title: Plp1 gene duplication inhibits airway responsiveness and induces lung inflammation.
abstract: Mice with Plp1 gene duplication model the most common form of Pelizaeus-Merzbacher disease (PMD), a CNS disease in which patients may suffer respiratory complications. We hypothesized that affected mice would lack airway responsiveness compared to wild-type and carrier mice during methacholine challenge. Wild-type (n = 10), carrier female (n = 6) and affected male (n = 8) mice were anesthetized-paralyzed, tracheostomized and ventilated. Respiratory mechanics were recorded at baseline and during escalating doses of nebulized methacholine followed by albuterol. Lung resistance (RL) was the primary endpoint. Lung tissues were assayed for inflammatory and histological differences. At baseline, phase angles were higher in carrier and affected mice than wild-type. Dose-response RL curves in affected and carrier mice indicated a lack of methacholine response. Albuterol reduced RL in wild-type and carrier, but not affected mice. Affected mice exhibited lower interleukin (IL)-6 tissue levels and alveolar inflammatory infiltrates. Affected and carrier mice, compared to wild-type, lacked airway reactivity during methacholine challenge, but only affected mice exhibited decreased lung tissue levels of IL-6 and inflammation.
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, USA; Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, USA; Thomas Jefferson University, Division of Clinical Pharmacology, Dept. of Pharmacology and Experimental Therapeutics, Philadelphia, PA 19107, USA. Electronic address: elena.radtke@iCloud.com.
authors.forename: Elena
authors.initials: E
authors.lastname: Rodriguez
authors.affiliation: Center for Applied Clinical Genomics, Nemours Biomedical Research, Wilmington, DE 19803, USA; University of Delaware, Department of Biological Sciences, Newark, DE 19716, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Sakowski
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, USA; Center for Applied Clinical Genomics, Nemours Biomedical Research, Wilmington, DE 19803, USA; University of Delaware, Department of Biological Sciences, Newark, DE 19716, USA; Thomas Jefferson University, Department of Pediatrics, Philadelphia, PA 19107, USA.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Hobson
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, USA.
authors.forename: Milena Hirata
authors.initials: MH
authors.lastname: Armani
authors.affiliation: Nemours Alfred I. duPont Hospital for Children, Department of Pathology, Wilmington, DE 19803, USA.
authors.forename: Portia A
authors.initials: PA
authors.lastname: Kreiger
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, USA; Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Thomas Jefferson University, Division of Clinical Pharmacology, Dept. of Pharmacology and Experimental Therapeutics, Philadelphia, PA 19107, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, USA; Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Shaffer
mesh_terms: D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020440:Gene Duplication; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics / Q000503:physiopathology*; D011014:Pneumonia / Q000235:genetics / Q000503:physiopathology*; D015656:Respiratory Mechanics / Q000187:drug effects / Q000235:genetics
chemical_list: D015850:Interleukin-6; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D016210:Methacholine Chloride; D000420:Albuterol
keywords: Airway pharmacology; Albuterol sulfate (PubChem CID: 39859); Lung mechanics; Methacholine chloride (PubChem CID: 6114); Pelizaeus-Merzbacher disease; Phase angle