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Transgenic mice expressing a surfactant protein B–urokinase fusion protein in the distal respiratory epithelium are protected against acute lung injury and postinflammatory fibrosis

Introduction

Persistent deposition of fibrin in the distal lung is thought to play a significant role in the pathogenesis of acute lung injury (ALI) and postinflammatory lung fibrosis. The therapeutic concept of the correction of the alveolar hemostatic balance, although effective in most models, needs further improvement in view of specific targeting of surfactant-containing alveolar fibrin clots.

Methods

In the present study we generated transgenic mice that express a surfactant protein B–urokinase fusion protein (SPUC) in the distal respiratory epithelium under the control of the 3.7 kb human SP-C promotor. Survival was determined in a lethal ALI model (inhalative LPS administration) in SPUC mice compared with wild-type mice of the same genetic background. Furthermore, the outcome, lung function, collagen content and histology were assessed in the model of bleomycin-induced pulmonary fibrosis.

Results

Transgenic mice showed an improved survival after inhalative LPS or bleomycin administration as compared with wild-type mice. The fibrotic response to inhalative bleomycin challenge was markedly attenuated in transgenic mice, as evident by reduced histological appearance of fibrosis, improved pulmonary compliance and reduced lung hydroxyproline content. As potential underlying mechanisms for the attenuated fibrotic response we observed an improvement in alveolar surface activity, a decrease in pulmonary fibrin deposition, increased hepatocyte growth factor levels and decreased gelatinase activity in the BAL fluids of transgenic mice as compared with control animals.

Conclusion

Lung-specific expression of a surfactant protein B–urokinase fusion protein protects against ALI after inhalative LPS challenge and prevents fibrosis associated with bleomycin-induced lung injury.

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Markart, P., Ruppert, C., Wygrecka, M. et al. Transgenic mice expressing a surfactant protein B–urokinase fusion protein in the distal respiratory epithelium are protected against acute lung injury and postinflammatory fibrosis. Crit Care 11, P183 (2007). https://0-doi-org.brum.beds.ac.uk/10.1186/cc5343

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Keywords

  • Hepatocyte Growth Factor
  • Acute Lung Injury
  • Bleomycin
  • Surfactant Protein
  • Fibrotic Response