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.
Oliveira
S H
SH
Department of Pathology, University of Michigan Medical School, 13012 Catherine, Ann Arbor, MI 48109-0602, USA.
Hogaboam
C M
CM
Berlin
A
A
Lukacs
N W
NW
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D006632:Histamine / Q000096:biosynthesis; D007211:Indoles / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017997:Leukotriene C4 / Q000096:biosynthesis; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors; D017999:Leukotriene E4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012130:Respiratory Hypersensitivity / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000378:metabolism* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D002722:Chlorobenzenes
D001094:Arachidonate 5-Lipoxygenase; D001578:Benzopyrans; D002264:Carboxylic Acids; D006632:Histamine; D007211:Indoles; D020024:Leukotriene Antagonists; D017997:Leukotriene C4; D017998:Leukotriene D4; D017999:Leukotriene E4; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D016210:Methacholine Chloride; D011422:Propionates; D011804:Quinolines; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; C060893:MK-886; D002722:Chlorobenzenes; C059141:verlukast; C089698:CP 105696