Submitted on December 24, 2008
Revised on February 23, 2009
Accepted on March 10, 2009
A severe deficiency of coagulation Factor VIIa results in attenuation of the asthmatic response in mice
Kazuhiko Shinagawa1, Victoria A Ploplis1, and Francis J. Castellino1*
1 University of Notre Dame
* To whom correspondence should be addressed. E-mail: fcastell{at}nd.edu.
Eosinophil counts in the bronchoalveolar lavage fluid (BALF) of wild-type (WT) mice increased after OVA-challenge, a response that was diminished in comparably-challenged low-expressing coagulation Factor VII (FVIItTA/tTA) mice. Levels of Th2 cytokines, IL-4, IL-5, and IL-13, and eosinophil-attracting chemokines, eotaxin and RANTES, were also lower in the OVA-challenged FVIItTA/tTA mice. Eosinophils purified from low-FVII mice underwent apoptosis at a faster rate compared to WT eosinophils and eosinophil migration in response to eotaxin was reduced in eosinophils obtained from FVIItTA/tTA mice. Airway hyperresponsiveness and mucous layer thickness were reduced in OVA-treated FVIItTA/tTA mice, and addition of exogenous FX enhanced mucin production in human epithelial NCI-H292 cells. Correspondingly, incubation of FX with NCI-H292 cells resulted in FXa production, suggesting that the components required for FX activation were present on NCI-H292 cells. These results demonstrate that FVIIa functions in the asthmatic response to an allergen by stimulating lung eosinophilia, airway hyperresponsiveness, and mucin production, this latter effect through its ability to activate FX in conjunction with TF.
