SCF-induced airway hyperreactivity is dependent on leukotriene production

Stem cell factor (SCF) is directly involved in the induction of airway hype rreactivity 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. In itial in vitro studies with bone marrow-derived mast cells indicated that S CF was able to induce the production of bronchospastic leukotrienes, LTC4 a nd 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 bronch oalveolar lavage (BAL) fluid and lungs of treated mice. These in vivo studi es clearly suggested that the previously observed SCF-induced airway hyperr eactivity may be related to the leukotriene production after SCF stimulatio n. To further investigate whether the released leukotrienes were the mediat ors of the SCF-induced airway hyperreactivity, an inhibitor of 5-lipoxygena se (5-LO) binding to the 5-LO activating protein (FLAP) was utilized. The F LAP inhibitor MK-886, given to the animals before intratracheal SCF adminis tration, 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/E-4, but no t LTB4, receptor attenuated the SCF-induced airway hyperreactivity. In addi tion, the FLAP inhibitor reduced other mast-derived mediators, including hi stamine and tumor necrosis factor. Altogether, these studies indicate that SCF-induced airway hyperreactivity is dependent upon leukotriene-mediated p athways.