Dose-dependent lung remodeling in transgenic mice expressing transforming growth factor-alpha.
Transgenic mice overexpressing human transforming growth factor-alpha (TGF-alpha) develop emphysema and fibrosis during postnatal alveologenesis. To assess dose-related pulmonary alterations, four distinct transgenic lines expressing different amounts of TGF-alpha in the distal lung under control of the surfactant protein C (SP-C) promoter were characterized. Mean lung homogenate TGF-alpha levels ranged from 388 +/- 40 pg/ml in the lowest expressing line to 1,247 +/- 33 pg/ml in the highest expressing line. Histological assessment demonstrated progressive alveolar airspace size changes that were more severe in the higher expressing TGF-alpha lines. Pleural and parenchymal fibrosis were only detected in the highest expressing line (line 28), and increasing terminal airspace area was associated with increasing TGF-alpha expression. Hysteresis on pressure-volume curves was significantly reduced in line 28 mice compared with other lines of mice. There were no differences in bronchoalveolar lavage fluid cell count or differential that would indicate any evidence of lung inflammation among all transgenic lines. Proliferating cells were increased in line 28 without alterations of numbers of type II cells. We conclude that TGF-alpha lung remodeling in transgenic mice is dose dependent and is independent of pulmonary inflammation.
Hardie
W D
WD
Division of Pulmonary Medicine, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. bill.hardie@chmcc.org
Piljan-Gentle
A
A
Dunlavy
M R
MR
Ikegami
M
M
Korfhagen
T R
TR
D000704:Analysis of Variance; D000818:Animals; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011510:Proteolipids / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000473:pathology / Q000502:physiology; D011656:Pulmonary Emphysema / Q000473:pathology / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000473:pathology / Q000503:physiopathology; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism; D014020:Tissue Extracts / Q000737:chemistry / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
D011510:Proteolipids; D011663:Pulmonary Surfactants; D014020:Tissue Extracts; D016211:Transforming Growth Factor alpha