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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/L176    most recent 90376.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bentley, J. K. Articles by Hershenson, M. B. Search for Related Content PubMed PubMed Citation Articles by Bentley, J. K. Articles by Hershenson, M. B.

Airway smooth muscle hyperplasia and hypertrophy correlate with glycogen synthase kinase-3β phosphorylation in a mouse model of asthma

The Departments of ¹Pediatrics and Communicable Diseases, ²Molecular and Integrative Physiology, and ³Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan; and ⁴Department of Medicine, University of Washington, Seattle, Washington

Submitted 8 July 2008 ; accepted in final form 10 November 2008

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)-3β, a constitutively active kinase that inhibits eukaryotic initiation factor-2 activity and binding of methionyl tRNA to the ribosome. Phosphorylation of GSK-3β 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-3β in this process. Immunofluorescent probes, confocal microscopy, and stereological methods were used to analyze the number and volume of cells expressing -smooth muscle actin and phospho-Ser⁹ GSK-3β (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 µm³; OVA, 1,310 ± 183 µm³). 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-3β phosphorylation and lower GSK-3β activity. Both hyperplasia and hypertrophy are responsible for increased ASM mass in OVA-treated mice. Phosphorylation and inactivation of GSK-3β are associated with ASM hypertrophy, suggesting that this kinase may play a role in asthmatic airway remodeling.

ovalbumin; remodeling; stereology