Stem Cell Factor-Induced Airway Hyperreactivity in Allergic and Normal Mice

Campbell, Emma M.; Hogaboam, Cory M.; Lincoln, Pamela M.; Lukacs, Nicholas W.

doi:10.1016/s0002-9440(10)65377-1

Cited by 52 publications

(53 citation statements)

References 36 publications

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“…mouse model of allergic disease characterized by airway hyperresponsiveness, mucus overproduction, eosinophil accumulation, and peribronchial collagen deposition. 11,13,14 Thus, SCF is up-regulated in inflammatory conditions and appears to be associated with chronic remodeling disease.…”

Section: Discussionmentioning

confidence: 99%

“…SCF can directly induce a dosedependent increase in airway hyperresponsiveness 11 via mast cell activation. 12 Examination of SCF-mutant mice, which were deficient in both SCF and pulmonary mast cells, demonstrated significant reduction in the allergen-induced airway hyperresponsiveness responses.…”

mentioning

confidence: 99%

“…12 Examination of SCF-mutant mice, which were deficient in both SCF and pulmonary mast cells, demonstrated significant reduction in the allergen-induced airway hyperresponsiveness responses. 11 Neutralization of SCF in vivo was very beneficial in murine models of asthma, attenuating Th2 responses, eosinophilia, mucus production, airway remodeling, and collagen deposition. 11,13,14 In the present study we investigated SCF-dependent cross talk between eosinophils and lung fibroblasts derived from chronic allergen-challenged animals (CRA fibroblasts) compared to those from control animals (naïve fibroblasts).…”

mentioning

confidence: 99%

“…11 Neutralization of SCF in vivo was very beneficial in murine models of asthma, attenuating Th2 responses, eosinophilia, mucus production, airway remodeling, and collagen deposition. 11,13,14 In the present study we investigated SCF-dependent cross talk between eosinophils and lung fibroblasts derived from chronic allergen-challenged animals (CRA fibroblasts) compared to those from control animals (naïve fibroblasts). The results from the present studies indicate that SCF has an important role in eosinophil-induced fibroblast activation.…”

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confidence: 99%

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Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Dolgachev

Berlin

Lukacs

2008

The American Journal of Pathology

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In the present studies the role of stem cell factor (SCF) in mediating eosinophil and fibroblast activation during their interaction was investigated. SCF was significantly higher in fibroblasts grown from lungs of chronic allergen-challenged mice compared to fibroblasts grown from normal mice. When eosinophils were layered onto fibroblasts from allergic mice, a significant increase in SCF was detected compared to fibroblasts from nonallergic mice. The interaction of fibroblasts with eosinophils also increased the production of asthmaassociated chemokines, CCL5 and CCL6, was dependent on cell-to-cell interaction, and was observed only with fibroblasts derived from lungs of chronic allergen-challenged mice and not from those derived from unchallenged normal mice. Chemokine production was significantly decreased when anti-SCF antibodies were added during eosinophil-fibroblast interaction. The interaction of fibroblasts from chronic allergen-challenged mice with eosinophils also increased ␣-smooth muscle cell actin and procollagen I expression as well as induced transforming growth factor-␤. The changes in myofibroblast activation were dependent on SCF-mediated pathways because anti-SCF antibody treatment reduced the expression of all three of these latter fibrosisassociated markers. Thus , our data suggest that SCF mediates an important activation pathway for fibroblasts during chronic allergic responses on interaction with recruited eosinophils and suggest a potential mechanism of airway remodeling during chronic disease. Allergic airway inflammation is characterized by peribronchial eosinophil accumulation accompanied by mucus production and airway changes. Structural changes in the asthmatic airway include an increase in smooth muscle mass and deposition of extracellular matrix proteins. These changes correlate with airway hyperresponsiveness, reduced lung function, and an increase in fibroblast and myofibroblast numbers. These debilitating effects are not specifically targeted by current therapeutic agents, presenting a clinical challenge that might be better addressed by an enhanced understanding of the mechanisms. 1 In addition to contributing to airway remodeling, lung fibroblasts may also play a role in local regulation of immune and inflammatory responses. Fibroblasts are a potential source of granulocyte monocyte-colony stimulating factor (GM-CSF) and stem cell factor (SCF), known to promote differentiation, activation, and survival of eosinophils and mast cells. 2 Eosinophils have been shown to highly express c-kit (SCF receptor) on their surface. 3,4 We have previously shown that SCF is an important eosinophil-activating factor 4 that influences eosinophil recruitment in allergic airway inflammation. 5 SCF-induced activation of eosinophils has been shown to up-regulate expression of fibroblast growth factors, such as FGF5 and FGF7 (KGF). 4 Eosinophils also express at least two potent mediators [interleukin (IL)-1␤ and transforming growth factor (TGF)-␤] that induce a myofibroblast phenotype. The emergi...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Dolgachev

Berlin

Lukacs

2008

The American Journal of Pathology

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“…This latter issue could be especially important as SCF/c-kit has a central role in multiple hematopoietic maturation pathways in bone marrow-derived cells. 7,8,33 Blocking SCF within the airway may have multiple effects on this inflammatory system. It has long been known that SCF significantly impacts on mast cell biology and can activate the cells for disease altering effects.…”

Section: Anti-scf Attenuates Chronic Allergen Responsesmentioning

confidence: 99%

Inhibition of SCF attenuates peribronchial remodeling in chronic cockroach allergen-induced asthma

Berlin

Hogaboam

Lukacs

2006

Laboratory Investigation

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The progression and severity of chronic asthma likely depends upon the intensity of the damage and remodeling of the tissue. We have developed a chronic model of allergic asthma using multiple cockroach allergen challenges. Using this clinically relevant allergen we have established significant peribronchial fibrosis and mucus overproduction. These remodeling events are accompanied by intense peribronchial inflammation, including lymphocytes and eosinophils. A cytokine that has been identified as having a prominent role in shortterm allergic events, stem cell factor (SCF), appears to have a significant role in this late-stage process. Using our polyclonal antibody specific for SCF administered into the airways of mice during the final allergen challenges, we find a significant effect on the chronic peribronchial allergen-induced fibrotic remodeling. This was characterized by reduced inflammation, especially eosinophils, as well as reduced hydroxyproline levels in anti-SCF compared to control antibody-treated animals. In addition, when we examined chemokines associated with the chronic disease and neutralized SCF in vivo we observed a corresponding decrease in CCL6 and CCL17. Using an inhibitor, imatinib mesylate, that blocks SCF/c-kit-associated RTK, we find similar results as with anti-SCF for attenuating AHR and fibrotic changes, suggesting that a potential clinical treatment for chronic asthma already exists related to this pathway. These results further support the potential use of SCF/c-kit inhibition for targeting chronic severe asthmatic responses.

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Modulation of Mast Cell Proliferative and Inflammatory Responses by Leukotriene D₄ and Stem Cell Factor Signaling Interactions

Al‐Azzam

Kondeti

Duah

et al. 2014

Journal Cellular Physiology

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Mast cells (MCs) are important effector cells in asthma and pulmonary inflammation, and their proliferation and maturation is maintained by stem cell factor (SCF) via its receptor, c-Kit. Cysteinyl leukotrienes (cys-LTs) are potent inflammatory mediators that signal through CysLT1R and CysLT2R located on the MC surface, and they enhance MC inflammatory responses. However, it is not known if SCF and cys-LTs cross-talk and influence MC hyperplasia and activation in inflammation. Here, we report the concerted effort of the growth factor SCF and the inflammatory mediator LTD4 in MC activation. Stimulation of MCs by LTD4 in the presence of SCF enhances c-Kit-mediated proliferative responses. Similarly, SCF synergistically enhances LTD4-induced calcium, c-fos expression and phosphorylation, as well as MIP1β generation in MCs. These findings suggest that integration of SCF and LTD4 signals may contribute to MC hyperplasia and hyper-reactivity during airway hyper-response and inflammation.

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Stem Cell Factor-Induced Airway Hyperreactivity in Allergic and Normal Mice

Cited by 52 publications

References 36 publications

Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Inhibition of SCF attenuates peribronchial remodeling in chronic cockroach allergen-induced asthma

Modulation of Mast Cell Proliferative and Inflammatory Responses by Leukotriene D₄ and Stem Cell Factor Signaling Interactions

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Stem Cell Factor-Induced Airway Hyperreactivity in Allergic and Normal Mice

Cited by 52 publications

References 36 publications

Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Inhibition of SCF attenuates peribronchial remodeling in chronic cockroach allergen-induced asthma

Modulation of Mast Cell Proliferative and Inflammatory Responses by Leukotriene D4 and Stem Cell Factor Signaling Interactions

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Modulation of Mast Cell Proliferative and Inflammatory Responses by Leukotriene D₄ and Stem Cell Factor Signaling Interactions