Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: I. Effects on lung remodeling and pathology

Respir Res. 2013 Oct 23;14(1):113. doi: 10.1186/1465-9921-14-113.


Background: Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that regulates multiple signalling proteins and transcription factors involved in a myriad of cellular processes. The kinase acts as a negative regulator in β-catenin signalling and is critically involved in the smad pathway. Activation of both pathways may contribute to pulmonary features of chronic obstructive pulmonary disease (COPD).

Methods: In the present study, we investigated the effect of the selective GSK-3 inhibitor SB216763 on pulmonary pathology in a guinea pig model of lipopolysaccharide (LPS)-induced COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pre-treated with either intranasally instilled SB216763 or corresponding vehicle 30 min prior to each LPS/saline challenge.

Results: Repeated LPS exposures activated β-catenin signalling, primarily in the airway epithelium and submucosa. LPS also induced pulmonary inflammation and tissue remodelling as indicated by inflammatory cell influx, increased pulmonary fibronectin expression and enhanced small airway collagen content. Inhibition of GSK-3 by SB216763 did not affect LPS-induced inflammatory cell influx, but prevented the small airway remodelling and, unexpectedly, inhibited the activation of β-catenin in vivo. LPS or SB216763 treatment had no effect on the airway smooth muscle content and alveolar airspace size. However, GSK-3 inhibition prevented LPS-induced right ventricle hypertrophy.

Conclusions: Our findings indicate that GSK-3 inhibition prevents LPS-induced pulmonary pathology in guinea pigs, and that locally reduced LPS-induced β-catenin activation appears in part to underlie this effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Collagen / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Fibronectins / metabolism
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / drug effects
  • Guinea Pigs
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Lipopolysaccharides / adverse effects
  • Lipopolysaccharides / pharmacology
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology*
  • Male
  • Maleimides / pharmacology
  • Maleimides / therapeutic use*
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / pathology
  • Pulmonary Disease, Chronic Obstructive / chemically induced
  • Pulmonary Disease, Chronic Obstructive / pathology*
  • Pulmonary Disease, Chronic Obstructive / prevention & control*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Smad Proteins / metabolism
  • beta Catenin / metabolism


  • Enzyme Inhibitors
  • Fibronectins
  • Indoles
  • Lipopolysaccharides
  • Maleimides
  • SB 216763
  • Smad Proteins
  • beta Catenin
  • Collagen
  • Glycogen Synthase Kinase 3