Palifermin induces alveolar maintenance programs in emphysematous mice.
BACKGROUND
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.


OBJECTIVE
To investigate whether therapeutic application of palifermin (DeltaN23-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 DeltaN23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase.


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. DeltaN23-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)-beta1, TGF-beta2, (phospho-) Smad2, plasminogen activator inhibitor-1, and elastin as assessed by quantitative reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. DeltaN23-KGF induced the expression of TGF-beta1 in and release of active TGF-beta1 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-beta1 but not DeltaN23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of DeltaN23-KGF in LA-4/MLF cocultures.


CONCLUSIONS
Our data demonstrate that therapeutic application of DeltaN23-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-beta1.
Yildirim
Ali O
AO
Clinical Research Group Chronic Airway Diseases, Medical Faculty, Philipps-University Marburg, Marburg, Germany.
Muyal
Vandana
V
John
Gerrit
G
Müller
Bernd
B
Seifart
Carola
C
Kasper
Michael
M
Fehrenbach
Heinz
H
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D018920:Coculture Techniques; D004195:Disease Models, Animal; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000378:metabolism
D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D051523:Fibroblast Growth Factor 7