Biomedical subjects

N W Lukacs

Publications and source records attributed to N W Lukacs.

At least 19 recordsLinked to original sources

PubMed2001

Selective CC chemokine receptor expression by central nervous system-infiltrating encephalitogenic T cells during experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell disease of the central nervous system (CNS) characterized by mononuclear cell infiltration, demyelination, and paralysis. Recent studies describing the relationship of chemokine expression with development of clinical disease have led to the hypothesis that distinct chemokine receptors corresponding to specific ligands are expressed by CNS-infiltrating antigen-specific encephalitogenic T cells as well as host-derived bystander T cells and monocytes. In an effort to study encephalitogenic T cell chemokine receptor expression, we examined CC chemokine receptor expression from resting, activated, and CNS-isolated CD4(+) T cells. CCR1, CCR2, CCR3, CCR5, CCR6, CCR7, and CCR8 mRNA is expressed by normal CD4(+) T cells. In vitro activated T cells expressed CCR1, CCR2, CCR3, CCR5, CCR6, CCR7, and CCR8 mRNA as well as CCR4. After EAE induction, CCR1 mRNA was expressed by donor-derived encephalitogenic and host-derived CD4(+) T cells isolated only from CNS and not from spleen. In vivo neutralization of the CCR1 ligand, macrophage inflammatory protein-1alpha (CCL3), resulted in less encephalitogenic CD4(+) T cell CNS infiltration. These results demonstrate the importance of CC chemokine receptor expression by CD4(+) encephalitogenic T cells for CNS infiltration and subsequent disease development.

Animals↗

PubMed2001

Constitutive expression of macrophage-inflammatory protein 2 (MIP-2) mRNA in bone marrow gives rise to peripheral neutrophils with preformed MIP-2 protein.

Macrophage-inflammatory protein 2 (MIP-2) is a major CXC chemokine involved in the migration of polymorphonuclear neutrophils (PMNs) to sites of inflammation. Although cell culture experiments have identified different cell types that can produce MIP-2, the cellular sources in vivo are not clearly defined. By using immunohistochemical staining and analysis of chemokine mRNA expression, the present study aimed to localize cells producing MIP-2 in tissues of normal mice and mice challenged with Yersinia enterocolitica. The results showed a constitutive expression of MIP-2 mRNA in bone marrow (BM) of normal mice, but not in other organs such as spleen, lung, or liver. MIP-2 protein was found in all organs tested but it was exclusively associated with PMNs that stained positive with the cell surface marker Gr-1. Bacterial infection caused a 5-fold increase in the number of MIP-2-positive PMNs recruited to spleens concomitant with a strong increase of splenic MIP-2 mRNA. This correlated well with a 3-fold loss of MIP-2-producing cells in BM. Because MIP-2 mRNA expression in PMNs was increased after stimulation with TNF, the results indicate that newly recruited PMNs can supplement their MIP-2 content through TNF-stimulated transcription. Together, the data imply a constitutive production of MIP-2 by a subset of PMNs in BM and argue for the possibility of a rapid mobilization of MIP-2 through its storage in circulating PMNs.

Animals↗

PubMed2001

Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation.

Allergic asthmatic responses in the airway are associated with airway hyperreactivity, eosinophil accumulation in the lung, and cytokine production by allergen-specific, T helper cell type 2 (Th2) lymphocytes. Here, we show that in a cockroach antigen (CA) model of allergic pulmonary inflammation, the chemokine macrophage inflammatory protein (MIP)-3alpha is expressed in the lung within hours of allergen challenge. To determine the biologic relevance of this expression, mice lacking CCR6, the only known receptor for MIP-3alpha, were studied for their response to CA. CCR6-deficient mice were immunized to the same extent as their wild-type counterparts, as judged by cytokine production in antigen-challenged lymphocytes. However, compared with CA-challenged wild-type mice, challenged CCR6-deficient mice had reduced airway resistance, fewer eosinophils around the airway, lower levels of interleukin 5 in the lung, and reduced serum levels of immunoglobulin E. Together, these data demonstrate that MIP-3alpha and CCR6 function in allergic pulmonary responses and suggest that these molecules might represent novel therapeutic targets for treatment of asthma.

Animals↗

PubMed2001

Respiratory syncytial virus predisposes mice to augmented allergic airway responses via IL-13-mediated mechanisms.

The development of severe childhood asthma may be influenced by several factors including environmental and infectious stimuli. The causal relationship between infectious viral responses, such as respiratory syncytial virus (RSV), and severe asthma during early childhood is unclear. In these studies, the ability for an initial RSV infection to exacerbate and promote a more severe asthmatic-type response was investigated by combining established murine models of disease. We examined the ability of RSV to induce exacerbation of allergic disease over a relatively long period, leading to development of severe airway responses including airway inflammation and hyperreactivity. The preferential production of IL-13 during a primary RSV infection appears to play a critical role for the exacerbation of cockroach allergen-induced disease. The depletion of IL-13 during RSV infections inhibited the exacerbation and acceleration of severe allergen-induced airway hyperreactivity. This was indicated by decreases in airway hyperreactivity and changes in lung chemokine production. These data suggest that the airway responses during asthma can be greatly affected by a previous RSV infection, even when infection occurs before allergen sensitization. Overall, infection of the airways with RSV can induce an IL-13-dependent change in airway function and promotes an environment that contributes to the development of severe allergic asthmatic responses.

Allergens↗

PubMed2001

CXCL10 (IFN-gamma-inducible protein-10) control of encephalitogenic CD4+ T cell accumulation in the central nervous system during experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) Th1-mediated demyelinating disease of the CNS that serves as a model for multiple sclerosis. A critical event in the pathogenesis of EAE is the entry of both Ag-specific and Ag-nonspecific T lymphocytes into the CNS. In the present report, we investigated the role of the CXC chemokine CXCL10 (IFN-gamma-inducible protein-10) in the pathogenesis of EAE. Production of CXCL10 in the CNS correlated with the development of clinical disease. Administration of anti-CXCL10 decreased clinical and histological disease incidence, severity, as well as infiltration of mononuclear cells into the CNS. Anti-CXCL10 specifically decreased the accumulation of encephalitogenic PLP(139-151) Ag-specific CD4+ T cells in the CNS compared with control-treated animals. Anti-CXCL10 administration did not affect the activation of encephalitogenic T cells as measured by Ag-specific proliferation and the ability to adoptively transfer EAE. These results demonstrate an important role for the CXC chemokine CXCL10 in the recruitment and accumulation of inflammatory mononuclear cells during the pathogenesis of EAE.

Acute Disease↗

PubMed2001

III. Chemokines and other mediators, 8. Chemokines and their receptors in cell-mediated immune responses in the lung.

Chemokines constitute a large family of chemotactic cytokines that belong to a super-gene family of 8-10 kDa proteins. The chemokines are considered to be primarily beneficial in host defense against invading pathogens. However, the reactions induced by chemokines can be occasionally excessive, resulting in a harmful response to the host. Recent studies in chemokine biology have elucidated that chemokines are involved in the initiation, development, and maintenance of numbers of diseases including lung diseases. In addition to its chemotactic activity, evidence suggests that chemokines can modify the outcome of the cell-mediated immune responses by altering the Th1/Th2 cytokine profile. Chemokines are also capable of dictating the direction of specific immune responses. Chemokine action is mediated by a large super-family of G-protein coupled receptors, and the receptors are preferentially expressed on Th1/Th2 cells. Certain chemokine receptors are constitutively expressed in immune surveying cells such as dendritic cells and naive T cells. The corresponding chemokines are present in normal lymphoid tissues, suggesting a role of chemokines/receptors in cell homing and cell-cell communication in lymphoid tissue that can be an initial step for immune recognition. Thus, comprehension of the chemokine biology in immune responses appears to be fundamental for understanding the pathogenesis of T cell-mediated immune responses. The following review will highlight the current insight into the role of chemokines and their receptors in the cell-mediated immune response, with a special focus on lung diseases.

Animals↗

PubMed2001

Regulatory effects of eotaxin on acute lung inflammatory injury.

Eotaxin, which is a major mediator for eosinophil recruitment into lung, has regulatory effects on neutrophil-dependent acute inflammatory injury triggered by intrapulmonary deposition of IgG immune complexes in rats. In this model, eotaxin mRNA and protein were up-regulated during the inflammatory response, resulting in eotaxin protein expression in alveolar macrophages and in alveolar epithelial cells. Ab-induced blockade of eotaxin in vivo caused enhanced NF-kappaB activation in lung, substantial increases in bronchoalveolar lavage levels of macrophage inflammatory protein (MIP)-2 and cytokine-induced neutrophil chemoattractant (CINC), and increased MIP-2 and CINC mRNA expression in alveolar macrophages. In contrast, TNF-alpha levels were unaffected, and IL-10 levels fell. Under these experimental conditions, lung neutrophil accumulation was significantly increased, and vascular injury, as reflected by extravascular leak of (125)I-albumin, was enhanced. Conversely, when recombinant eotaxin was administered in the same inflammatory model of lung injury, bronchoalveolar lavage levels of MIP-2 were reduced, as was neutrophil accumulation and the intensity of lung injury. In vitro stimulation of rat alveolar macrophages with IgG immune complexes greatly increased expression of mRNA and protein for MIP-2, CINC, MIP-1alpha, MIP-1beta, TNF-alpha, and IL-1beta. In the copresence of eotaxin, the increased levels of MIP-2 and CINC mRNAs were markedly diminished, whereas MIP-1alpha, MIP-1beta, TNF-alpha, and IL-1beta expression of mRNA and protein was not affected. These data suggest that endogenous eotaxin, which is expressed during the acute lung inflammatory response, plays a regulatory role in neutrophil recruitment into lung and the ensuing inflammatory damage.

Acute Disease↗

PubMed2001

Pivotal role of signal transducer and activator of transcription (Stat)4 and Stat6 in the innate immune response during sepsis.

Signal transducer and activator of transcription (Stat)4 and Stat6 are transcription factors that provide type 1 and type 2 response, respectively. Here, we explored the role of Stat4 and Stat6 in innate immunity during septic peritonitis. Stat4-/- and Stat6-/- mice were resistant to the lethality compared with wild-type (WT) mice. At the mechanistic level, bacterial levels in Stat6-/- mice were much lower than in WT mice, which was associated with increased peritoneal levels of interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, macrophage-derived chemokine (MDC), and C10, known to enhance bacterial clearance. In Stat4-/- mice, hepatic inflammation and injury during sepsis were significantly ameliorated without affecting local responses. This event was associated with increased hepatic levels of IL-10 and IL-13, while decreasing those of macrophage inflammatory protein (MIP)-2 and KC. Sepsis-induced renal injury was also abrogated in Stat4-/- mice, which was accompanied by decreased renal levels of MIP-2 and KC without altering IL-10 and IL-13 levels. Thus, Stat6-/- and Stat4-/- mice appeared to be resistant to septic peritonitis by enhancing local bacterial clearance and modulating systemic organ damage, respectively, via balancing cytokine responses. These results clearly highlight an important role of local type 1 and systemic type 2 cytokine response in protective immunity during sepsis, which can be regulated by Stat proteins.

Animals↗

PubMed2001

Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice.

Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (-/-) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8(-/)- mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo.

Administration, Inhalation↗

PubMed2001

IL-13-induced airway hyperreactivity during respiratory syncytial virus infection is STAT6 dependent.

Airway damage and hyperreactivity induced during respiratory syncytial virus (RSV) infection can have a prolonged effect in infants and young children. These infections can alter the long-term function of the lung and may lead to severe asthma-like responses. In these studies, the role of IL-13 in inducing and maintaining a prolonged airway hyperreactivity response was examined using a mouse model of primary RSV infection. Using this model, there was evidence of significant airway epithelial cell damage and sloughing, along with mucus production. The airway hyperreactivity response was significantly increased by 8 days postinfection, peaked during days 10-12, and began to resolve by day 14. When the local production of Th1- and Th2-associated cytokines was examined, there was a significant increase, primarily in IL-13, as the viral response progressed. Treatment of RSV-infected mice with anti-IL-13 substantially inhibited airway hyperreactivity. Anti-IL-4 treatment had no effect on the RSV-induced responses. Interestingly, when IL-13 was neutralized, an early increase in IL-12 production was observed within the lungs, as was a significantly lower level of viral Ags, suggesting that IL-13 may be regulating an important antiviral pathway. The examination of RSV-induced airway hyperreactivity in STAT6(-/-) mice demonstrated a significant attenuation of the response, similar to the anti-IL-13 treatment. In addition, STAT6(-/-) mice had a significant alteration of mucus-producing cells in the airway. Altogether, these studies suggest that a primary factor leading to chronic RSV-induced airway dysfunction may be the inappropriate production of IL-13.

Animals↗

PubMed2001

Antifungal and airway remodeling roles for murine monocyte chemoattractant protein-1/CCL2 during pulmonary exposure to Asperigillus fumigatus conidia.

Asperigillus fumigatus spores or conidia are quickly eliminated from the airways of nonsensitized individuals but persist in individuals with allergic pulmonary responsiveness to fungus. A. fumigatus-induced allergic airway disease is characterized by persistent airway hyperreactivity, inflammation, and fibrosis. The present study explored the role of CCR2 ligands in the murine airway response to A. fumigatus conidia. Nonsensitized and A. fumigatus-sensitized CBA/J mice received an intratracheal challenge of A. fumigatus conidia, and pulmonary changes were analyzed at various times after conidia. Whole lung levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), but neither MCP-3/CCL7 nor MCP-5/CCL12, were significantly elevated at days 3 and 7 after conidia in nonsensitized mice. MCP-1/CCL2 was significantly increased in lung samples from A. fumigatus-sensitized mice at days 14 and 30 after a conidia challenge. Administration of anti-MCP-1/CCL2 antiserum to nonsensitized mice for14 days after the conidia challenge attenuated the clearance of conidia and significantly increased airway hyperreactivity, eosinophilia, and peribronchial fibrosis compared with nonsensitized mice that received conidia and normal serum. Adenovirus-directed overexpression of MCP-1/CCL2 in A. fumigatus-sensitized mice markedly reduced the number of conidia, airway inflammation, and airway hyperresponsiveness at day 7 after the conidia challenge in these mice. Immunoneutralization of MCP-1/CCL2 levels in A. fumigatus-sensitized mice during days14-30 after the conidia challenge did not affect the conidia burden but significantly reduced airway hyperreactivity, lung IL-4 levels, and lymphocyte recruitment into the airways compared with the control group. These data suggest that MCP-1/CCL2 participates in the pulmonary antifungal and allergic responses to A. fumigatus conidia.

Adenoviridae↗

PubMed2001

Granulocyte-macrophage colony stimulating factor up-regulates CCR1 in human neutrophils.

Neutrophils (polymorphonuclear leukocytes; PMN) are phagocytic cells instrumental in the clearance of infectious pathogens. Human PMN are commonly thought to respond primarily to chemokines from the CXC family. However, recent findings suggest that under specific cytokine activation conditions, PMN can also respond to some CC chemokines. In this study, the effect of GM-CSF, a well-characterized PMN priming and maturation factor, on CC-chemokine receptor (CCR) expression in PMN was investigated. Constitutive expression of CCR1 and CCR3 mRNA in PMN was detected by ribonuclease protection assay. Following incubation of PMN with GM-CSF (0.01-10 ng/ml; 6 h) CCR1 mRNA expression was rapidly (approximately 1 h) up-regulated. In contrast, no significant induction of CCR2, CCR3, CCR4, or CCR5 mRNA was observed. CCR1 protein was also up-regulated by GM-CSF stimulation. GM-CSF-induced up-regulation of CCR1 showed functional consequences because GM-CSF-treated PMN, but not control cells, responded to the CC chemokines macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-3, and RANTES in assays of chemotactic migration and intracellular calcium mobilization. These results suggest that PMN activated by the proinflammatory cytokine GM-CSF can change their receptor expression pattern and become responsive to CC chemokines.

Calcium↗

PubMed2001

Stem cell factor and igE-stimulated murine mast cells produce chemokines (CCL2, CCL17, CCL22) and express chemokine receptors.

OBJECTIVE AND DESIGN: In the present study we investigated the effect of SCF and/or IgE on histamine, TNF-alpha and chemokines released from bone marrow-derived mast cells (BMMC) as well as chemokine receptor expression. MATERIAL AND METHODS: BMMC were derived from femoral bone marrow of CBA/J mice. The purity of BMMC was >98% after 3 weeks. BMMC (2.5 x 10(6) cells/well) were incubated in the presence or absence of either SCF, IgE plus DNP or a combination of SCF and IgE for 6 and 18 h. Cell-free supernatants were recovered to measure CC chemokines, TNF-alpha and histamine release utilizing ELISA assays. CC chemokine family receptors were detected by RT-PCR analysis, and confirmed using functional chemotactic assays. RESULTS: Histamine levels were comparable between SCF and IgE stimulated cells, whereas TNF-alpha production was significantly greater after IgE compared to SCF stimulation. SCF and/or IgE-stimulated BMMC released CC chemokines, CCL22 (MDC), CCL17 (TARC) and CCL2 (MCP-1). Increased mRNA expression of CCR1, CCR2, CCR3, and CCR5 was detected in SCF and IgE-stimulated BMMCs. Functional chemotactic assays confirmed the expression data. CONCLUSION: SCF and IgE can up-regulate the expression of chemokines and chemokine receptors on mast cells. Thus, SCF may play a significant role in their activation and inflammation during allergic responses.

Animals↗

PubMed2001

Role of interleukin-12 and stat-4 in the regulation of airway inflammation and hyperreactivity in respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is a respiratory pathogen that can cause significant morbidity in infants and young children. Interestingly, the majority of children who acquire a RSV infection do not exhibit severe symptoms. Development of a Th1 response has been associated with resolution of symptoms in viral infections and may explain mild RSV illness. The current study investigated the cytokine response observed in mild disease in C57BL/6 mice that had low airway resistance and mucus production with little pulmonary inflammation. RSV infection in these mice was accompanied by a fourfold increase in interleukin-12(IL-12). Treatment of RSV-infected mice with anti-IL-12 resulted in an increase in airway hyperreactivity, mucus production, and airway inflammation (eosinophilia). Since IL-12 activation is dependent on Stat-4-mediated intracellular signal transduction, similar experiments were performed in Stat-4 deficient mice and demonstrated similar results to those obtained from anti-IL-12 treated mice. Again, there was an increase in airway hyperreactivity and mucus production, and goblet cell hypertrophy. These studies support the importance of IL-12 in the immune response to RSV infection resulting in resolution of disease and protection from inappropriate inflammatory responses.

Animals↗

PubMed2001

Thrombin regulates chemokine induction during human retinal pigment epithelial cell/monocyte interaction.

Thrombin, an important clotting factor, extravasates at sites of blood-retina barrier breakdown that is often associated with many retinal diseases. Here we investigated the effects of thrombin on human retinal pigment epithelial (HRPE) cells, monocytes, and HRPE cell/monocyte co-cultures. Thrombin induced secretion and mRNA expression of HRPE interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1). Thrombin also enhanced IL-8 and MCP-1 by HRPE cell/monocyte co-cultures, by apparently enhancing cell-cell contact mechanisms. The thrombin effects on IL-6 secretion were similar to those on chemokine secretion. Thrombin-induced chemokines by co-cultures were inhibited by anti-tumor necrosis factor-alpha (TNF-alpha) antibody, but not by anti-IL-1beta antibody. TNF-alpha was detected in cell lysates of monocytes detached from HRPE cells after co-culture stimulation with thrombin. HRPE cells mainly produced these chemokines. However, thrombin generally potentiated exogenous IL-1beta- and TNF-alpha-induced chemokine production by HRPE cells, monocytes, and co-cultures. Interferon-gamma potentiated chemokine secretion by co-cultures with or without thrombin. Our results indicate that thrombin may cause leukocyte recruitment by inducing HRPE cell and monocyte chemokine and by enhancing HRPE cell/monocyte interactions, in part because of monocyte TNF-alpha induction, suggesting important mechanisms for ocular inflammation during blood-retina barrier breakdown and intra-ocular hemorrhage.

Antibodies↗

PubMed2001

Role of chemokines in the pathogenesis of asthma.

The prevalence of asthma has risen drastically in the last two decades, with a worldwide impact on health care systems. Although several factors contribute to the development of asthma, inflammation seems to be a common factor that leads to the most severe asthmatic responses. In the past decade, researchers have characterized a large group of chemotactic cytokines, also known as chemokines, which are implicated in asthmatic inflammation. These chemokines control and direct the migration and activation of various leukocyte populations. Targeting chemokines should lead to new ways of controlling the inflammatory asthmatic response.

Animals↗

PubMed2001

Complement-dependent immune complex-induced bronchial inflammation and hyperreactivity.

Bronchoconstriction responses in the airway are caused by multiple insults and are the hallmark symptom in asthma. In an acute lung injury model in mice, IgG immune complex deposition elicited severe airway hyperreactivity that peaked by 1 h, was maintained at 4 h, and was resolved by 24 h. The depletion of complement with cobra venom factor (CVF) markedly reduced the hyperreactive airway responses, suggesting that complement played an important role in the response. Blockade of C5a with specific antisera also significantly reduced airway hyperreactivity in this acute lung model. Complement depletion by CVF treatment significantly reduced tumor necrosis factor and histamine levels in bronchoalveolar lavage fluids, correlating with reductions in airway hyperreactivity. To further examine the role of specific complement requirement, we initiated the immune complex response in C5-sufficient and C5-deficient congenic animals. The airway hyperreactivity response was partially reduced in the C5-deficient mice. Complement depletion with CVF attenuated airway hyperreactivity in the C5-sufficient mice but had a lesser effect on the airway hyperreactive response and histamine release in bronchoalveolar lavage fluids in C5-deficient mice. These data indicate that acute lung injury in mice after deposition of IgG immune complexes induced airway hyperreactivity that is C5 and C5a dependent.

Animals↗

PubMed2001

SCF-induced airway hyperreactivity is dependent on leukotriene production.

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, LTC(4) and LTE(4). Subsequently, when SCF was instilled in the airways of naive mice, we were able to observe a similar induction of LTC(4) and LTE(4) 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 LTC(4) and LTE(4) into the BAL fluid. More importantly, use of the FLAP inhibitor nearly abrogated the SCF-induced airway hyperreactivity. In addition, blocking the LTD(4)/E(4), but not LTB(4), 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.

Animals↗