Title: The influence of mouse strain on murine airway smooth muscle proliferation in culture
Description: Expansion of the smooth muscle mass in the asthmatic airway wall is thought to be the most likely cause of airway hyperresponsiveness and airway obstruction. Inbred strains of laboratory mice are widely used as animal models of asthma and exhibit interstrain differences in airway smooth muscle mass expansion in response to chronic airway allergen exposure. The inbred A/J mouse strain develops increased airway smooth muscle (ASM) mass in response to chronic antigenic stimulation whereas the C3H/HeJ and C57Bl/6 strains do not. In an attempt to identify the genomic differences underlying these interstrain differences, we developed strains of non-transformed cultured murine ASM cells from three inbred mouse strains (A/J, C3H/HeJ, and C57Bl/6). We investigated differences in the proliferative responses of cultured ASM cells from these three strains. The A/J ASM cell demonstrated increased proliferative responses to fetal bovine serum, PDGF-BB, and serotonin. Cell cycle analysis and conditioned media studies suggested that the A/J ASM cell may have enhanced proliferative capacity in culture due to an autocrine/paracrine signaling mechanism. No interstrain differences in hydrogen peroxide stimulated apoptotic cell death were identified. Using microarray analysis, we identified 720 genes that were differentially expressed in cultured A/J murine ASM relative to both of the other two strains. We identified seventeen mitogen genes for which the expression level in A/J murine ASM cells exceeded that of ASM cells from the other two strains of mice. One of these mitogens, FGF21, was further investigated and found to increase murine ASM proliferative responses to PDGF-BB, but was not itself mitogenic for murine ASM.