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Reversibility of Pulmonary Abnormalities by Conditional Replacement of Surfactant Protein D (SP-D) in Vivo

December 11, 2018 By Airway Therapeutics

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.

Surfactant protein D (SP-D)1 is a 43-kDa member of the collectin family of mammalian lectins (for review, see Refs. 1 and 2). SP-D is synthesized in many organs including the lung where it is expressed primarily in type II epithelial cells in alveoli and in non-ciliated bronchiolar cells in conducting airways (3). Studies in SP-D gene targeted animals demonstrated its unexpected role in surfactant phospholipid homeostasis. SP-D/ mice developed increased tissue and alveolar phospholipid pool sizes that were established soon after birth (4, 5).

Abnormalities in alveolar macrophage morphology and emphysema were also apparent before 1 month of age and increased with age (6). Increased oxidant production, activation of NFB, and enhanced metalloproteinase expression by alveolar macrophages were observed, perhaps contributing to the alveolar remodeling seen in SP-D/ mice (6, 7). In addition to abnormalities in lung structure and phospholipid metabolism, SPD/ mice were highly susceptible to pulmonary infections by respiratory synctial and influenza A viruses. SP-D/ mice failed to clear either virus effectively and developed exaggerated inflammatory responses following infection (8).

Since SPD-dependent abnormalities in lipid metabolism were established immediately following birth and continued postnatally, it has been unclear whether SP-D is required during lung morphogenesis or whether there is an ongoing requirement for SP-D for regulation of pulmonary surfactant metabolism in the adult lung. To further clarify the role of SP-D in pulmonary homeostasis, recombinant SP-D was conditionally expressed in respiratory epithelial cells under control of the Clara cell secretory protein (CCSP) promoter in SP-D/ gene targeted mice in vivo. Abnormalities in surfactant lipid homeostasis and monocytic infiltrates were reversed by expression of SP-D in adult SP-D/ mice. Reversal of complementation in adult SP-D/ mice caused emphysema and alveolar infiltrates but did not perturb phospholipid homeostasis.

Zhang, L, et al.
The Journal of Biological Chemistry 2002

Filed Under: Scientific Publications

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