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Role of Secretoglobin 3A2 in Lung Development

¹ Laboratory of Metabolism, and ² Section on the Molecular Biology of Selenium, Laboratory of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Shioko Kimura, Ph.D., Bldg. 37, Room 3112B, National Institutes of Health, Bethesda, MD 20892. E-mail: kimuras{at}mail.nih.gov

Rationale: Secretoglobin 3A2 (SCGB3A2) was originally identified as a downstream target in lung for the homeodomain transcription factor NKX2-1, whose null mutation resulted in severely hypoplastic lungs. A very low level of SCGB3A2 is expressed in lungs at Embryonic Day (E) 11.5 during mouse development, which markedly increases by E16.5, the time when lung undergoes dramatic morphologic changes, suggesting that SCGB3A2 may be involved in lung development in addition to a known role in lung inflammation.

Objectives: To determine whether SCGB3A2 plays a role in lung development.

Methods: To assess a potential role for SCGB3A2 during early lung development, wild-type and Nkx2-1–null fetal lungs of early developmental stages were subjected to ex vivo organ culture in the presence of SCGB3A2. Nkx2-1–null fetuses were exposed to SCGB3A2 during early organogenesis period through intravenous administration of this protein to Nkx2-1–heterozygous pregnant females carrying these null fetuses. Cultured lungs and fetal lungs were subjected to histologic and immunohistochemical analyses. To assess a role for SCGB3A2 in late lung development, SCGB3A2 was administered to pregnant wild-type females during mid- to late organogenesis stages, and the preterm pups and/or their lungs were evaluated for extent of maturity using breathing motion, gross morphology and histology of lungs, expression of gestational stage-specific genes, and phospholipid profiles.

Measurements and Main Results: SCGB3A2 significantly promoted both early and late stages of lung development.

Conclusions: SCGB3A2 is a novel growth factor in lung.

Key Words: secretoglobin 3A2 • uteroglobin-related protein 1 • NKX2-1 • fetal lung development • growth factor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Secretoglobin 3A2 (SCGB3A2) is predominantly expressed in the airways and functions as an antiinflammatory agent. Whether SCGB3A2 plays any physiologic role other than inflammation is not known. What This Study Adds to the Field SCGB3A2 is a novel growth factor, promoting both early and late stages of fetal lung development.