title: Airway smooth muscle hyperplasia and hypertrophy correlate with glycogen synthase kinase-3(beta) phosphorylation in a mouse model of asthma.
abstract: Increased airway smooth muscle (ASM) mass, a characteristic finding in asthma, may be caused by hyperplasia or hypertrophy. Cell growth requires increased translation of contractile apparatus mRNA, which is controlled, in part, by glycogen synthase kinase (GSK)-3beta, a constitutively active kinase that inhibits eukaryotic initiation factor-2 activity and binding of methionyl tRNA to the ribosome. Phosphorylation of GSK-3beta inactivates it, enhancing translation. We sought to quantify the contributions of hyperplasia and hypertrophy to increased ASM mass in ovalbumin (OVA)-sensitized and -challenged BALB/c mice and the role of GSK-3beta in this process. Immunofluorescent probes, confocal microscopy, and stereological methods were used to analyze the number and volume of cells expressing alpha-smooth muscle actin and phospho-Ser(9) GSK-3beta (pGSK). OVA treatment caused a 3-fold increase in ASM fractional unit volume or volume density (Vv) (PBS, 0.006 +/- 0.0003; OVA, 0.014 +/- 0.001), a 1.5-fold increase in ASM number per unit volume (Nv), and a 59% increase in volume per cell (Vv/Nv) (PBS, 824 +/- 76 microm(3); OVA, 1,310 +/- 183 mum(3)). In OVA-treated mice, there was a 12-fold increase in the Vv of pGSK (+) ASM, a 5-fold increase in the Nv of pGSK (+) ASM, and a 1.6-fold increase in Vv/Nv. Lung homogenates from OVA-treated mice showed increased GSK-3beta phosphorylation and lower GSK-3beta activity. Both hyperplasia and hypertrophy are responsible for increased ASM mass in OVA-treated mice. Phosphorylation and inactivation of GSK-3beta are associated with ASM hypertrophy, suggesting that this kinase may play a role in asthmatic airway remodeling.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.forename: Huan
authors.initials: H
authors.lastname: Deng
authors.forename: Marisa J
authors.initials: MJ
authors.lastname: Linn
authors.forename: Jing
authors.initials: J
authors.lastname: Lei
authors.forename: Gregoriy A
authors.initials: GA
authors.lastname: Dokshin
authors.forename: Diane C
authors.initials: DC
authors.lastname: Fingar
authors.forename: Khalil N
authors.initials: KN
authors.lastname: Bitar
authors.forename: William R
authors.initials: WR
authors.lastname: Henderson
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D048429:Cell Size; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D006984:Hypertrophy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage; D010766:Phosphorylation; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D016212:Transforming Growth Factor beta; D010047:Ovalbumin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3