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Dis Model Mech. 2019 Sep 27. pii: dmm.040139. doi: 10.1242/dmm.040139. [Epub ahead of print]

Lack of whey acidic protein four disulphide core (WFDC) 2 protease inhibitor causes neonatal death from respiratory failure in mice.

Author information

1
Department of Histology and Cell Biology, Yokohama City University, School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
2
Department of Stem Cell Biology, Kyushu University, Faculty of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka City, 812-8582, Japan.
3
Department of Respiratory Medicine, Toho University, School of Medicine, 5-21-16, Ohmorinishi, Ohta-ku, Tokyo, Japan.
4
Department of Respiratory Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
5
Department of Computational Biology and Medical Sciences, Graduate School of 21 Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan.
6
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22, Tsurumi-ku, Yokohama, 230-0045, Japan.
7
Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
8
Cancer Science Institute of Singapore, National Singapore University Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
9
International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
10
Department of Histology and Cell Biology, Yokohama City University, School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan kohbo@yokohama-cu.ac.jp.

Abstract

Respiratory failure is a life-threatening problem for pre-term and term infants yet many causes remain unknown. Here, we present evidence that whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (Wfdc2), a protease inhibitor previously unrecognized in respiratory disease, may be a causal factor in infant respiratory failure. Transcripts are detected in the embryonic lung and analysis of a Wfdc2-GFP knock-in mouse line shows that both basal and club cells, and type II alveolar epithelial cells (AECIIs), express Wfdc2 neonatally. Null mutant mice display progressive atelectasis after birth with a lethal phenotype. Mutant lungs have multiple defects including impaired cilia and absence of mature club cells from the tracheo-bronchial airways and malformed lamellar bodies in AECIIs. RNA sequencing shows significant activation of a pro-inflammatory pathway, but with low-quantity infiltration of mononuclear cells in the lung. These data demonstrate that Wfdc2 function is vitally important for lung aeration at birth and that gene deficiency likely causes failure of the lung mucosal barrier.

KEYWORDS:

Atelectasis; Cilia; Protease inhibitor; Respiratory failure; Surfactant

PMID:
31562139
DOI:
10.1242/dmm.040139
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