The anti-inflammatory activity of SCGB3A2 was previously demonstrated using Scgb3a2-knockout mice in ovalbumin-induced airway inflammation model. In order to further validate the anti-allergic inflammatory role for this protein, Scgb3a2-knockout mice were subjected to a different allergic inflammation model. Scgb3a2-null ( Scgb3a2-/-) mice were subjected to nasal inhalation of Dermatophagoides pteronyssinus (house dust mite (HDM)) extract for 5 days/week for 5 consecutive weeks; control mice received nasal inhalation of saline as a comparator. Airway inflammation was assessed by histological analysis, the number of inflammatory cells and various Th2-type cytokine levels in the lungs and bronchoalveolar lavage fluids by qRT-PCR and ELISA, respectively. These analyses revealed that exacerbated inflammation was found in the airway of Scgb3a2-/- mice subjected to HDM-induced allergic airway inflammation compared with saline-treated control groups. All the inflammation end points were increased in the Scgb3a2-/- mice. The Ccr4 and Ccl17 mRNA levels were higher in HDM-treated lungs of Scgb3a2-/- mice than wild-type mice or saline-treated Scgb3a2-/- mice, whereas no changes were observed for Ccr3 and Ccl11 mRNA levels. These results demonstrate that SCGB3A2 has an anti-inflammatory activity in the HDM-induced allergic airway inflammation model, in which SCGB3A2 may modulate the CCR4-CCL17 pathway. SCGB3A2 may provide a useful tool to treat allergic airway inflammation, and further studies on the levels and function of SCGB3A2 in asthmatic patients are warranted In collaboration, we studied the role of ASCL1 (achaete-scute homologue-1) as well as SCGB1A1, the prototypical member of the SCGB gene superfamily, and CGRP (calcitonin gene-related peptide) in a tobacco carcinogen NNK (4-(methylnitrosamino)-1-(3-pyridyl)-butanone)-induced pulmonary neuroendocrine (NE) hyperplasia and carcinogenesis in hamsters. ASCL1 is known to play a role in neural development and pulmonary NE differentiation, and is expressed in certain lung cancers. SCGB1A1 is expressed in non-ciliated airway epithelial cells similar to SCGB3A1 and SCGB3A2. Hamsters were injected 3 times weekly with either NNK or solvent alone (control) for treatment periods of 6 and 24 weeks, both without and with 6-week recovery. Immunohistochemical analysis was carried out to examine the expressions of ASCL1, CGRP (a NE marker with known proliferation-promoting properties), SCGB1A1, synaptophysin (SYP, another NE marker), and PCNA (proliferating cell nuclear antigen). The number of ASCL1-expressing NE foci per airway increased from 0.8 in controls to 1.6 and 2.0 during NNK exposure for 6 and 24 weeks, respectively, and the number of cells per foci doubled after NNK exposure. Most ASCL1-expressing cells in NEBs (neuroepithelial bodies) were also CGRP immunoreactive; NNK enhanced this co-expression with CGRP. Expression of SCGB1A1 was observed fairly consistently within NEBs of both control and NNK-exposed hamsters. NNK also increased PCNA expression within NE foci. NNK-induced tumors showed no immunoreactivity for NE markers. This study confirms ASCL1 as an excellent marker for pulmonary NE cells and demonstrates CGRP co-expression in ASCL1-positive NEB cells participating in NNK-induced NE hyperplasia.

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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

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