title: Preclinical evaluation of human secretoglobin 3A2 in mouse models of lung development and fibrosis.
abstract: Secretoglobin (SCGB) 3A2 is a member of the SCGB gene superfamily of small secreted proteins, predominantly expressed in lung airways. We hypothesize that human SCGB3A2 may exhibit anti-inflammatory, growth factor, and antifibrotic activities and be of clinical utility. Recombinant human SCGB3A2 was expressed, purified, and biochemically characterized as a first step to its development as a therapeutic agent in clinical settings. Human SCGB3A2, as well as mouse SCGB3A2, readily formed a dimer in solution and exhibited novel phospholipase A2 inhibitory activity. This is the first demonstration of any quantitative biochemical measurement for the evaluation of SCGB3A2 protein. In the mouse as an experimental animal, human SCGB3A2 exhibited growth factor activity by promoting embryonic lung development in both ex vivo and in vivo systems and antifibrotic activity in the bleomycin-induced lung fibrosis model. The results suggested that human SCGB3A2 can function as a growth factor and an antifibrotic agent in humans. When SCGB3A2 was administered to pregnant female mice through the tail vein, the protein was detected in the dam's serum and lung, as well as the placenta, amniotic fluids, and embryonic lungs at 10 min postadministration, suggesting that SCGB3A2 readily crosses the placenta. The results warrant further development of recombinant SCGB3A2 as a therapeutic agent in treating patients suffering from lung diseases or preterm infants with respiratory distress.
authors.affiliation: Bldg. 37, Rm. 3106, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892. kimuras@mail.nih.gov.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Winn
authors.forename: John K
authors.initials: JK
authors.lastname: Zehmer
authors.forename: William K
authors.initials: WK
authors.lastname: Gillette
authors.forename: Jacek T
authors.initials: JT
authors.lastname: Lubkowski
authors.forename: Aprile L
authors.initials: AL
authors.lastname: Pilon
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001682:Biological Availability; D001761:Bleomycin; D004353:Drug Evaluation, Preclinical; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D064801:Phospholipase A2 Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D054467:Phospholipases A2 / Q000737:chemistry; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D060765:Secretoglobins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D046509:Tissue Culture Techniques
chemical_list: D064801:Phospholipase A2 Inhibitors; D011994:Recombinant Proteins; C449940:SCGB3A2 protein, human; D060765:Secretoglobins; D001761:Bleomycin; D054467:Phospholipases A2
keywords: SCGB; bleomycin-induced pulmonary fibrosis; drug candidate treating lung diseases; embryonic lung ex vivo organ culture; phospholipase A2 inhibitory activity