element is present in the promoter region
of the MMP-9 gene (10, 30), supporting the concept that
SN-50 may suppress MMP-9 production by blocking NF-B activity.
However, NF-B binding sites have not been detected in the promoter
region of the MMP-2 (12), and it is unclear whether the
inhibitory effects of SN-50 on MMP-2 production are regulated by direct
or indirect effects on MMP-2 transcription. Alternatively, NF-B may
bind to and enhance expression of other transcription factors,
including AP-1 and p53, that may increase MMP-2 expression directly or
through protein-protein interactions (31, 32). Finally,
SN-50 shares the nuclear localization sequence that competes for the
nuclear import of endogenous NF-B. The specificity of SN-50 for
NF-B nuclear import has been questioned because other nuclear
proteins share this nuclear import system (33).
Nonetheless, the present finding supports the concept that SP-D plays a
central role in the modulation of MMP expression in AMs by influencing
NF-B activity.
The present study demonstrates an oxidant-dependent activation of
NF-B and enhanced MMP expression by AMs from
SP-D-/- mice that may be involved in the
pathogenesis of emphysema characteristic of this model
(4). Oxidants derived from air pollution, cigarette
smoking, and activated inflammatory cells have been implicated in the
pathogenesis of emphysema in human lung disease (34).
Findings that SP-D concentrations are reduced in lung lavage from
smoking individuals (35) and patients with cystic fibrosis
(36) supports a potential role for SP-D in the regulation
of oxidant-induced lung inflammation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jeffrey A. Whitsett, Division of Neonatology and Pulmonary Biology, Children’s Hospital Medical Center, 3333Burnet Avenue, Cincinnati, OH 45229-3039. E-mail address: jeff.whitsett{at}chmcc.org
3 Abbreviations used in this paper: SP-D, surfactant protein D; AM, alveolar macrophage; MMP, matrix metalloproteinase(s); ROS, reactive oxygen species; WT, wild type; BAL, bronchoalveolar lavage; LPO, lipid hydroperoxide; OHNAH, 3-OH-2-naphthoic acid hydrazine; CDCFH, 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate; NAC, N-acetylcysteine; PDTC, pyrolidine dithiocarbamate; DPI, diphenylene iodonium chloride.
Received for publication December 12, 2000. Accepted for publication April 2, 2001.
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A. P. Senft, T. R. Korfhagen, J. A. Whitsett, S. D. Shapiro, and A. M. LeVine Surfactant Protein-D Regulates Soluble CD14 through Matrix Metalloproteinase-12 J. Immunol., April 15, 2005; 174(8): 4953 - 4959. [Abstract] [Full Text] [PDF]
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M. Ikegami, C.-L. Na, T. R. Korfhagen, and J. A. Whitsett Surfactant protein D influences surfactant ultrastructure and uptake by alveolar type II cells Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L552 - L561. [Abstract] [Full Text] [PDF]
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M. Ochs, L. Knudsen, L. Allen, A. Stumbaugh, S. Levitt, J. R. Nyengaard, and S. Hawgood GM-CSF mediates alveolar epithelial type II cell changes, but not emphysema-like pathology, in SP-D-deficient mice Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1333 - L1341. [Abstract] [Full Text] [PDF]
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 V. Dave, T. Childs, and J. A. Whitsett Nuclear Factor of Activated T Cells Regulates Transcription of the Surfactant Protein D Gene (Sftpd) via Direct Interaction with Thyroid Transcription Factor-1 in Lung Epithelial Cells J. Biol. Chem., August 13, 2004; 279(33): 34578 - 34588. [Abstract] [Full Text] [PDF]
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A. M. LeVine, J. Elliott, J. A. Whitsett, A. Srikiatkhachorn, E. Crouch, N. DeSilva, and T. Korfhagen Surfactant Protein-D Enhances Phagocytosis and Pulmonary Clearance of Respiratory Syncytial Virus Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2): 193 - 199. [Abstract] [Full Text] [PDF]
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) or without (
) treatment showed that both NAC
(C) and PDTC (D) significantly inhibited
gelatinolytic activities of MMP-2 and -9 in the conditioned medium from
SP-D-/- mice. Values were normalized to matched untreated
control ± SE; n = 3; *,
p < 0.05.
