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Nitric oxide (NO) is a short-lived free radical that is secreted by pulmonary macrophages (Mø). An inducible isoform of NO synthase (iNOS) catalyses the production of NO and is activated by lipopolysaccharide and certain T-helper(h) 1 cytokines, including interferon-
and TNF-
. In the present study,
iNOS+ interstitial cells were demonstrated in the alveolar wall of normal Lewis rat lung. Enzymatic digests of normal lung showed that approximately one third of pulmonary ED1+ interstitial Mø (IM)
were iNOS+ and secreted modest amounts of NO without ex vivo stimulation, whereas normal alveolar macrophages (AM) were iNOS
and showed no basal NO secretion. When incubated with heat-killed Listeria monocytogenes (HKL) in vitro, AM secreted larger amounts of NO than did IM. Recombinant murine GM-CSF stimulated production of NO by AM but not by IM. However, when IM were
costimulated with GM-CSF and IFN-, they expressed a marked increase in NO production. Intratracheal challenge with HKL yielded decreased NO production by IM. We conclude that iNOS+ IM are
present in normal rat lung, where they regulate the pulmonary cell-mediated immune response to
antigen.
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INTRODUCTION
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Nitric oxide (NO), a nitrogenous radical secreted by a variety of mammalian cells, is recognized to have pleiotropic biologic activities (1). In addition to its role as a pulmonary vasodilator and neurotransmitter (2), NO promotes the cytotoxic and microbiocidal activities of lung macrophages (MAC) and modulates cell-mediated immunity (3). Nitric oxide synthases (NOS) catalyze the generation of NO via the 5-electron oxidation of the guanidino nitrogen moiety of L-arginine (4), and an inducible NOS (iNOS) isoform is primarily responsible for the production of NO by activated MAC (5).
The production of iNOS is stimulated by certain microbes
(6, 7), lipopolysaccharide (LPS) (8), and type 1 cytokines, including IFN- and TNF- (4). In contrast, corticosteroids, cyclosporine A, and type 2 cytokines, including TGF-
, IL-4,
and IL-10 (4, 9), all downregulate iNOS.
In the normal lung, resident AM are located along alveolar surfaces where they serve as the first line of cellular defense against inhaled particulate allergens (10, 11). It has been demonstrated by Holt and coworkers (11) that some AM are within 0.2 µM of pulmonary interstitial dendritic cells (DC) within the normal lung, so that the release of NO by AM may be able to modulate the antigen-presenting cell (APC) activities of interstitial DC, directly (12).
Pulmonary interstitial macrophages (IM) are distinguished from AM by their location, phenotype, and functional activities (12). Schneeberger and coworkers (17) have suggested that pulmonary IM can cooperate in the antigen-presenting cell (APC) activities of DC. However, immune suppression was observed when increased numbers of IM were added to lymphocyte mitogen assays.
The role of IM in the pulmonary immune response to inhaled antigen has not been established nor has the ability of IM to produce NO been examined in depth. We hypothesized that pulmonary IM might play a role in the regulation of cell-mediated immunity by virtue of their ability to secrete NO in vivo.
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METHODS
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DISCUSSION
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Animals
Inbred pathogen-free 6 to 8 wk-old female Lewis rats weighing 150 to 250 g were obtained from Charles River Laboratories (Cambridge, MA). The rats were housed in a restricted access animal care facility and permitted access to food and water ad libitum.
Reagents
Heat-killed Listeria monocytogenes (HKL) were obtained from the
M.G.H. Bacteriology Laboratory (Boston, MA). The concentration of
organisms was determined by McFarland Standards, and the bacteria were heat-killed in a water bath at 63° C for 90 min, and their nonviability was assessed by failure of the bacteria to grow on blood agar
plates. Aliquots of 109 bacteria /ml in saline were stored at 
20° C. Indocyanine green (2.5 mg/ml; Becton Dickinson Microbiology Systems,
Mountain View, CA) was used as a marker for the distribution of
HKL in the lung after intratracheal administration. Chloral hydrate
(Fisher Scientific, Boston, MA) was administered as an anesthetic at a
dose of 400 mg/kg. Collagenase (150 U/ml; Worthington Biochemical
Corp., Freehold, NJ) and DNAse (50 U/ml; Sigma Chemical Co., St.
Louis, MO) were freshly prepared for digestion of rat lung. Bovine serum albumin (BSA) powder (10.5 g), fraction V (Intergen, Purchase,
NY) was solubilized in 2.9 ml 1 N NaOH, 5.8 ml double-distilled water, and 18.6 ml phosphate buffered saline (PBS) to yield a final pH of
7.35 ± 0.05 and a density of 1.080, as judged by density refractometry (ABBE-31, 33-46-10; VWR Scientific, Boston, MA). The solution was
filtered using a 0.45 µM filter with prefilter (Nalgene; Fisher Scientific) and maintained at 4° C before use.
Complete Medium and Culture Conditions
Cells were cultured in RPMI-1640 (JRH Biosciences, Lenexa, KS),
10% heat-inactivated FBS (Sigma), 50 µg/ml gentamycin (Gibco BRL, Gaithersburg, MD), 0.5% 1 M HEPES buffer (Gibco BRL),
and 2-mercaptoethanol (5 × 10 5 M) (Sigma) and incubated at 37° C
in a humidified chamber of 95% air and 5% CO2. In some experiments, macrophages were preincubated with N'mono-methyl-L-arginine (L-NMMA) (Calbiochem, La Jolla, CA), and cultured ± stimulation. The Griess reagent used for the assay of NO2 (nitrite) contained
1% sulfanilamide, 0.1% (N-1) naphthylehylene diamine hydrochloride, and 2.5% phosphoric acid (all Sigma).
Murine Antibodies
Antirat murine antibodies (mAbs) were used to purify and characterize the cells examined in these studies. These included anti-RMA (18) and ED1 (Biosource International, Camarillo, CA), which react with all lung macrophages, OX-6 (Ia), which binds to Class II MHC molecules of Lewis rat that are normally expressed by B cells, alveolar type II cells, and DC in the noninflamed Lewis rat lung as well as W3 /25 (anti-CD4), OX-8 (anti-CD8), and OX-12 (anti-B cell kappa chain) (all from Accurate Chemical and Scientific Co., Westbury, NY). The mAbs were prepared either from ascites or from supernatants and used at predetermined optimal concentrations to characterize the immune phenotype of the macrophage populations. Murine anti-iNOS (1:100), anti-eNOS (1:100), anti-bNOS (1:100) (all Transduction Laboratories, Lexington, KY) were used for staining in an indirect avidin-biotin immunoperoxidase method.
Intratracheal Instillation of Antigen
Rats were lightly anesthetized with chloral hydrate (400 mg / kg), and
the trachea was surgically exposed. Equal volumes (0.1 ml) of the test
antigen HKL (10 7 to 10 10 bacteria/ml) or normal saline, with indocyanine green (2.5 mg/ml), were introduced into the trachea slowly via a
25
-gauge needle. The rats were killed 12 h later.
Purification of Macrophages
As described previously (19), rats were injected intraperitoneally with sodium pentabarbital (5 mg/100 g) and killed by exsanguination via the abdominal aorta. After tracheal cannulation, a bronchoalveolar lavage (BAL) was performed on intact lungs with seven 5-ml aliquots of PBS containing 0.6 mM EDTA, and the lungs were perfused via the pulmonary artery with Hank's balanced salt solution at pH 7.3 until they blanched. The lavaged cells were kept on ice and washed with PBS, and the cell pellet was treated with 0.2% NaCl for 30 s in order to lyse red blood cells. Cells were washed with PBS, counted in a hemocytometer, assessed for viability by trypan blue dye exclusion, and resuspended in complete medium (CM) for assessment of NO secretion.
To isolate pulmonary interstitial cells (IC), the lungs were first excised and separated from the trachea and major conducting airways, minced with sterile scissors, and enzymatically digested with collagenase and DNAse, using 10 ml of the digest mixture per gram lung, for 90 min at 37 ° C with constant stirring. The enzymatically digested lungs were passed serially through an 80-µM mesh steel screen and through four layers of sterile gauze to produce a single cell suspension; the cells were washed twice by centrifugation (400 × g) in RPMI-1640-10% FBS. Approximately 1 × 10 8 cells were loaded onto a BSA column (density, 1.080) and centrifuged at 10,000 × g for 30 min at 4° C, and the interface cells were harvested and washed three times with PBS-5% FBS. The cell pellet was resuspended in CM and plated at 30 × 10 6/dish in tissue culture dishes (No. 3003; Falcon, Lincoln Park, NJ) and allowed to adhere overnight in a humidified chamber at 37 ° C in 5% CO2 and 95% air. The dishes were washed with warm CM, and nonadherent cells were discarded. The dishes were subjected to a second round of adherence for 2 h; the nonadherent cells were discarded and the adherent cells were retrieved by gentle scraping with a rubber policeman (No. 179707, NUNC; Intermed, Naperville, IL). Viability was assessed by trypan blue exclusion, and the cells were resuspended in CM. OX-6+ DC were purified as previously described (19). In some experiments, peripheral blood was obtained by venipuncture of the dorsal tail vein. Blood monocytes were isolated by adherence on plastic after Ficoll-hypaque column separation.
Generation of Nitric Oxide in vitro
Machrophages (1.5 × 10 5/well) were plated in Lab-tek chamber slides
(Miles Laboratory Inc., Kamkakee, IL) in an atmosphere of 5% CO2
and 95% air and incubated at 37 ° C in a humidified chamber. Supernatants were prepared from cultures of rat AM or lung IM incubated
alone or in CM ± HKL (10 8/ml) ± recombinant murine interferon-
(IFN-) (500 U/ml; Genentech Inc., San Francisco, CA). In some
experiments, macrophages were pretreated with the NOS inhibitor
L-NMMA (1 to 10 mM). In other experiments cells were cultured with
recombinant murine GM-CSF (2 to 2,000 U/ml; Sigma) for 1 to 7 d.
At 48 h, the supernatants were collected for immediate use or stored
at 20° C.
Nitric Oxide Assay
Nitrite in the conditioned supernatants was measured by the method of Ding and coworkers (20) with slight modifications. Briefly, 50 ml of conditioned supernatant were incubated with an equal volume of Griess reagent in triplicate µ-titer wells at 25° C for 20 min. Chromophore absorbance at 562 nm was determined in a µ-plate reader (Biotek Instruments, Inc., Winooski, VT). Nitrite concentration was assessed by using sodium nitrite as a standard.
Immunohistochemistry
Lungs from the dead rats were excised and frozen in cryoembedding medium, sectioned at 5 mM, treated with murine anti-iNOS, and stained by an indirect avidin-biotin immunoperoxidase method for localization of antigens in situ. Endogenous peroxidase activity was blocked by incubation with 0.3% H2O2 for 30 min. The stained sections were evaluated with a Zeiss light microscope, and the positive cells were localized and enumerated by counting a minimum of 10 random hpf (×40 objective). Macrophages from BAL, blood, or pulmonary enzymatic digests were plated in Labtek chamber slides (Miles Laboratory) and cultured with CM alone or with medium containing graded dosages of cytokines at 37 ° C in a humidified chamber of 95% air and 5% CO2. After culture, the supernatants were harvested and the cell monolayers were air-dried and immunostained for iNOS.
Statistical Analysis
Each experiment was repeated at least three times. Data are expressed as mean ± standard deviation (SD) or mean ± standard error of the mean (SEM). Students' unpaired t test was used to assess the significance of differences between nitrite production by AM and IM.
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RESULTS |
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Interstitial Macrophages in the Normal Lung Show iNOS Expression
Immunostaining revealed dim iNOS+ mononuclear cells
within the lung interstitium of normal Lewis rats (Figure 1),
whereas AM were iNOS. Neither interstitial mononuclear
cells nor AM stained positively for endothelial (eNOS) or
brain (bNOS) isoforms (not shown).
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In order to ascertain the cellular source of iNOS-staining within the normal pulmonary interstitium, the lungs were subjected to BAL and subsequently to enzymatic digestion. The yield of mononuclear cells from the BAL fluid of normal rats was 3.4 ± 1.1 × 106 cells per rat. Histochemical staining for nonspecific esterase (NSE) and the MAC-related ED1 antigen showed that ~ 95% of the BAL cells were AM (Table 1). The yield of interstitial mononuclear cells (ICs) after purification from lung digests was 0.38 ± 0.19 × 106 cells per gram wet lung. Approximately 80% of ICs were judged to be IM on the basis of their staining for nonspecific esterase and ED1 antigen (Table 1). Subsets of the purified pulmonary ICs were judged to be OX-12+ B-cells (12%), and fewer than 5% of IC stained positively for T-cell antigens.
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Approximately one-third of IM showed intracytoplasmic staining for iNOS (Figure 2A), whereas less than 5% of AM purified from the BAL were iNOS+ (Figure 2B). Dual-color immunohistochemical staining confirmed colocalization of iNOS antigen in a subset of ED1+ IM (Figure 2C). When pulmonary IC were subjected to purification procedures for the isolation of DC (19), < 5% of the OX-6+ DC were also iNOS+ (not shown), effectively excluding them as a source of pulmonary interstitial iNOS expression in situ.
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Secretion of NO by Subsets of Pulmonary Macrophages
IM and AM purified from the normal lung were compared for their ability to secrete NO without ex vivo stimulation. IM cultured in CM alone for as long as 48 h released modest amounts of NO, whereas AM yielded little NO (Figure 3). When IM were cultured in the presence of L-NMMA, basal nitrite production fell to < 10 µM, comparable to levels produced by unstimulated AM. As the culture medium contains nitrates that may be detected by the Griess reagent, medium blanks were examined in each experiment and showed nitrite levels < 5 µM.
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In order to determine whether MAC could be stimulated to produce NO by the enzymes used to digest the lung, normal AM were incubated with collagenase (150 U/ml) ± DNAse (50 U/ml) for as long as 90 min. Exposure to these enzymes led to no increase in either immunoreactive iNOS expression or NO secretion (not shown).
The release of NO by AM has been implicated in the suppression of DC and T-cell responses (12, 13, 21, 22) and in the
response to Listeria (22). IFN- is recognized to be both a
potent stimulator of NO production (24) and a critical factor in limiting murine listeriosis (25). For these reasons, we first examined the ability of HKL and IFN- to costimulate the secretion of NO by AM and IM in vitro. After costimulation
with HKL (107 to 109) + IFN- (500 U/ml), > 90% of AM and
IM stained strongly for intracytoplasmic iNOS (Figure 4), and
NO secretion was increased above that yielded by HKL alone
(Figure 2).
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Production of NO by Lung Macrophages Is Increased by GM-CSF
As neither AM nor blood monocytes (not shown) expressed iNOS without ex vivo stimulation, the basal expression of iNOS by IM was considered to reflect a possible source of iNOS stimulation in the normal lung. The activities of GM-CSF with respect to NO production were investigated, as this cytokine is constitutively secreted by normal alveolar type II epithelial lining cells and is recognized to modulate the functional activities of MAC (26, 27).
GM-CSF yielded a modest dose-dependent increase in NO
production by AM compared with controls in vitro. Stimulating IM with graded dosages of GM-CSF + IFN- (500 U/ml)
resulted in a substantial increase in NO secretion by IM (Figure 5), whereas AM showed no increase in NO secretion
above that produced by IFN- alone (Figure 5).
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Production of NO in vivo After Intratracheal Administration of HKL
In a previously reported study from this laboratory (10), an intratracheal challenge with < 109 HKL failed to stimulate the APC activities of pulmonary DC purified from the HKL-challenged lungs at time points up to 14 d, and a subsequent intratracheal challenge with comparable dosages of HKL did not lead to a pulmonary cell-mediated immune response. Although this finding was attributed to the sequestration of HKL by phagocytes in vivo, a role for the immunosuppressive effects of pulmonary MAC was not excluded (12, 13).
In order to examine the effect of an airway challenge with HKL on NO production by pulmonary MAC, normal Lewis rats received HKL (107 to 1010 bacteria/rat) intratracheally; AM and IM (both 5 × 105/well) were purified from the challenged lungs at 12 h and cultured in CM alone, and the conditioned supernatants were examined for NO secretion at 48 h. Nitric oxide production by AM was increased only at the highest dosage of HKL (1010), whereas NO production by IM was decreased from saline controls with dosages of HKL > 108 (Figure 6).
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0.05).
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There have been no previous reports of iNOS expression by
macrophrages in the normal rat lung interstitium. IM but not
AM from the normal lung were judged to be a source of NO,
as judged by (1) the detection of immunoreactive cytoplasmic
iNOS protein in IM in the noninflamed germ-free lung and (2)
the secretion of NO by IM purified from normal lung in the
absence of ex vivo stimulation. Although it can be argued that
the rats were exposed to low levels of proinflammatory agents
in the ambient air that could promote iNOS expression, this
would not explain why AM in these rats were routinely
iNOS. In a report of the distribution of iNOS in the lungs of
Sprague-Dawley rats, Kobzik and coworkers (28) failed to detect iNOS staining cells in the lung interstitium. This finding
may reflect differences in the mAb probes used to detect
iNOS or in the immunostaining technique. For example, histochemical dye counterstaining can obscure dimly positive immunostained cells in the lung. In four separate experiments,
we were able to detect iNOS staining in the pulmonary interstitium of Sprague-Dawley rats by our immunostaining technique as well as NO production by IM ex vivo, so that the current observation cannot be attributed to possible rat stain differences.
Unlike AM and blood monocytes, a substantial subset (approximately one-third) of IM showed iNOS activation, and NO production in the absence of exogenous stimulation. For this reason, a local source of iNOS stimulation in the normal lung was considered. The cytokine GM-CSF is secreted by a variety of bone-marrow-derived cells and by normal alveolar type II epithelial lining cells. GM-CSF can prime MAC for their release of cytokines (26, 29) and promote the differentiation of DC precursors in blood and solid tissues (30). It has been suggested that GM-CSF may play an important role in regulating pulmonary cell-mediated immunity by virtue of its ability to inhibit the suppressive activities of activated AM (21).
AM, but not IM, showed increased NO secretion when
stimulated by high concentrations (> 1,000 U/ml) of GM-CSF.
However, a marked increase in NO secretion was observed in
response to relatively low levels of GM-CSF (> 20 U/ml), when
IM were costimulated with IFN-. The potent cooperative effect of GM-CSF and IFN- in the production of NO raises the
possibility that the secretion of IFN- by activated T-cells in
vivo could provide a stimulus for NO secretion by IM during a
T-cell-mediated response in vivo.
Listeria monocytogenes is a potent stimulus for NO secretion by MAC (31) and the progression of murine listeriosis is
substantially enhanced in iNOS/ knockout mice (32). In the
current experiments, HKL proved to be a potent inducer of
NO production by both AM and IM in vitro. Normal AM
showed a consistently greater capacity for NO production in
vitro, a finding that may be attributed to their relative functional maturity with respect to IM (33).
The intratracheal administration of HKL yielded complex
and unexpected differences in iNOS expression and NO secretion by pulmonary MAC. Whereas AM showed little increase
in NO production, except in response to the highest intratracheal dosage of HKL (1010), IM purified from the HKL-challenged rats showed significantly reduced NO production from
saline controls with increasing dosages of HKL in all experiments. In view of the ability of HKL to augment NO production by AM and IM in vitro, the present findings suggest that
factors may be released in response to the HKL challenge that
can actively inhibit NO production by IM in vivo. Whereas TGF- and type 2 cytokines are recognized to inhibit the induction of iNOS (4), the results suggest that factors that antagonize the post-transcriptional secretion of NO may be involved.
The production of NO by pulmonary IM may serve physiologic functions in the normal lung that have not been previously considered. For example, we speculate that modest amounts of NO secreted by IM in the normal pulmonary interstitium may be able to downregulate the accessory activities of DC and inhibit the proliferation of pulmonary interstitial T-lymphocytes (11). This would diminish inflammation in response to modest inhaled particulate antigenic challenges that might otherwise lead to cell-mediated damage of the normal gas-exchange surface.
The findings in the present study further suggest that pulmonary IM, possible primed for NO production by GM-CSF
secreted by nonimmune cells in the lung, may have the capacity to secrete relatively large amounts of NO, if they are exposed to a second proinflammatory stimulus, e.g., IFN-, during an antigen-mediated response in vivo. In this scenario, the
increased pulmonary interstitial production of NO would be
expected to limit further inflammation.
Finally, the diminished secretion of NO by IM in response to increasing dosages of particulate antigens delivered via the airways suggest a mechanism via which suppressed immunoregulatory events in the alveolar wall may be disinhibited in order to yield an effective cell-mediated immune response in vivo. Future studies will address how NO production is regulated by factors released during a pulmonary immune response in vivo.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Richard L. Kradin, M.D., Cox 5, Immunopathology Unit, 100 Blossom Street, Massachusetts General Hospital, Boston, MA 02114.
(Received in original form September 30, 1996 and in revised form February 6, 1997).
Acknowledgments: The writers wish to thank Clare Pinto, Kim Springer, and Long-Hai Zhao for their expert technical assistance, and Maria Valles for her help in compiling the manuscript.
Supported by Grants No. HL-48385 from the National Institutes of Health.
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References |
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REFERENCES
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 D. L. Laskin, B. Weinberger, and J. D. Laskin Functional heterogeneity in liver and lung macrophages J. Leukoc. Biol., August 1, 2001; 70(2): 163 - 170. [Abstract] [Full Text] [PDF]
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 D. Ito, K. Tanaka, S. Suzuki, T. Dembo, and Y. Fukuuchi Enhanced Expression of Iba1, Ionized Calcium-Binding Adapter Molecule 1, After Transient Focal Cerebral Ischemia In Rat Brain Stroke, May 1, 2001; 32(5): 1208 - 1215. [Abstract] [Full Text] [PDF]
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H. Kobayashi, R. Hataishi, H. Mitsufuji, M. Tanaka, M. Jacobson, T. Tomita, W. M. Zapol, and R. C. Jones Antiinflammatory Properties of Inducible Nitric Oxide Synthase in Acute Hyperoxic Lung Injury Am. J. Respir. Cell Mol. Biol., April 1, 2001; 24(4): 390 - 397. [Abstract] [Full Text]
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 C. SITTIPUNT, K. P. STEINBERG, J. T. RUZINSKI, C. MYLES, S. ZHU, R. B. GOODMAN, L. D. HUDSON, S. MATALON, and T. R. MARTIN Nitric Oxide and Nitrotyrosine in the Lungs of Patients with Acute Respiratory Distress Syndrome Am. J. Respir. Crit. Care Med., February 1, 2001; 163(2): 503 - 510. [Abstract] [Full Text]
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R. L. KRADIN, H. SAKAMOTO, F. I. PREFFER, D. DOMBKOWSKI, K. M. SPRINGER, and C. P. LEARY Accumulation of Macrophages with Dendritic Cell Characteristics in the Pulmonary Response to Listeria Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): 535 - 542. [Abstract] [Full Text]
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R. L. KRADIN, H.-W. LIU, N. van ROOIJEN, K. SPRINGER, L.-H. ZHAO, and C. P. LEARY Pulmonary Immunity to Listeria Is Enhanced by Elimination of Alveolar Macrophages Am. J. Respir. Crit. Care Med., June 1, 1999; 159(6): 1967 - 1974. [Abstract] [Full Text]
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 W. S. Cruz, J. A. Corbett, W. J. Longmore, and M. A. Moxley Nitric oxide participates in early events associated with NNMU-induced acute lung injury in rats Am J Physiol Lung Cell Mol Physiol, February 1, 1999; 276(2): L263 - L268. [Abstract] [Full Text] [PDF]
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 M. Weiss, L. L. Moldawer, and E. M. Schneider Granulocyte Colony-Stimulating Factor to Prevent the Progression of Systemic Nonresponsiveness in Systemic Inflammatory Response Syndrome and Sepsis Blood, January 15, 1999; 93(2): 425 - 439. [Full Text] [PDF]
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Y. FUJII, P. GOLDBERG, and S. N. A. HUSSAIN Contribution of Macrophages to Pulmonary Nitric Oxide Production in Septic Shock Am. J. Respir. Crit. Care Med., May 1, 1997; 157(5): 1645 - 1651. [Abstract] [Full Text]
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