Lack of whey acidic protein four disulphide core (WFDC) 2 protease inhibitor causes neonatal death from respiratory failure in mice
| Autor: | Yutaka Suzuki, Shin-ichi Tomizawa, Kazuyuki Ohbo, Selma Dizdarević, Masahide Seki, Kuniko Nakajima, Takayuki Shirakawa, Kazushige Kuroha, Risa Matsunaga, Haruhiko Koseki, Yasunari Miyazaki, Uroš Radović, Michio Ono, Takeyuki Kurosawa, Ikue Hoshi, Masataka Nakamura, Toshio Suda, Go Nagamatsu |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Lung Respiratory disease Neuroscience (miscellaneous) Medicine (miscellaneous) respiratory system Biology Lamellar granule medicine.disease Peripheral blood mononuclear cell General Biochemistry Genetics and Molecular Biology Protease inhibitor (biology) Microbiology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Immunology and Microbiology (miscellaneous) WFDC2 Respiratory failure medicine biology.protein Whey Acidic Protein 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Disease Models & Mechanisms. |
| ISSN: | 1754-8411 1754-8403 |
| Popis: | 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. Wfdc2 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. Wfdc2-null-mutant mice display progressive atelectasis after birth with a lethal phenotype. Mutant lungs have multiple defects, including impaired cilia and the 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. |
| Databáze: | OpenAIRE |
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