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Loss of regulator of G protein signaling 5 promotes airway hyperresponsiveness in the absence of allergic inflammation.

ABSTRACT: BACKGROUND:Although eosinophilic inflammation typifies allergic asthma, it is not a prerequisite for airway hyperresponsiveness (AHR), suggesting that underlying abnormalities in structural cells, such as airway smooth muscle (ASM), contribute to the asthmatic diathesis. Dysregulation of procontractile G protein-coupled receptor (GPCR) signaling in ASM could mediate enhanced contractility. OBJECTIVE:We explored the role of a regulator of procontractile GPCR signaling, regulator of G protein signaling 5 (RGS5), in unprovoked and allergen-induced AHR. METHODS:We evaluated GPCR-evoked Ca(2+) signaling, precision-cut lung slice (PCLS) contraction, and lung inflammation in naive and Aspergillus fumigatus-challenged wild-type and Rgs5(-/-) mice. We analyzed lung resistance and dynamic compliance in live anesthetized mice using invasive plethysmography. RESULTS:Loss of RGS5 promoted constitutive AHR because of enhanced GPCR-induced Ca(2+) mobilization in ASM. PCLSs from naive Rgs5(-/-) mice contracted maximally at baseline independently of allergen challenge. RGS5 deficiency had little effect on the parameters of allergic inflammation, including cell counts in bronchoalveolar lavage fluid, mucin production, ASM mass, and subepithelial collagen deposition. Unexpectedly, induced IL-13 and IL-33 levels were much lower in challenged lungs from Rgs5(-/-) mice relative to those seen in wild-type mice. CONCLUSION:Loss of RGS5 confers spontaneous AHR in mice in the absence of allergic inflammation. Because it is selectively expressed in ASM within the lung and does not promote inflammation, RGS5 might be a therapeutic target for asthma.

SUBMITTER: Balenga NA

PROVIDER: S-EPMC4119844 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Loss of regulator of G protein signaling 5 promotes airway hyperresponsiveness in the absence of allergic inflammation.

Balenga Nariman A NA Jester William W Jiang Meiqi M Panettieri Reynold A RA Druey Kirk M KM

The Journal of allergy and clinical immunology 20140322 2

<h4>Background</h4>Although eosinophilic inflammation typifies allergic asthma, it is not a prerequisite for airway hyperresponsiveness (AHR), suggesting that underlying abnormalities in structural cells, such as airway smooth muscle (ASM), contribute to the asthmatic diathesis. Dysregulation of procontractile G protein-coupled receptor (GPCR) signaling in ASM could mediate enhanced contractility.<h4>Objective</h4>We explored the role of a regulator of procontractile GPCR signaling, regulator of ...[more]

PMID: 24666695

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Project description:Introduction: Intrauterine growth restriction (IUGR) is associated with asthma. Murine models of IUGR have altered airway responsiveness in the absence of any inflammatory exposure. Given that a primary feature of asthma is airway inflammation, IUGR-affected individuals may develop more substantial respiratory impairment if subsequently exposed to an allergen. This study used a maternal hypoxia-induced mouse model of IUGR to determine the combined effects of IUGR and allergy on airway responsiveness. Methods: Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11-GD 17.5 (IUGR group; term = GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A second group of pregnant mice were housed under normoxic conditions throughout pregnancy (Control). All offspring were sensitized to ovalbumin (OVA) and assigned to one of four treatment groups: Control - normoxic and saline challenge; IUGR - hypoxic and saline challenge; Allergy - normoxic and OVA challenge; and IUGR + Allergy - hypoxic and OVA challenge. At 8 weeks of age, and 24 h post-aerosol challenge, mice were tracheostomised for methacholine challenge and assessment of lung mechanics by the forced oscillation technique, and lungs subsequently fixed for morphometry. Results: IUGR offspring were lighter than Control at birth and in adulthood. Both Allergy and IUGR independently increased airway resistance after methacholine challenge. The IUGR group also exhibited an exaggerated increase in tissue damping and elastance after methacholine challenge compared with Control. However, there was no incremental effect on airway responsiveness in the combined IUGR + Allergy group. There was no impact of IUGR or Allergy on airway structure and no effect of sex on any outcome. Conclusion: IUGR and aeroallergen independently increased bronchoconstrictor response, but when combined the pathophysiology was not worsened. Findings suggest that an association between IUGR and asthma is mediated by baseline airway responsiveness rather than susceptibility to allergen.

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Loss of regulator of G protein signaling 5 promotes airway hyperresponsiveness in the absence of allergic inflammation.

Publications

Loss of regulator of G protein signaling 5 promotes airway hyperresponsiveness in the absence of allergic inflammation.

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