In order to address whether SCGB3A2 has any additional function than those already known such as anti-inflammatory and growth factor activities, in vitro and in vivo studies were carried out to determine for its role in fibrosis. In in vitro studies, SCGB3A2 was found to inhibit TGFbeta-induced differentiation of fibroblasts to myofibroblasts, a hallmark of the fibrogenic process, using pulmonary fibroblasts isolated from adult mice. This inhibition was through increased phosphorylation of STAT1 and expression of SMAD7, and decreased phosphorylation of SMAD2 and SMAD3. INFgamma is known to suppress fibrosis through the exact pathway as the one that we identified for SCGB3A2. Interestingly, STAT1 phosphorylation by SCGB3A2 takes about 3 hours to reach peak levels as compared to 10-30 min by INFgamma and requires protein synthesis, suggesting that the SCGB3A2 pathway may be different from the INFgamma pathway and mediated through an unknown SCGB3A2-specific receptor. INFgamma was recently used as a therapy to treat pulmonary fibrosis. However, it exhibits toxic side effects and thus a better alternative is desirable. In order to demonstrate the effect of SCGB3A2 on the TGFbeta signaling in vivo, a bleomycin-induced pulmonary fibrosis mouse model was used. Mice were administered bleomycin intratracheally followed by intravenous injection of recombinant SCGB3A2. Histological examination of lungs in conjunction with inflammatory cell counts in bronchoalveolar lavage fluids demonstrated that SCGB3A2 suppressed bleomycin-induced pulmonary fibrosis. Microarray analysis was carried out using RNAs from lungs of bleomycin-treated and normal mice with or without SCGB3A2. These results confirmed the in vitro results that SCGB3A2 affects TGFbeta signaling and reduces the expression of genes involved in fibrosis. This study suggests the potential utility of SCGB3A2 for targeting the TGFbeta signaling in the treatment of pulmonary fibrosis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Kim, Jung-Hwan; Yamaori, Satoshi; Tanabe, Tomotaka et al. (2017) Lack of epithelial PPAR? causes cystic adenomatoid malformations in mouse fetal lung. Biochem Biophys Res Commun 491:271-276
Tanaka, Naoki; Aoyama, Toshifumi; Kimura, Shioko et al. (2017) Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol Ther :
Yoneda, Mitsuhiro; Xu, Lei; Kajiyama, Hiroaki et al. (2016) Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice. Int Arch Allergy Immunol 171:36-44
Naizhen, Xu; Linnoila, R Ilona; Kimura, Shioko (2016) Co-expression of Achaete-Scute Homologue-1 and Calcitonin Gene-Related Peptide during NNK-Induced Pulmonary Neuroendocrine Hyperplasia and Carcinogenesis in Hamsters. J Cancer 7:2124-2131
Xu, Ming-Jiang; Cai, Yan; Wang, Hua et al. (2015) Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans. Gastroenterology 149:1030-41.e6
Yoneda, Mitsuhiro; Molinolo, Alfredo A; Ward, Jerrold M et al. (2015) A Simple Device to Rapidly Prepare Whole Mounts of the Mouse Intestine. J Vis Exp :e53042
Cai, Yan; Kimura, Shioko (2015) Secretoglobin 3A2 Exhibits Anti-Fibrotic Activity in Bleomycin-Induced Pulmonary Fibrosis Model Mice. PLoS One 10:e0142497
Kurotani, Reiko; Shima, Reika; Miyano, Yuki et al. (2015) SCGB3A2 Inhibits Acrolein-Induced Apoptosis through Decreased p53 Phosphorylation. Acta Histochem Cytochem 48:61-8
Cai, Yan; Yoneda, Mitsuhiro; Tomita, Takeshi et al. (2015) Transgenically-expressed secretoglobin 3A2 accelerates resolution of bleomycin-induced pulmonary fibrosis in mice. BMC Pulm Med 15:72
Cheng, Jie; Fang, Zhong-Ze; Nagaoka, Kenjiro et al. (2014) Activation of intestinal human pregnane X receptor protects against azoxymethane/dextran sulfate sodium-induced colon cancer. J Pharmacol Exp Ther 351:559-67

Showing the most recent 10 out of 30 publications