SCF-induced airway hyperreactivity is dependent on leukotriene
production
Sandra H. P.
Oliveira,
Cory M.
Hogaboam,
Aaron
Berlin, and
Nicholas W.
Lukacs
Department of Pathology, University of Michigan Medical School, Ann
Arbor, Michigan 48109-0602
 |
ABSTRACT |
Stem cell factor (SCF) is directly involved in the
induction of airway hyperreactivity during allergen-induced pulmonary
responses in mouse models. In these studies, we examined the specific
mediators and mechanisms by which SCF can directly induce airway
hyperreactivity via mast cell activation. Initial in vitro studies with
bone marrow-derived mast cells indicated that SCF was able to induce
the production of bronchospastic leukotrienes, LTC4 and
LTE4. Subsequently, when SCF was instilled in the airways
of naive mice, we were able to observe a similar induction of
LTC4 and LTE4 in the bronchoalveolar lavage
(BAL) fluid and lungs of treated mice. These in vivo studies clearly
suggested that the previously observed SCF-induced airway hyperreactivity may be related to the leukotriene production after SCF
stimulation. To further investigate whether the released leukotrienes were the mediators of the SCF-induced airway hyperreactivity, an
inhibitor of 5-lipoxygenase (5-LO) binding to the 5-LO activating protein (FLAP) was utilized. The FLAP inhibitor MK-886, given to the
animals before intratracheal SCF administration, significantly inhibited the release of LTC4 and LTE4 into the
BAL fluid. More importantly, use of the FLAP inhibitor nearly abrogated
the SCF-induced airway hyperreactivity. In addition, blocking the
LTD4/E4, but not LTB4, receptor
attenuated the SCF-induced airway hyperreactivity. In addition, the
FLAP inhibitor reduced other mast-derived mediators, including
histamine and tumor necrosis factor. Altogether, these studies indicate
that SCF-induced airway hyperreactivity is dependent upon
leukotriene-mediated pathways.
bone marrow-derived mast cells; stem cell factor; bronchoalveolar
lavage; 5-lipoxygenase activating protein
 |
INTRODUCTION |
THE INITIAL INDUCTION
OF allergen-induced airway responses leads to IgE-mediated mast
cell degranulation and early airway hyperreactivity (AHR) responses.
The activation and degranulation of local mast cell populations is an
immediate response in the airway, mediated both by antigen-specific,
surface-bound IgE and by stem cell factor (SCF)-induced activation
(38, 51). IgE-mediated mast cell activation induces
immediate degranulation and release of inflammatory mediators that can
acutely increase responses, such as vascular permeability,
bronchoconstriction, edema, and mucus secretion, all of which
contribute to decreased pulmonary function and immediate AHR (8,
38, 48, 50). However, prolonged mast cell activation mediated by
other factors, such as SCF, may contribute to the chronicity of the
late-phase response. In addition, recent investigations have identified
the production of interleukin (IL)-1, IL-4, tumor necrosis factor
(TNF), and chemokines upon mast cell degranulation (1, 4, 17, 27, 28, 30). Earlier studies from our laboratory have indicated that
SCF plays an important role in the intensity of allergen-induced AHR
and eosinophilia (4). SCF can directly induce AHR in
normal mice but not in mast cell-deficient mice (4).
Thus SCF-mediated mast cell activation appears to be an
important mechanism for initiating the pathways leading to AHR.
Several different types of mediators that lead to mechanisms that
initiate airway reactivity responses in asthma-type responses have been
identified. However, the cysteinyl leukotrienes (LTC4, LTD4, and LTE4) appear to be very potent
mediators of prolonged airway responsiveness (3, 9, 34, 36,
52). Several studies and clinical trials have now shown that
blocking the action of these lipid mediators significantly diminishes
the intensity of AHR. Although these findings have already led to the
development of a number of novel therapeutic options, the mechanisms of
leukotriene activation and release have not been fully identified. In
these studies, we find that SCF initiates pathways of leukotriene
production that may be responsible for the induction of the subsequent
induction of AHR.
 |
MATERIALS AND METHODS |
Animals.
Six-week-old female CBA/J mice (~20 g) purchased from Jackson
Laboratories (Bar Harbor, ME) were maintained under standard pathogen-free conditions.
Isolation and expansion of bone marrow-derived mast cells.
Primary mast cell lines were derived from femoral bone marrow of
pathogen-free CBA/J mice (Jackson Laboratory; see Refs. 5 and 27). The cells were incubated with DMEM (BioWhittaker,
Walkersville, MA) supplemented with 1 mM L-glutamine, 10 mM
HEPES, 100 U/ml penicillin, 100 µg/ml streptomycin, and 15% FCS
combined with 10% T-stimulated rat splenocyte culture supplement
medium with IL-3 (15 ng/ml) and SCF (15 ng/ml). Without
addition of exogenous SCF, there was poor mast cell growth. The medium
was changed every 3 days. By the end of 2-3 wk, a nonadherent
population of large granular cells was observed. These isolated cells
appeared homogeneous in cytospin preparations stained by Diff-Quik
(Baxter, McGaw Park, IL) with typical mast cell granular appearance.
The homogeneity of these cell lines was determined by flow cytometric
analysis of surface markers, by histamine release assays, and by
electron microscopy. In particular, these cells were c-kit
positive (SCF receptor) but were negative for CD3, CD4, CD8, CD23,
B220, and F480 by flow cytometry. The purity of bone marrow-derived
mast cells (BMMC) was >98%. These cell lines were expanded routinely, as described above, for 3-6 wk. Before each experiment, BMMC were washed, and new medium was added without SCF.
Stimulation of BMMC with murine recombinant SCF.
BMMC (2.5 × 106 cells/well) were incubated in
complete DMEM with 15% FCS in the presence or absence of SCF in
different concentrations (0.1, 1, 10, 100, and 200 ng/ml) at 37°C in
5% CO2 for 1, 6, 18, and 24 h. After stimulation,
cells were centrifuged, and the cell-free supernatant was recovered to
measure leukotrienes.
Collection of bronchoalveolar lavage fluid and lung homogenate
preparation.
Lungs from mice were instilled with 1 ml of PBS via intratracheal
injection with a 1-ml syringe and a 26-gauge needle. After 30-40
s, the PBS was collected by aspiration with the same syringe and
needle. Between 700 and 800 µl could routinely be recollected from
the lung. Whole lungs were collected from the treated mice and
homogenized in 1 ml of PBS containing protease inhibitors (Complete;
Boehringer Mannheim) and 0.05% Triton X-100 (nonionic detergent) using
a tissue homogenizer. The homogenate was then centrifuged at high
speed, and the cell-free supernatant was collected. Leukotriene levels
were measured in cell-free supernatants with specific ELISA
(Calbiochem, Ann Arbor, MI). Histamine levels were measured in the
bronchoalveolar lavage (BAL) fluid and culture supernatants by ELISA
using commercially available kits (Amac, Westbrook, MA).
Intratracheal instillation of SCF.
Recombinant murine SCF (Genzyme, Cambridge, MA) was instilled directly
in the airways of normal CBA/J mice at various concentrations (1-1,000 ng) in 25 µl of saline. Subsequently, mice were
assessed for their AHR responses.
Administration of leukotriene inhibitors to mice.
Animals were pretreated with MK-886 (1 mg/kg two times a day, orally;
Calbiochem) for 3 days. On the 4th day, 2 h before SCF instillation, animals were pretreated with MK-886 (1 mg/kg). Animals were assessed for their AHR responses 4 h after intratracheal instillation of SCF.
The administration of 100 and 10 mg/kg of MK-571 (Calbiochem) or
CP-105696 (gift from H. Showell, Pfizer), respectively, was done orally
the day before and 1 h before SCF administration. These
antagonists block the action of either LTD4 (MK-571) or LTB4 (CP-105696). This treatment protocol has been shown to
significantly inhibit leukotriene activation in previous studies
(2, 41).
Measurement of AHR.
AHR was measured using a Buxco (Troy, NY) mouse plethysmograph that is
specifically designed for the low tidal volumes, as previously
described (4, 5). Briefly, the mouse to be tested was
anesthetized with pentobarbital sodium and intubated via cannulation of
the trachea with an 18-gauge metal tube. The mouse was subsequently ventilated with a Harvard pump ventilator (tidal volume = ~0.15, frequency = 120 breaths/min, positive end-expiratory pressure 2.5-3.0 cmH2O), and the tail vein was cannulated with
a 27-gauge needle for injection of the methacholine challenge. The
plethysmograph was sealed, and readings were monitored by computer.
Because the box is a closed system, a change in lung volume was
represented by a change in box pressure (Pbox) that was
measured by a differential transducer. The system was calibrated with a
syringe that delivered a known volume of 2 ml. A second transducer was
used to measure the pressure swings at the opening of the trachea tube
(Paw), referenced to the body box (i.e., pleural pressure),
and to provide a measure of transpulmonary pressure
(Ptp = Paw
Pbox). The
tracheal transducer was calibrated at a constant pressure of 20 cmH2O. Resistance was calculated with Buxco software by
dividing the change in pressure (Ptp) by the change in flow
(F;
Ptp/
F; units = cmH2O · ml
1 · s
1)
at two time points from the volume curve based on a percentage of the
inspiratory volume. after being hooked up to the box, the mouse was
ventilated for 5 min before readings were acquired. Once baseline
levels were stabilized and initial readings were taken, a methacholine
challenge was given via the cannulated tail vein. After determination
of a dose-response curve (0.001-0.5 mg), an optimal dose was
chosen (0.1 mg methacholine). This dose was used throughout the rest of
the experiments in this study. After the methacholine challenge, the
response was monitored, and the peak airway resistance was recorded as
a measure of AHR.
Statistics.
Statistical significance was determined by ANOVA, and individual groups
were analyzed further using the Student-Newman-Keuls test. P
values <0.05 were considered significant.
 |
RESULTS |
SCF-induced LTC4 and LTE4 release.
Previous investigations have identified that SCF can initiate the
arachidonic acid metabolism pathways and lead to the induction of
LTB4 and prostaglandins (6, 10, 21, 23, 39, 49, 56). Our initial studies extended these findings and
demonstrated that SCF causes the production of LTC4 and
LTE4 from BMMC in a dose- and time-dependent manner, with
at least 100 ng/ml of SCF needed to induce the release of the
leukotrienes (Fig. 1A). The SCF-induced production appears to be sustained over time (Fig. 1B) and may represent a mechanism for continuous release of
these bronchoconstrictive mediators. Thus SCF can induce the activation of the cysteinyl leukotriene pathways and may directly impact airway
pathophysiology.

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Fig. 1.
Stem cell factor (SCF) induces leukotriene production in
bone marrow-derived mast cells. Bone marrow-derived mast cells were
cultured with various doses of SCF for 6 h (A and
C) or in a time-dependant manner (B and
D; with 100 ng/ml SCF), and the supernatants were examined
for leukotreine C4 (LTC4; A and
B) and leukotreine E4 (LTE4;
C and D) by specific ELISA. The mast
cells were cultured at 2 × 106 cells/ml. The purity
of the cells (98%) was assessed by c-kit surface expression
and flow cytometric analysis. Data are means ± SE of 3 separate
experiments. *P < 0.05.
|
|
Our next set of experiments was centered on whether SCF instilled in
the airways of normal mice similarly induced the increased expression
and release of LTC4 and LTE4. Previous studies
have clearly shown that SCF can induce bronchoconstriction directly and
is also involved in the progression of allergen-induced airway responsiveness and hyperreactivity (4). These leukotriene
mediators have long been known to induce the bronchoconstriction
responses. When a dose of SCF (100 ng/mouse) known to induce AHR was
instilled, a time-dependent increase in LTC4 and
LTE4 could be observed in pulmonary samples (Fig.
2). These data correlated well with the progression of AHR in these mice after SCF instillation (Fig. 3). Thus SCF instillation correspondingly
induces AHR and cysteinyl leukotriene production in normal mice.

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Fig. 2.
SCF instilled in the airways of normal CBA/J mice induces
significant increases of LTC4 (A) and
LTE4 (B) levels in whole lung homogenates. SCF
(100 ng/mouse; ) or saline (control; )
was instilled, and lungs were removed at various time points
poststimulation. As indicated by the data, the 4- to 8-h time point
demonstrated peak leukotriene production in the lungs of mice.
*P < 0.05.
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Fig. 3.
SCF instilled in the airways of mice induces a
time-dependent induction of long-term airway hyperreactivity. Normal
CBA/J mice were instilled intratracheally with SCF (100 ng/mouse), and
the airway hyperreactivity response was assessed using an anesthetized
mouse intubated via cannulation of the trachea. The ventilated
unconscious animal was given a methacholine challenge (100 µg/kg)
that induces a low level of airway resistance in normal mice, as
indicated by the saline-treated animals. Background resistance of mice
was similar at all time points and ranged from 1.8 to 2.2 cmH2O · ml 1 · s 1.
Data are means ± SE of 5-6 mice/time point.
*P < 0.05.
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Attenuation of SCF-induced LTC4, LTE4, and
AHR with a 5-lipoxygenase activating protein inhibitor.
5-Lipoxygenase (5-LO) activating protein (FLAP) inhibitors have been
shown to be very effective in blocking allergen-induced AHR by
decreasing the levels of leukotriene production and release during the
responses (15, 16, 19, 43). To determine whether the
SCF-induced AHR was dependent on the release of the leukotrienes, we
used a specific FLAP inhibitor (MK-886). The animals given the FLAP
inhibitor demonstrated a significant decrease in the level of
LTC4 and LTE4 in the BAL fluid (Fig.
4), indicating that the lipoxygenase
metabolism pathway was blocked sufficiently. Our studies have indicated
that SCF can induce significant and long-term AHR. The use of MK-886
treatment significantly attenuated the induction of AHR by SCF
instillation (Fig. 5), indicating that
leukotrienes play a primary role in the induction of these responses.
Overall, these studies indicated that SCF produced during immune
responses in the lung may lead to the activation and release of
leukotrienes and significantly contributed to the induction of AHR
during asthma-type responses.

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Fig. 4.
Mice treated with MK-866, 5-lipoxygenase activating
protein (FLAP) inhibitor, demonstrate significantly reduced
LTC4 (A and B) and LTE4
(C and D) increases in lungs (B and
D) and bronchoalveolar lavage (BAL) fluid (A and
C) of SCF-instilled mice. Animals were treated with MK-866
(1 mg/kg) before SCF instillation (100 ng/mouse), and 1-ml saline BAL
washes and whole lung homogenates were harvested at 4 h
postinstillation. The cell and debris-free fluids were assessed for
leukotriene levels by specific ELISAs. Data are means ± SE from
5-6 mice/group and clearly demonstrate that MK-886 inhibits
increases in leukotriene levels after SCF instillation.
*P < 0.05.
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Fig. 5.
Inhibition of FLAP by MK-886 significantly reduces induction of
airway hyperreactivity by SCF. Mice were treated with MK-866 (1 mg/kg),
as described in Fig. 4, and after SCF instillation (100 ng/mouse), the
airway hyperreactivity to a methacholine challenge (100 µg/kg) was
assessed by plethysmography at 4 h postchallenge. Data are
means ± SE of 5-6 mice/group. *P < 0.05.
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|
We next wanted to determine if there was a difference in the
participation of LTB4 or the cysteinyl leukotrienes. To
examine this aspect, we used previously described inhibitors CP-105696 (LTB4 antagonist) or MK-571 (LTD4 and
LTE4 antagonist; see Refs. 2 and 41). These
inhibitors were used at the optimal doses, as previously described (100 and 10 mg/kg). Animals that were treated with the leukotriene
inhibitors demonstrated a differential effect. Blocking
LTB4 had very little effect at either the 10 or 100 mg/kg
level, whereas use of MK-571 (100 mg/kg) significantly reduced the AHR
induced by SCF (Fig. 6). Thus it appears
that the SCF has a specific effect on the AHR by inducing the release of cysteinyl leukotrienes.

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Fig. 6.
Treatment of mice with LTD4/LTE4
antagonist, but not LTB4 antagonist, reduces SCF-induced
airway hyperreactivity. Mice were treated orally with either MK-571 or
CP-105696 (100 mg/kg) the night before and 1 h before
intratracheal SCF (100 ng/mouse) administration. After 4 h, the
airway hyperreactivity was assessed in the mice by treating them with
methacholine (100 µg/kg iv) and measuring changes in airway
resistance by plethysmograph. Bkgd, background; Meth, methacholine.
Data are means ± SE of 6-8 mice/group. *P < 0.05.
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|
SCF-induced pulmonary histamine and cytokine production is reduced
by MK-866 treatment.
Previous studies have suggested that leukotrienes have a role in
promoting and maintaining inflammatory responses. In this respect, we
also examined whether blocking the production of leukotrienes would
alter other mediators released after SCF instillation into the airways.
SCF-induced mast cell activation induces the release of TNF and
histamine both in vitro and in vivo (11, 19, 27, 33, 52).
Instillation of SCF in the airways clearly induced the
release/production of these early response mediators (Table 1). Use of MK-886 treatment significantly
reduced the level of these mediators in the BAL fluid from
SCF-instilled animals (Table 1). The leukotriene antagonist (MK-571)
did not demonstrate these same inhibitory effects (data not shown),
suggesting that the lipoxygenase pathway and not the specific
leukotrienes may have a role in the TNF and histamine levels. Thus, by
inhibiting lipoxygenase pathways during SCF instillation, acute
mediators were also significantly affected, suggesting that a cascade
of related events may be at least partially dependent on lipoxygenase
activation pathways.
 |
DISCUSSION |
Several pathways of activation likely mediate the induction of
AHR. One major pathway for inducing severe and prolonged airway reactivity in human asthma and in animal models of asthma is via leukotriene production (29, 36, 44). Our previous studies have identified that SCF production during allergic inflammation can
contribute significantly to the induction of the eosinophilic inflammatory responses and the AHR (4, 28). Furthermore, it appears that SCF can directly induce AHR via the activation of local
mast cell populations. In the present study, we have identified that
the primary mediators that are released during SCF-induced AHR are the
cysteinyl leukotriene metabolites LTC4 and
LTE4. These mediators have a long history in the asthma
field for the induction of airway reactivity. In addition, previous studies have clearly indicated that SCF also has a role in airway inflammation induced by allergens. A number of studies, including those
in our own laboratory, have demonstrated that SCF can also induce the
production of chemokines that could augment the inflammatory responses
(25, 26, 31, 40, 47). Together with the leukotriene release upon SCF-mediated activation, the chemokines may represent a
significant amplification system for allergic inflammation. The
production of SCF appears to be maximal at 6-8 h after allergen challenge, therefore associating its production at the time of the
late-phase responses (28). The overproduction of SCF at this relatively later time point prolongs mast cell activation and may
maintain or reinitiate leukotriene release from these cells,
intensifying the late-phase response. The identification of SCF as an
activator of leukotriene release within the airway may open up
additional therapeutic options for blocking prolonged airway dysfunction.
Mast cells appear to have a central role in asthmatic responses;
however, this has been a controversial area in animal models of
allergen-induced airway responses (4, 5, 12, 28, 45, 55).
Recent studies demonstrate that prolonged mast cell activation can have
a devastating effect in the lung, leading to AHR and damaging
inflammation. There are a number of known mediators that can activate
mast cells, including complement mediators (C3a and C5a) and IgE.
However, SCF may be the most widely expressed mast cell activator
within the lung (28). SCF is a cytokine that has a complex
pattern of expression (1, 13, 30). It is initially
expressed as a transmembrane protein on the surface of a number of cell
populations, including fibroblasts, endothelial cells, epithelial
cells, and production by macrophages and mast cells themselves. There
appears to be a reservoir of SCF that can be found in the lungs of mice
(~20 ng/lung) that can be further upregulated by cytokines such as
TNF and IL-4 and subsequently cleaved from the surface of cells
(28). This may set up a situation of a ready supply of
mast cell-activating factor that, when released during allergen- or
virus-induced responses, could initiate a leukotriene- mediated airway reactivity response in asthmatics. Indeed, virus-induced responses have a substantial leukotriene-mediated component associated with them (50). These latter
statements are justified, since SCF can initiate hyperreactive airway
responses by itself without allergen or virus.
FLAP inhibitors and agents that block 5-LO activation have been
shown to be very effective for blocking leukotriene synthesis (15, 43). In these studies, we used the FLAP inhibitor
MK-588 and a LTD4 and LTE4 inhibitor, MK-571,
for demonstrating that SCF has its effects via leukotriene release.
Previous studies in humans and guinea pigs have demonstrated that
instillation of LTD4 in the airways induces airway
reactivity, indicating a direct causal effect of cysteinyl leukotreines
with induction of physiological changes in the lung (18,
22). Although there are some conflicting data in animal models
of allergen-induced AHR, it appears that leukotrienes play a
significant role in the induction of the inflammation and contribute to
the development of AHR (2, 15, 18, 46). Although the
LTD4 and LTE4 antagonist was not as effective
as the FLAP inhibitor, the studies indicate that the SCF-induced
effects were mediated predominantly via the cysteinyl leukotreines and
not via LTB4. This difference was likely a result of the
effect of the reagents used. The FLAP inhibitor (MK-588)
quite effectively inhibited the production of leukotrienes, whereas the
antagonist (MK-571) competed for binding to the receptor. However,
there were other effects of using the FLAP inhibitor that may be
separate from the leukotriene pathway but contribute to the development
of lung hyperreactivity. Significant decreases in histamine and TNF
production were also observed with MK-588 but not with MK-571. The
ability of arachidonic acid metabolites to drive mediator
release/production has been reported previously in several studies
(7, 33, 37, 42), demonstrating that lipoxygenase
activation pathways promote and enhance other aspects of inflammatory
responses. This may suggest that SCF-driven lipoxygenase activation
during the late-phase response (6-8 h postallergen) may enhance
the allergic environment. Thus blocking these pathways may have a more
global benefit than merely affecting the bronchospastic events. This
has been observed clinically in asthma where blocking the lipoxygenase
pathways therapeutically has been very beneficial for many patients and
reduces the inflammation-related chronic disease (14, 24,
53). These issues become important because the long-term effects
of chronic inflammation are likely the most devastating to asthmatics,
possibly leading to airway thickening and peribronchial fibrosis. Most
interesting in these studies is the idea that SCF may provide a primary
stimulus to promote and enhance prolonged leukotriene biosynthesis and
provide a plausible target in the activation pathway for alteration of
prolonged mast cell mediator release.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: N. W. Lukacs, Univ. of Michigan, Pathology, 1301 Catherine, Ann Arbor, MI
48109-0602 (E-mail: nlukacs{at}umich.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 3 November 2000; accepted in final form 9 January 2001.
 |
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