Strain-Dependent Genomic Factors Affect Allergen-Induced Airway Hyperresponsiveness in Mice

Abstract

Asthma is etiologically and clinically heterogeneous, making the genomic basis of asthma difficult to identify. We exploited the straindependence of a murine model of allergic airway disease to identify different genomic responses in the lung. BALB/cJ and C57BL/6J mice were sensitized with the immunodominant allergen from the Dermatophagoides pteronyssinus species of house dust mite (Der p 1), without exogenous adjuvant, and the mice then underwent a single challenge with Der p 1. Allergic inflammation, serum antibody titers, mucous metaplasia, and airway hyperresponsiveness were evaluated 72 hours after airway challenge. Whole-lung gene expression analyses were conducted to identify genomic responses to allergen challenge. Der p 1-challenged BALB/cJ mice produced all the key features of allergic airway disease. In comparison, C57BL/6J mice produced exaggerated Th2-biased responses and inflammation, but exhibited an unexpected decrease in airway hyperresponsiveness compared with control mice. Lung gene expression analysis revealed genes that were shared by both strains and a set of down-regulated genes unique to C57BL/6J mice, including several G-protein-coupled receptors involved in airway smooth muscle contraction, most notably the M2 muscarinic receptor, which we show is expressed in airway smooth muscle and was decreased at the protein level after challenge with Der p 1. Murine strain-dependent 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 downmodulation of expression of G-protein-coupled receptors involved in regulating airway smooth muscle contraction may contribute to this dissociation.

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

“…A mutation in Cftr led to airway hyperresponsiveness in the BALB Cftr tm1UNC mice, but not in B6 Cftr tm1UNC mice; this finding is consistent with the strain-dependent lung function in challenge models (35,36,45,46) and likely occurred through an increase in pulmonary CD3 + cells. The absence of altered lung function in B6 Cftr tm1UNC mice agrees with previous airway response phenotyping of this strain (47), although changes in breathing rate and minute volume (48,49) have been reported for B6 Cftr tm1UNC mice; therefore, lung function changes apart from airway hyperresponsiveness may exist in this strain.…”

“…We are not aware of prior reports of the lung function in BALB Cftr tm1UNC mice. Regarding mechanism, strain-dependent increases in mucus (36) or in smooth muscle (46) have been implicated in the development of the hyperresponsive trait in BALB mice, but they do not appear to contribute to the differences identified in this study. Indeed, that we did not detect an increase in the number of PAS positive cells in the lungs of BALB Cftr tm1UNC mice, even in the presence of an enhanced Th2 environment, is consistent with the findings of Hauber et al (50), who showed that explanted mucosal tissue from CF patients did not produce increased amounts of MUC5AC or mucin protein following IL-4 or IL-13 stimulation in vitro.…”

Genetic Regulation ofZfp30, CXCL1, and Neutrophilic Inflammation in Murine Lung

“…On day 14, mice were challenged with 50 mg of Der p 1, administered by orotracheal aspiration (Kelada et al 2011;Kelada et al 2014). Mice were phenotyped on day 17 by performing lavage followed by differential cell counts.…”

“…There is ample prior evidence that these traits have a genetic basis (Levitt and Mitzner 1988;Brewer et al 1999;Whitehead et al 2003;Kelada et al 2011) and QTL have been identified for airway hyperresponsiveness on several chromosomes (De Sanctis et al 1995Karp et al 2000;Ackerman et al 2005;Camateros et al 2010;Leme et al 2010;Himes et al 2013). However, a systematic evaluation of whether variation in gene expression underlies these traits has not been conducted.…”

Revisão Sistemática Sobre Modelos Experimentais De Asma Aguda E Crônica Induzidos Com Extrato De Ácaro Da Poeira Doméstica

“…Pode ser seguido ou não da presença de adjuvante 10 . Reproduz muitas características da asma, como elevado nível de inflamação das vias aéreas, IgE 20 Significativo aumento de linfócitos, macrófagos e da produção de muco.…”