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*
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Department of Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110; and
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, and the Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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). The purpose of this
study was to examine the effect of HA fragments on the expression of
MME in alveolar M. The mouse alveolar M cell line MH-S was
stimulated with HA fragments over time, total RNA was isolated, and
Northern blot analysis was performed. HA fragments induced MME mRNA in
a time-dependent fashion, with maximal levels at 6 h. HA
fragments also induced MME protein expression as well as enzyme
activity. The induction of MME gene expression was specific for low
m.w. HA fragments and dependent upon new protein synthesis; it occurred
at the level of gene transcription. We also examined the effect
of HA fragments on MME expression in inflammatory alveolar M from
bleomycin-injured rat lungs. Although normal rat alveolar M did not
express MME mRNA in response to HA fragments, alveolar M from the
bleomycin-treated rats responded to HA fragment stimulation by
increasing MME mRNA levels. Furthermore, baseline and HA
fragment-induced MME gene expression in alveolar M from
bleomycin-treated rats was inhibited by IFN-
. These data suggest
that HA fragments may be an important mechanism for the expression of
MME by M in inflammatory lung disorders. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) play an essential role in
regulating inflammatory matrix turnover through the release of a
variety of mediators, including chemokines, cytokines, and growth
factors as well as reactive oxygen and nitrogen species, proteinases,
and proteinase inhibitors (1, 2, 3, 4, 5, 6, 7). Although the mechanisms regulating
M-induced matrix turnover in inflammatory tissues are incompletely
defined, recent studies suggest a role for ECM components as activators
of inflammatory M (8, 9, 10). Thus, ECM components themselves may
induce M expression of matrix-modifying agents.
M metalloelastase (MME) is a recently identified matrix
metalloproteinase (MMP) secreted by activated M (11, 12). MMPs are a
family of matrix-modifying enzymes that are able to collectively
degrade all components of the ECM (13, 14, 15). MMPs play an important role
in a variety of normal physiological processes such as development,
angiogenesis, cell migration, tissue remodeling, inflammation, and
wound healing and have also been implicated in emphysema, interstitial
fibrosis, granulomatous diseases, and cancer (6, 13, 16, 17, 18, 19, 20, 21, 22). Like
other MMPs, MME is a zinc2+-dependent neutral endopeptidase
secreted by M in a 53-kDa proform that undergoes proteolytic
cleavage to an active 22-kDa enzyme (12). In addition to elastin, MME
also degrades type IV collagen, type I gelatin, fibronectin, laminin,
vitronectin, proteoglycans, chrondroitin sulfate, myelin basic protein,
-1-antitrypsin, and plasminogen (23, 24, 25). MME is also necessary for
M to penetrate basement membranes and appears to play an integral
role in the development of emphysema (17, 26, 27, 28).
The regulation of MME expression in chronic inflammatory states is not
completely understood. There are conflicting data regarding the effects
of LPS on the induction of MME in M, but it has been clearly
demonstrated that dexamethasone, IFN-, and M CSF all
down-regulate constitutive MME expression, whereas granulocyte-M CSF
up-regulates MME expression (9, 29, 30, 31). Although previous
investigators have demonstrated that specific ECM components induce
M expression of interstitial collagenase, the effect of ECM
components on M expression of MME is unknown (9).
Recently, fragments of the ECM glycosaminoglycan hyaluronan (HA) have
been shown to stimulate inflammatory M production of mediators of
tissue injury and repair (10, 32, 33, 34, 35). HA is a ubiquitously distributed
component of the ECM that exists in healthy tissues as a high m.w.
nonsulfated glycosaminoglycan polymer composed of repeating
disaccharide units of (ß, 1–4)-D-glucuronic acid-(ß,
1–3)-N-acetyl-D-glucosamine (36). High
m.w. HA appears to play a role in water homeostasis, plasma protein
distribution, and matrix structuring (36, 37). In contrast, lower m.w.
HA fragments that accumulate at sites of inflammation have different
biological properties than the higher m.w. HA polymers (38, 39, 40). These
lower m.w. HA fragments induce the M expression of numerous
cytokines (IL-1, IL-12, and TNF-) and chemokines (M inflammatory
protein-1, M inflammatory protein-1ß, monokine chemoattractive
protein-1, RANTES, IFN-inducible protein-10, IL-8, and KC) as well as
inducible nitric oxide synthase (iNOS) (10, 32, 33, 34, 35).
In this report, we examined the effect of low m.w. HA fragments on M
expression of MME. We show that HA fragments induce MME in murine M,
notably in alveolar M. These results identify a previously
uncharacterized mechanism by which matrix components may control the
further degradation of the ECM by regulating M expression of MME.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mouse alveolar M cell line MH-S was purchased from
American Type Culture Collection (Manassas, VA) (41). Cells were
maintained in RPMI 1640 supplemented with 10% heat-inactivated low-LPS
FBS and 1% penicillin-streptomycin/1% glutamine (Biofluids,
Rockville, MD) at 37°C under 5% CO2. Mouse bone
marrow-derived M were isolated as described previously from female
C3H/HeJ LPS hyporesponsive mice purchased from The Jackson
Laboratory (Bar Harbor, ME) (35). After harvest, cells (11 x
106 cells/dish) were cultured for 5 days in DMEM
supplemented with 10% heat-inactivated low-LPS FBS, 15% L cell media,
and 1% penicillin-streptomycin/1% glutamine (Biofluids) at 37°C
under 8% CO2. Thioglycollate-elicited peritoneal M were
lavaged from female C3H/HeJ mice at 4 days after injection
of 2 ml of sterile thioglycollate (Sigma, St. Louis, MO). The cells
were allowed to adhere overnight in RPMI 1640 supplemented with 10%
heat-inactivated low-LPS FBS and 1% penicillin-streptomycin/1%
glutamine before use. To exclude the effects of contaminating LPS on
experimental conditions, cell stimulation was conducted in the presence
of 10 µg/ml polymixin B (Calbiochem, La Jolla, CA).
Chemicals and reagents
Purified HA fragments from human umbilical cords were purchased
from ICN Biomedicals (Costa Mesa, CA). The HA-ICN preparation is free
of protein (<2%) and other glycosaminoglycans, with a peak molecular
mass of 200,000 Da (10). Mouse rIFN- (specific activity,
3.0 x 105 U/ml; endotoxin level <0.2 ng/mg) was from
Genzyme (Cambridge, MA), and the bleomycin sulfate, 10 µg/ml
cycloheximide (CHX), and 50 µg/ml actinomycin D were from Sigma.
Polymixin B was purchased from Calbiochem. Protein G-Sepharose was
purchased from Pharmacia Biotech (Piscataway, NJ), and Promix
[35S]methionine and cysteine were purchased from Amersham
(Arlington Heights, IL). Stock solutions of reagents were tested for
LPS contamination using the Limulus amoebacyte assay (Sigma).
Northern blot analysis of mRNA production
RNA was extracted from confluent cell monolayers using 4 M guanidine isothiocyanate and purified by centrifugation through 5.7 M cesium chloride for 12–18 h at 35,000 rpm as described previously (35). A total of 10 µg of total RNA was electrophoresed under denaturing conditions through a 1% formaldehyde-containing agarose gel, and RNA was transferred to Nytran (Schleicher and Schuell, Keene, NH) hybridization filters. Blots were briefly rinsed in 5x SSC, RNA was cross-linked to the filter by UV cross-linking (Stratagene, La Jolla, CA), and blots were hybridized overnight with 106 cpm/ml of 32P-labeled DNA labeled by the random prime method (Amersham). After hybridization, blots were washed once in 2x SSC/0.1% SDS at room temperature for 30 min with shaking and then washed twice in 0.1x SSC/0.1% SDS at 50°C with shaking for 20 min each wash. Blots were exposed at -70°C against Kodak XAR diagnostic film (Rochester, NY). Differences in RNA loading were documented by hybridizing selected blots with 32P-labeled cDNA for aldolase (42). Densitometric scanning was performed using a Molecular Dynamics Personal Densitometer SI (Sunnyvale, CA).
Immunoprecipitation of MME from conditioned media
Immunoprecipitation was performed as described by Bonifacino (43). Briefly, cells were incubated in the absence or presence of 4 µCi/ml of promix under given conditions for 24 h. Conditioned media were precleared for 1 h with 50 µl/ml protein G-Sepharose at 4°C. The precleared supernatant was then incubated overnight at 4°C with 2 µl/ml of polyclonal Ab specific to MME. The immune complexes were subsequently precipitated with 50 µl/ml of protein G-Sepharose for 1 h at 4°C. The beads were then washed four times with dilution and wash buffers as described previously (43). The Ab-Ag complex was dissociated from the protein G beads by boiling the sample in a reducing SDS buffer for 5 min. The supernatant was subsequently applied to a 10% SDS-PAGE gel and run for 1 h. The gel was dried for 1 h at 80°C, and autoradiography was performed.
Zymography
As described above, MME was precipitated from the conditioned media with polyclonal Ab specific to MME. The Ag-Ab-protein G complex was dissociated by boiling for 5 min in nonreducing SDS-buffer before running on a 10% SDS-PAGE gel impregnated with 25 mg/ml of casein under nonreducing conditions for 2 h at 4°C. The gel was then washed twice for 15 min in 2.5% Triton X-100 (Sigma) and once for 5 min in incubation buffer (0.05 M Tris (pH 8.2)/0.005 M CaCl2/0.5 µM ZnCl2) before being incubated at 37°C for 48 h. The gel was stained for 30 min in Coomassie blue and then destained.
Nuclear run-on
Nuclei from confluent monolayers of MH-S cells were harvested by scraping in ice-cold PBS and subsequently isolated by centrifugation through a sucrose cushion as described previously (34, 44). Nuclei were then incubated for 30 min with 1 M DTT, 20 mM NTPs, and 100 µCi [32P]UTP in transcription buffer. The reaction was stopped by addition of the termination buffer, DNase (Promega, Madison, WI), and RNase inhibitor (Boehringer Mannheim, Indianapolis, IN). The nuclei were then incubated with transfer RNA (Sigma) for 15 min before the addition of 10% SDS, 0.2 M EDTA, and proteinase K (Sigma). After a 15-min incubation, the RNA was extracted with phenol/chloroform/isoamyl alcohol, precipitated with 20% TCA, washed with 5% TCA/5% inorganic pyrophosphate, dissolved in 0.1% SET, and precipitated for a second time with 4 M NaAc and 100% ethanol (EtOH) at -80°C for 30 min. Purified radiolabeled RNA was washed once in 70% EtOH, dried with a speed vac concentrator (Savant Instruments, Hicksville, NY), and resuspended in 100 µl diethyl pyrocarbonate water. A total of 5 µl of the radioactive RNA was counted; samples, equalized for radioactivity, were hybridized with Optitran-S membranes (Schleicher and Schuell) containing the cDNAs of interest. Blots were hybridized for 3–4 days, washed once in 2x SSC/0.1% SDS at room temperature for 5 min with shaking, and washed twice in 0.1x SSC/0.1% SDS at 50°C with shaking for 20 min each wash. The blots were then exposed and quantitated with a PhosphorImager (Molecular Dynamics).
Bleomycin administration and bronchoalveolar lavage (BAL)
Bleomycin was administered to male Harlan Sprague-Dawley rats according to published methods (45). Rats were anesthetized using inhaled isofluorane. Following tracheostomy, 500 µl of sterile normal saline with 4 U/kg of bleomycin sulfate was instilled into the lungs through a 25-gauge needle inserted between the cartilagenous rings of the trachea. Control animals received saline alone. The tracheostomy site was sutured, and the animals were allowed to recover until the time of BAL. Rats were killed with a lethal injection of sodium pentathol (Ampro Pharmaceutical, Arcadia, CA) at specified timepoints after intratracheal (i.t.) instrumentation.
BAL was preformed by cannulating the trachea and instilling and
retrieving 
50 ml of sterile normal saline in 5-ml aliquots. The
entire lavage volume was centrifuged, and the cell pellet was
resuspended in RPMI 1640 supplemented with FBS and antibiotics.
A cell differential was preformed on the lavage fluid by Wright-Giemsa
staining before centrifugation and repooling of cells consistently
showed 
95% M. Cell viability was determined using trypan blue
exclusion. Alveolar M were purified by adherence to plastic tissue
culture dishes for 1 h at 37°C in RPMI 1640 without serum
or antibiotics under 5% CO2; nonadherent cells were
removed by aspiration, and adherent M were washed once in 1x
sterile PBS. All subsequent experiments were performed in RPMI
1640 without serum or antibiotics.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cell line
Previously, we have shown that HA fragments with low molecular
masses (200,000 Da) induce the expression of a number of inflammatory
mediators including several members of the chemokine family, IL-1,
TNF-, IL-12, and iNOS (10, 32, 33, 34, 35). Hence, we were interested in
determining whether low m.w. HA fragments could induce MME expression.
To assess the effect of HA fragments on MME gene expression, M were
stimulated with HA fragments for varying periods of time, RNA was
isolated, and Northern blot analysis was performed. Unstimulated MH-S
cells have little baseline MME mRNA expression, but HA fragments
increase MME mRNA levels in a time-dependent fashion (Fig. 1
). The induction of MME mRNA by HA
fragments is maximal after 9–12 h of stimulation and decreases toward
baseline levels after 18 h. HA fragments had no effect on the M
expression of tissue inhibitors of metalloproteinases-1 and stromelysin
(MMP-3), which were both expressed at low levels in MH-S cells (data
not shown).
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or bone marrow-derived M
from the LPS hyporesponsive C3H/HeJ mice (data not shown). HA fragments induce MME mRNA in a dose-dependent and -specific fashion
To further delineate the effects of HA fragments on MME mRNA
expression, we determined the dose-response relationship for HA
fragment-induced MME gene expression in MH-S cells. HA fragments
increase steady-state levels of MME mRNA in a dose-dependent manner
(Fig. 2). To determine whether the
induction of MME was specific to low m.w. HA fragments, we stimulated
MH-S cells in the presence of various other glycosaminoglycans. Only HA
fragments increased steady-state MME mRNA; high m.w. HA, chrondroitin
sulfate A or B, or HA disaccharides had no effect on MME gene
expression in MH-S cells. Thus, the effect of HA fragments on MME gene
expression in MH-S cells appears to be specific to the low m.w. HA
fragments.
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Having identified the effect of HA fragments on MME mRNA levels,
we then investigated MME production at the protein level. MH-S cells
with or without HA fragment stimulation were metabolically labeled with
[35S]methionine/cysteine for 24 h. MME protein
production was determined in the cell culture media by
immunoprecipitation with a polyclonal Ab directed against MME followed
by autoradiography. MME protein was present at very low levels in the
conditioned media from unstimulated cells (Fig. 3). However, low m.w. HA fragments
increased the steady-state protein levels of the 53-kDa MME protein
(Fig. 3). Thus, HA fragments also induce MME expression at the protein
level.
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To assess whether or not the MME induced by HA fragments is
active, casein zymography was performed on MME precipitated from the
conditioned media of unstimulated cells and cells stimulated with HA
fragments for 24 h. MME activity was detected in the media of
resting cells, but there was increased MME activity in the media of
MH-S cells stimulated for 24 h with HA fragments (Fig. 4). The lytic zone at 53 kDa can be
identified as MME based on its isolation with polyclonal Ab specific to
MME, its relative electrophoretic mobility, and its ability to lyse
casein. Furthermore, this 53-kDa band was absent when zymography was
performed in the presence of 15 mM of EDTA, an inhibitor of MMPs (data
not shown). The identity of the higher band (70 kDa) present on
zymography is unclear, but because it was not inhibited by EDTA it most
likely is not an MMP. Taken together, these studies indicate that HA
fragments induce MME activity.
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To further dissect the mechanism for the induction of MME mRNA by
HA fragments, we examined the effect of inhibiting new protein
synthesis upon the induction of MME. We treated MH-S cells with CHX for
30 min before the addition of HA fragments and continued CHX treatment
for 6 h after the addition of HA. CHX had no effect on
basal MME gene expression from unstimulated cells, but it did inhibit
the HA fragment-induced expression of MME (Fig. 5). Thus, the induction of MME gene
expression by HA appears to require new protein synthesis. This is in
contrast to previous studies from our laboratory that have shown that
the induction of chemokines by HA fragments occurs in the
presence of CHX. These results suggest that HA fragment induction of
MME may occur by mechanisms distinct from the induction of
chemokines.
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We examined the effect of HA fragments on MME mRNA transcription
by stimulating cells in the presence of the transcription inhibitor
actinomycin D. Actinomycin D blocked the ability of HA fragments to
increase MME mRNA, whereas the levels of the constitutively expressed
aldolase were unaffected (Fig. 6). Thus,
HA fragments do not appear to increase steady-state MME mRNA levels by
altering the t1/2 of MME mRNA.
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300-fold (Fig. 7). Thus, HA fragments induce
steady-state levels of MME mRNA by increasing MME
transcription.
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from bleomycin-treated rats
Next, we explored the physiological relevance of HA fragment
induction of MME in an animal model of lung injury. When administered
i.t., bleomycin causes initial alveolitis followed by a
fibroproliferative phase and ultimately fibrosis. In
bleomycin-injured rat lungs, there is an increased accumulation of
HA fragments in a size range similar to that of our active lower m.w.
HA fragments, and total lung MME mRNA levels are increased in the lungs
of rats exposed to bleomycin (46, 47). Thus, we hypothesized that
bleomycin induces fragmentation of HA, which in turn induces MME
expression in alveolar M.
Bleomycin or saline was administered to rats i.t., and alveolar M
were isolated from rat BAL fluid after 5 and 9 days. Alveolar M were
stimulated with HA in the absence or presence of IFN- for
6 h, RNA was isolated, and Northern blot analysis was performed.
Alveolar M isolated from control rats express minimal MME mRNA
levels regardless of whether they were resting or stimulated
with HA fragments (Fig. 8). In contrast,
alveolar M from rats treated with bleomycin expressed increased
baseline levels of MME mRNA, and MME expression was further enhanced by
stimulation with HA fragments (Fig. 8). Furthermore, IFN- decreased
MME mRNA levels in both resting and HA fragment-stimulated alveolar
M harvested from bleomycin-injured lungs (Fig. 8). Thus, HA
fragments not only induce MME expression in the alveolar M cell line
MH-S, but also induce MME expression in primary inflammatory alveolar
M.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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expression of the metalloproteinase MME. We have shown previously
that low m.w. fragments of the ECM component HA can stimulate mouse
M to express numerous chemokines and cytokines (10, 32, 33, 34, 35). MME has
been shown to be induced in M by 4ß-phorbol 12-myristate
and granulocyte-M CSF, whereas its expression is inhibited by the
presence of IFN-, M CSF, and dexamethasone (29, 30, 31, 48).
The major finding of this study is that low m.w. HA fragments induce
transcription of MME in M. This effect of HA fragments on MME gene
expression is specific to HA fragments and is quite sensitive, because
it occurs with low concentrations of HA. The induction of MME by HA
fragments was inhibited in the presence of the protein synthesis
inhibitor CHX. This finding suggested that HA fragments may induce MME
by mechanisms distinct from those involved in chemokine expression
(10). To further pursue this possibility, we examined the induction of
MME mRNA in the presence of anti-CD44 Abs that we have shown
inhibit HA fragment-induced chemokine gene expression (10). Unlike
chemokine expression, HA fragment-induced MME mRNA expression was not
inhibited by anti-CD44 Abs, suggesting that MME is induced by a
CD44-independent pathway (data not shown). We also examined HA
fragment-induced MME mRNA expression in the presence of inhibitors of
NF-
B activity that, as we have shown previously, inhibit HA
fragment-induced nitric oxide production (33). Unlike the results
observed during nitric oxide production, inhibitors of NF-B activity
did not affect HA fragment-induced MME mRNA expression (data not
shown). However, similar to what was observed with iNOS mRNA
expression (33), HA fragments also induce MME gene expression in
primary inflammatory alveolar M from bleomycin-injured rat lungs.
These results identify a new role for the ECM in inducing M gene
expression of the metalloproteinase MME in inflammation and suggest
that the mechanisms regulating MME expression in M are distinct from
those for chemokines and nitric oxide.
The HA fragment-induced expression of MME is not just a characteristic
of the alveolar M cell line MH-S but rather appears to be a
characteristic of inflammatory alveolar M. Alveolar M isolated
from rats given i.t. saline show low baseline levels of MME mRNA that
are not further induced by HA fragments. In contrast, inflammatory
alveolar M from rats at 5 and 9 days after i.t. bleomycin have
increased baseline levels of MME and show further induction of MME mRNA
expression upon stimulation with HA fragments. Other primary mouse M
such as thioglycollate-elicited peritoneal M and bone marrow-derived
M have high baseline levels of MME mRNA and do not respond to HA
fragment stimulation. Thus, similar to the results of other
investigators, the regulation of M gene expression by HA fragments
depends in part upon the origin and state of activation of the M
studied (10, 32).
M play an important role in tissue injury, wound healing, and tissue
remodeling. Inflammatory M are not only immunoregulators capable of
effectively phagocytosing pathogens; they also directly and indirectly
contribute to the turnover of the ECM by secreting matrix-modifying
agents such as MMPs (49, 50). The MMP family of matrix-degrading
enzymes has been implicated in tissue injury and disease, and MME has
been shown to play a potential role in both emphysema and tumor
metastasis (6, 17, 25). Furthermore, Shipley et al. (26) have shown
that M require MME to penetrate basement membranes both in vivo and
in vitro. Similarly, it has been demonstrated recently that alveolar
M from patients with emphysema have increased elastolytic activity
and that MME is required for cigarette smoke-induced emphysema in mice
(17, 27). Thus, determining the mechanisms regulating MME expression in
inflammatory states may contribute to a better understanding of
numerous biological processes.
However, the role of MME in fibrotic lung diseases is not well
understood. Bleomycin-induced lung injury is a well-characterized
animal model of pulmonary fibrosis that mimics the pathology found in
the human disease idiopathic pulmonary fibrosis (45, 51). When
administered i.t., bleomycin, an antineoplastic drug, induces acute
alveolitis followed by a prolonged fibroproliferative phase with
disregulated matrix remodeling and ultimately pulmonary fibrosis (45, 51). BAL fluid from bleomycin-treated animals has increased
concentrations of both the native high m.w. HA as well as lower m.w. HA
fragments (46). Immunohistochemistry of bleomycin-injured rat lungs
shows increased concentrations of HA in the alveolar septa as well as
increased HA in alveolar M (46). Furthermore, BAL fluid from
patients with pulmonary fibrosis also contains elevated levels of HA
when compared with normal controls, and the amount of HA correlates
with disease severity (39, 52). Although investigators have
shown recently that total lung MME expression is increased in
bleomycin-induced lung injury, the role and regulation of M
elastases in pulmonary fibrosis are unclear (47).
In this report, we have shown that inflammatory alveolar M from
bleomycin-injured rat lungs express MME mRNA, and that this expression
of MME is further enhanced by HA fragments. Similarly, we have
demonstrated that IFN-, a known down-regulator of MME, inhibits both
baseline MME expression as well as HA-induced MME mRNA in inflammatory
alveolar M (31). The role of IFN- as an antifibrotic agent that
can decrease bleomycin-induced lung injury has been suggested
previously, although the mechanisms for mediating this effect are
unclear (34, 53). These data suggest that HA-induced MME may play a
role in pulmonary fibrosis, and that IFN- may ameliorate the
fibrotic response by inhibiting MME expression.
The regulation of inflammatory genes by interactions among ECM
components, cytokines, and inflammatory cells may have an important
role in determining how inflammatory responses are resolved. These data
suggest that ECM fragments generated at sites of inflammation may be an
important mechanism for stimulating MME expression by inflammatory M
and may suggest a previously unknown mechanism for the regulation of
matrix remodeling.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Paul W. Noble, Yale University School of Medicine, Veterans Affairs Connecticut Healthcare System, Pulmonary Section/111A, 950 Campbell Avenue, West Haven, CT 06516. E-mail address:
3 Abbreviations used in this paper: ECM, extracellular matrix; M, macrophage(s); MME, macrophage metalloelastase; MMP, matrix metalloproteinases; HA, hyaluronan; iNOS, inducible nitric oxide synthase; CHX, cycloheximide; BAL, bronchoalveolar lavage; i.t., intratracheal(ly).
Received for publication June 9, 1998. Accepted for publication January 4, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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fusion protein. Biochem. Biophys. Res. Commun. 228:421.[Medline]
. J. Clin. Invest. 86:1204.
B-dependent mechanism. J. Biol. Chem. 272:8013. in mouse macrophages. J. Immunol. 160:3023.-dependent mechanism in murine macrophages. J. Clin. Invest. 91:2368.
interferon on the cellular responses to bleomycin in mice. Exp. Lung Res. 14:687.[Medline]
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P. L. Bollyky, J. D. Lord, S. A. Masewicz, S. P. Evanko, J. H. Buckner, T. N. Wight, and G. T. Nepom Cutting Edge: High Molecular Weight Hyaluronan Promotes the Suppressive Effects of CD4+CD25+ Regulatory T Cells J. Immunol., July 15, 2007; 179(2): 744 - 747. [Abstract] [Full Text] [PDF]
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 B. W. A. van der Strate, D. S. Postma, C.-A. Brandsma, B. N. Melgert, M. A. Luinge, M. Geerlings, M. N. Hylkema, A. van den Berg, W. Timens, and H. A. M. Kerstjens Cigarette Smoke-induced Emphysema: A Role for the B Cell? Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 751 - 758. [Abstract] [Full Text] [PDF]
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 M A Dentener, J H J Vernooy, S Hendriks, and E F M Wouters Enhanced levels of hyaluronan in lungs of patients with COPD: relationship with lung function and local inflammation Thorax, February 1, 2005; 60(2): 114 - 119. [Abstract] [Full Text] [PDF]
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 C. D. Blundell, P. L. DeAngelis, A. J. Day, and A. Almond Use of 15N-NMR to resolve molecular details in isotopically-enriched carbohydrates: sequence-specific observations in hyaluronan oligomers up to decasaccharides Glycobiology, November 1, 2004; 14(11): 999 - 1009. [Abstract] [Full Text] [PDF]
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T. S. Wilkinson, S. Potter-Perigo, C. Tsoi, L. C. Altman, and T. N. Wight Pro- and Anti-Inflammatory Factors Cooperate to Control Hyaluronan Synthesis in Lung Fibroblasts Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 92 - 99. [Abstract] [Full Text] [PDF]
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K. M. F. Khan, L. R. Howe, and D. J. Falcone Extracellular Matrix-induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression J. Biol. Chem., May 21, 2004; 279(21): 22039 - 22046. [Abstract] [Full Text] [PDF]
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 K. M. Stuhlmeier and C. Pollaschek Glucocorticoids inhibit induced and non-induced mRNA accumulation of genes encoding hyaluronan synthases (HAS): hydrocortisone inhibits HAS1 activation by blocking the p38 mitogen-activated protein kinase signalling pathway Rheumatology, February 1, 2004; 43(2): 164 - 169. [Abstract] [Full Text] [PDF]
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 J. E. A. Wells, T. K. Rice, R. K. Nuttall, D. R. Edwards, H. Zekki, S. Rivest, and V. W. Yong An Adverse Role for Matrix Metalloproteinase 12 after Spinal Cord Injury in Mice J. Neurosci., November 5, 2003; 23(31): 10107 - 10115. [Abstract] [Full Text] [PDF]
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B. Suki, K. R. Lutchen, and E. P. Ingenito On the Progressive Nature of Emphysema: Roles of Proteases, Inflammation, and Mechanical Forces Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 516 - 521. [Full Text] [PDF]
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P. E. Pummill and P. L. DeAngelis Alteration of Polysaccharide Size Distribution of a Vertebrate Hyaluronan Synthase by Mutation J. Biol. Chem., May 23, 2003; 278(22): 19808 - 19814. [Abstract] [Full Text] [PDF]
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G. M. Turino and J. O. Cantor Hyaluronan in Respiratory Injury and Repair Am. J. Respir. Crit. Care Med., May 1, 2003; 167(9): 1169 - 1175. [Full Text] [PDF]
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M. R. Horton, S. Boodoo, and J. D. Powell NF-kappa B Activation Mediates the Cross-talk between Extracellular Matrix and Interferon-gamma (IFN-gamma ) Leading to Enhanced Monokine Induced by IFN-gamma (MIG) Expression in Macrophages J. Biol. Chem., November 8, 2002; 277(46): 43757 - 43762. [Abstract] [Full Text] [PDF]
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A. L. Lazaar, M. I. Plotnick, U. Kucich, I. Crichton, S. Lotfi, S. K. P. Das, S. Kane, J. Rosenbloom, R. A. Panettieri Jr., N. M. Schechter, et al. Mast Cell Chymase Modifies Cell-Matrix Interactions and Inhibits Mitogen-Induced Proliferation of Human Airway Smooth Muscle Cells J. Immunol., July 15, 2002; 169(2): 1014 - 1020. [Abstract] [Full Text] [PDF]
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E. A. Turley, P. W. Noble, and L. Y. W. Bourguignon Signaling Properties of Hyaluronan Receptors J. Biol. Chem., February 8, 2002; 277(7): 4589 - 4592. [Full Text] [PDF]
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D. J. Mahoney, R. T. Aplin, A. Calabro, V. C. Hascall, and A. J. Day Novel methods for the preparation and characterization of hyaluronan oligosaccharides of defined length Glycobiology, December 1, 2001; 11(12): 1025 - 1033. [Abstract] [Full Text] [PDF]
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B. Schneider, R. Gross, and A. Haas Phagosome Acidification Has Opposite Effects on Intracellular Survival of Bordetella pertussis and B. bronchiseptica Infect. Immun., December 1, 2000; 68(12): 7039 - 7048. [Abstract] [Full Text] [PDF]
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T. D. Camenisch and J. A. McDonald Hyaluronan . Is Bigger Better? Am. J. Respir. Cell Mol. Biol., October 1, 2000; 23(4): 431 - 433. [Full Text]
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 M. R. Horton, M. A. Olman, C. Bao, K. E. White, A. M. K. Choi, B.-Y. Chin, P. W. Noble, and C. J. Lowenstein Regulation of plasminogen activator inhibitor-1 and urokinase by hyaluronan fragments in mouse macrophages Am J Physiol Lung Cell Mol Physiol, October 1, 2000; 279(4): L707 - L715. [Abstract] [Full Text] [PDF]
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 G. E. Davis, K. J. Bayless, M. J. Davis, and G. A. Meininger Regulation of Tissue Injury Responses by the Exposure of Matricryptic Sites within Extracellular Matrix Molecules Am. J. Pathol., May 1, 2000; 156(5): 1489 - 1498. [Abstract] [Full Text] [PDF]
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K. A. Fitzgerald, A. G. Bowie, B. S. Skeffington, and L. A. J. O'Neill Ras, Protein Kinase C{zeta}, and I{kappa}B Kinases 1 and 2 Are Downstream Effectors of CD44 During the Activation of NF-{kappa}B by Hyaluronic Acid Fragments in T-24 Carcinoma Cells J. Immunol., February 15, 2000; 164(4): 2053 - 2063. [Abstract] [Full Text] [PDF]
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