(demarcate time periods (3 minutes each) spent measuring resistance at each concentration of methacholine. show is expressed in airway smooth muscle and was decreased at the protein level after challenge with Der p 1. Murine strainCdependent genomic responses in the lung offer insights into the different biological pathways that develop after allergen challenge. This study of two different murine strains demonstrates that inflammation and airway hyperresponsiveness can be decoupled, and suggests that the down-modulation of expression of G-proteinCcoupled receptors involved in regulating airway smooth muscle contraction may contribute to this dissociation. (Der p 1), we identified genomic factors that affect the response to Der p 1. Identifying YAF1 the genetic basis of asthma is difficult because asthma is etiologically and clinically heterogeneous (1, 2). The severity and persistence of asthma differ between patients, and some patients present with airway hyperresponsiveness (AHR) and elevated markers of inflammation and/or atopy, whereas others present only with AHR (3, 4). GeneCenvironment interactions are also likely to be important in the development of asthma (5). Thus, although recent genome-wide association studies (GWAS) were successful at beginning to identify common genetic variants associated with asthma, many GWAS studies are underpowered to detect genetic loci that are important in certain phenotypes of asthma, and those PF-2341066 (Crizotinib) studies are also underpowered to detect geneCenvironment interactions because of the large sample sizes and detailed exposure assessments required. Hence other complementary approaches are needed. Hallmark features of asthma can be modeled in the mouse (6), and that mouse strain (i.e., genome) strongly affects the phenotype (7C9). For example, the two most commonly used inbred strains, C57BL/6J and BALB/cJ, differ in ovalbumin models of allergic disease (10, 11). Furthermore, the link between allergic inflammation and AHR is also strain-dependent and model-dependent, with certain strains manifesting either or both phenotypes as a function PF-2341066 (Crizotinib) of the induction of different allergen-response pathways (e.g., IL-4/CD4+ T-cellCdependent pathways (12) versus IL-5/eosinophilCdependent pathways (13)), and of the route or timing of exposure (9). We therefore exploited the strain-dependence of murine models of allergic airway disease to help understand the genomic basis of the different etiologic pathways that lead to the primary phenotypes of airway inflammation and AHR. We used the immunodominant allergen from the species of house dust mite (HDM), Der p 1, a relevant PF-2341066 (Crizotinib) human allergen. As expected based on previous studies (8, 11), C57BL/6J mice exhibited a stronger inflammatory response than did BALB/cJ mice, yet showed a striking decrease in airway responsiveness to methacholine. Using gene expression analysis, we identified a set of down-regulated G-proteinCcoupled receptors (GPCRs) involved in airway smooth muscle contraction that may mediate this response. Our results imply that airway smooth muscle gene expression is an important determinant of the physiologic response to allergen, and serves as one explanation for strain-dependent differences in murine models of allergic airway disease. Materials and Methods Mice C57BL/6J and BALB/cJ male mice were purchased from Jackson Laboratory (Bar Harbor, ME) and used beginning at age 7C8 weeks. PF-2341066 (Crizotinib) Mice were housed 3C5 to a cage within an Association for Assessment and Accreditation of Laboratory Animal CareCapproved facility. Allergen Protocol Mice were sensitized intraperitoneally with 10 g low endotoxin Der PF-2341066 (Crizotinib) p 1 (Indoor Biotechnology, Charlottesville, VA), without exogenous adjuvant, on Days 1 and 7 of the study. On Day 14, Der p 1Csensitized mice were challenged by orotracheal aspiration with 50 g of Der p 1 in 40 l of saline, or by saline alone (control mice). Seventy-two hours after the airway challenge, the.