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

Machiko Ikegami,Jeffrey A Whitsett,Liqian Zhang,Chitta R Dey,Thomas R Korfhagen

doi:10.1074/jbc.m206200200

Machiko Ikegami, Jeffrey A Whitsett + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m206200200

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Abstract

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.

Highlights

Surfactant protein D (SP-D)1 is a 43-kDa member of the collectin family of mammalian lectins
In adult SP-DϪ/Ϫ mice, extinction of the transgene expression resulted in a rapid decrease in alveolar SP-D, consistent with the known clearance rate of SP-D [14] and the pharmacodynamics of doxycycline on which reversal of transgene expression was dependent [15]
In complemented adult SP-DϪ/Ϫ mice treated with doxycycline from birth, removal from doxycycline resulted in decreased tissue SP-D, reappearance of abnormal alveolar macrophage infiltrates, and airspace remodeling that were detected within 7–14 days

Summary

Introduction

Surfactant protein D (SP-D) is a 43-kDa member of the collectin family of mammalian lectins (for review, see Refs. 1 and 2). SP-DϪ/Ϫ mice developed increased tissue and alveolar phospholipid pool sizes that were established soon after birth [4, 5]. 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-DϪ/Ϫ gene targeted mice in vivo. Abnormalities in surfactant lipid homeostasis and monocytic infiltrates were reversed by expression of SP-D in adult SP-DϪ/Ϫ mice. Reversal of complementation in adult SP-DϪ/Ϫ mice caused emphysema and alveolar infiltrates but did not perturb phospholipid homeostasis

Methods

Conclusion