Keratinocyte Growth Factor induces alveolisation in emphysematous mouse lungs via TGFβ-1

Abstract

Rationale: Emphysema is characterized by destruction of alveoli and extracellular matrix (ECM) with ensuing airspace enlargement. Induction of alveolar and ECM regeneration is still a major challenge in emphysema therapy. Methods: Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10mg rHuKGF per kg body weight after induction of emphysema by porcine pancreatic elastase (PPE). Results: Airflow limitation associated with emphysema was largely reverse. PPE induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. The therapeutically effect of rHuKGF related with induced proliferation of epithelium, endothelium and fibroblasts as well as increased expression and activation of TGFβ-1, p-Smad2, PAI-1, and elastin as assessed by quantitative RT-PCR, Western blotting and immuno histochemistry. Thus rHuKGF induced activation of TGFβ-1 from primary mouse AE2 cells, LA-4 cells but not in MLF cultured alone. Recombinant TGFβ-1 but not rHuKGF induced elastin gene expression in MLF. Blockade of TGFβ-signaling by neutralizing antibody abolished these effects. Conclusions: These data indicate that therapeutic application of rHuKGF has the potential to induce alveolar maintenance and ECM in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to activation of TGFβ-1.