Palifermin Induces Alveolar Maintenance Programs in Emphysematous Mice

Rationale Emphysema is characterized by destruction of alveoli with ensuing airspace enlargement and loss of alveoli. Induction of alveolar regeneration is still a major challenge in emphysema therapy. Objectives: To investigate whether therapeutic application of palifermin (Delta N23-KGF) is able to induce a regenerative response in distal lung parenchyma after induction of pulmonary emphysema. Methods: Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10 mg Delta N23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase. Measurements and Main Results: Airflow limitation associated with emphysema was largely reversed as assessed by noninvasive head-out body plethysmography. Porcine pancreatic elastase induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. AI Delta N23-KGF induced proliferation of epithelium, endothelium, and fibroblasts being associated with enhanced differentiation as well as increased expression of vascular endothelial growth factor, vascular endothelial growth factor receptors, transforming growth factor (TGF)-beta 1, TGF-beta 2, (phospho-) Smad2, plasminogen activator inhibitor-1, and elastin as assessed by quantitative reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. Delta N23-KGF induced the expression of TGF-beta 1 in and release of active TGF-beta 1 from primary mouse alveolar epithelial type 2 (AE2) cells, murine AE2-like cells LA-4, and cocultures of LA-4 and murine lung fibroblasts (MLF), but not in MLF cultured alone. Recombinant TGF-beta 1 but not Delta N23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of Delta N23-KGF in LA-4/MLF cocultures. Conclusions: Our data demonstrate that therapeutic application of Delta N23-KGF has the potential to induce alveolar maintenance programs in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to AE2 cell-derived TGF-beta 1.