title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Md.
authors.forename: Nariman A
authors.initials: NA
authors.lastname: Balenga
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, Philadelphia, Pa.
authors.forename: William
authors.initials: W
authors.lastname: Jester
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Meiqi
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Md. Electronic address: kdruey@niaid.nih.gov.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002118:Calcium / Q000276:immunology*; D020013:Calcium Signaling; D005260:Female; D005786:Gene Expression Regulation; D007274:Injections, Intraperitoneal; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins / Q000276:immunology; D009119:Muscle Contraction; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000473:pathology*; D010991:Plethysmography; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D020545:Respiratory Mucosa; D046509:Tissue Culture Techniques
chemical_list: D000485:Allergens; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D009077:Mucins; D020710:RGS Proteins; C105346:Rgs5 protein, mouse; D002118:Calcium
keywords: Aspergillus fumigatus; Asthma; G proteins; airway hyperresponsiveness; regulator of G protein signaling proteins