Reversibility of pulmonary abnormalities by conditional replacement of surfactant protein D (SP-D) in vivo.
Surfactant protein D (SP-D) gene-targeted mice develop severe pulmonary disease associated with emphysema, pulmonary lipidosis, and foamy macrophage infiltrations. To determine the potential reversibility of these abnormalities, transgenic mice were developed in which SP-D was conditionally replaced in the respiratory epithelium of SP-D(-/-) mice. SP-D was not detected in the absence of doxycycline. Treatment with doxycycline after birth restored pulmonary SP-D concentrations and corrected pulmonary pathology at adulthood. When SP-D was replaced in adult SP-D(-/-) mice, alveolar SP-D was restored within 3 days, pulmonary lipid abnormalities were corrected, but emphysema persisted. In corrected adult SP-D(-/-) mice, loss of SP-D caused focal emphysema and pulmonary inflammation but did not cause phospholipid abnormalities characteristic of SP-D(-/-) mice. Thus, abnormalities in surfactant phospholipid homeostasis and alveolar macrophage abnormalities were readily corrected by restoration of SP-D. However, once established, emphysema was not reversed by SP-D. SP-D-dependent processes regulating surfactant lipid homeostasis were disassociated from those mediating emphysema.
Zhang
Liqian
L
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Ikegami
Machiko
M
Dey
Chitta R
CR
Korfhagen
Thomas R
TR
Whitsett
Jeffrey A
JA
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004646:Emphysema / Q000503:physiopathology; D006706:Homeostasis; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors
D000900:Anti-Bacterial Agents; D010743:Phospholipids; D037663:Pulmonary Surfactant-Associated Protein D; D011994:Recombinant Proteins; D004318:Doxycycline