title: Mechanisms of emphysema in autosomal dominant cutis laxa.
abstract: Heterozygous elastin gene mutations cause autosomal dominant cutis laxa associated with emphysema and aortic aneurysms. To investigate the molecular mechanisms leading to cutis laxa in vivo, we generated transgenic mice by pronuclear injection of minigenes encoding normal human tropoelastin (WT) or tropoelastin with a cutis laxa mutation (CL). Three independent founder lines of CL mice showed emphysematous pulmonary airspace enlargement. No consistent dermatological or cardiovascular pathologies were observed. One CL and one WT line were selected for detailed studies. Both mutant and control transgenic animals showed elastin deposition into pulmonary elastic fibers, indicated by increased desmosine levels in the lung and by colocalization of transgenic and endogenous elastin by immunostaining. CL mice showed increased static lung compliance and decreased stiffness of lung tissue. In addition, markers of transforming growth factor-β (TGFβ) signaling and the unfolded protein response (UPR) were elevated together with increased apoptosis in the lungs of CL animals. We conclude that the synthesis of mutant elastin in CL activates multiple downstream disease pathways by triggering a UPR, altered mechanical signaling, increased release of TGFβ and apoptosis. We propose that the combined effects of these processes lead to the development of an emphysematous pulmonary phenotype in CL.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Qirui
authors.initials: Q
authors.lastname: Hu
authors.forename: Adrian
authors.initials: A
authors.lastname: Shifren
authors.forename: Carla
authors.initials: C
authors.lastname: Sens
authors.forename: Jiwon
authors.initials: J
authors.lastname: Choi
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szabo
authors.forename: Barry C
authors.initials: BC
authors.lastname: Starcher
authors.forename: Russell H
authors.initials: RH
authors.lastname: Knutsen
authors.forename: J Michael
authors.initials: JM
authors.lastname: Shipley
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Urban
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003483:Cutis Laxa / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003895:Desmosine / Q000378:metabolism; D004195:Disease Models, Animal; D055119:Elastic Modulus / Q000502:physiology; D004549:Elastin / Q000235:genetics* / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D016368:Frameshift Mutation / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015656:Respiratory Mechanics / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014333:Tropoelastin / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D015852:Eukaryotic Initiation Factor-2; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D014333:Tropoelastin; C485184:enhanced green fluorescent protein; D003895:Desmosine; D049452:Green Fluorescent Proteins; D004549:Elastin