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Am J Physiol Lung Cell Mol Physiol 280: L1242-L1249, 2001;
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Vol. 280, Issue 6, L1242-L1249, June 2001

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
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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; delta Ptp/delta 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
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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; triangle ) 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.

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.

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.

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.

                              
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  		Table 1.   Use of FLAP inhibitors significantly reduces histamine and TNF-alpha in the BAL fluid of SCF-challenged mice


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Lung Cell Mol Physiol 280(6):L1242-L1249
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