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It involves progressive pulmonary tissue damages which are usually irreversible and incurable. Therefore, strategies to facilitate drug development against lung injury are needed. Here, we characterized the zebrafish folate-deficiency (FD) transgenic line that lacks a fully-developed swim bladder. Whole-mount <jats:italic>in-situ<\/jats:italic> hybridization revealed comparable distribution patterns of swim bladder tissue markers between wild-type and FD larvae, suggesting a proper development of swim bladder in early embryonic stages. Unexpectedly, neutrophils infiltration was not observed in the defective swim bladder. Microarray analysis revealed a significant increase and decrease of the transcripts for cathepsin L and a cystatin B (CSTB)-like (zCSTB-like) proteins, respectively, in FD larvae. The distribution of cathepsin L and the zCSTB-like transcripts was spatio-temporally specific in developing wild-type embryos and, in appropriate measure, correlated with their potential roles in maintaining swim bladder integrity. Supplementing with 5-formyltetrahydrofolate successfully prevented the swim bladder anomaly and the imbalanced expression of cathepsin L and the zCSTB-like protein induced by folate deficiency. Injecting the purified recombinant zebrafish zCSTB-like protein alleviated FD-induced swim bladder anomaly. We concluded that the imbalanced expression of cathepsin L and the zCSTB-like protein contributed to the swim bladder malformation induced by FD and suggested the potential application of this transgenic line to model the lung injury and ECM remodeling associated with protease\/protease inhibitor imbalance.<\/jats:p>","DOI":"10.1038\/s41598-019-49152-7","type":"journal-article","created":{"date-parts":[[2019,9,2]],"date-time":"2019-09-02T18:11:06Z","timestamp":1567447866000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A novel zebrafish model to emulate lung injury by folate deficiency-induced swim bladder defectiveness and protease\/antiprotease expression imbalance"],"prefix":"10.1038","volume":"9","author":[{"given":"Gang-Hui","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai-Wei","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Hsuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7221-2334","authenticated-orcid":false,"given":"Jen-Ning","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsunglin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Hong","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Hung","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Fun","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,2]]},"reference":[{"key":"49152_CR1","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1136\/thoraxjnl-2014-206084","volume":"70","author":"N Mercado","year":"2015","unstructured":"Mercado, N., Ito, K. & Barnes, P. J. Accelerated ageing of the lung in COPD: new concepts. Thorax 70, 482\u2013489, https:\/\/doi.org\/10.1136\/thoraxjnl-2014-206084 (2015).","journal-title":"Thorax"},{"key":"49152_CR2","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1111\/j.1476-5381.2009.00448.x","volume":"158","author":"CM Greene","year":"2009","unstructured":"Greene, C. M. & McElvaney, N. G. Proteases and antiproteases in chronic neutrophilic lung disease - relevance to drug discovery. British journal of pharmacology 158, 1048\u20131058, https:\/\/doi.org\/10.1111\/j.1476-5381.2009.00448.x (2009).","journal-title":"British journal of pharmacology"},{"key":"49152_CR3","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2015-0166PS","author":"T Kulkarni","year":"2016","unstructured":"Kulkarni, T., O\u2019Reilly, P., Antony, V. B., Gaggar, A. & Thannickal, V. J. Matrix Remodeling in Pulmonary Fibrosis and Emphysema. American journal of respiratory cell and molecular biology. https:\/\/doi.org\/10.1165\/rcmb.2015-0166PS (2016).","journal-title":"American journal of respiratory cell and molecular biology"},{"key":"49152_CR4","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1136\/thx.2011.159087","volume":"66","author":"I Haq","year":"2011","unstructured":"Haq, I., Lowrey, G. E., Kalsheker, N. & Johnson, S. R. Matrix metalloproteinase-12 (MMP-12) SNP affects MMP activity, lung macrophage infiltration and protects against emphysema in COPD. Thorax 66, 970\u2013976, https:\/\/doi.org\/10.1136\/thx.2011.159087 (2011).","journal-title":"Thorax"},{"key":"49152_CR5","doi-asserted-by":"publisher","first-page":"11032","DOI":"10.1074\/jbc.M115.648311","volume":"290","author":"DM Ariestanti","year":"2015","unstructured":"Ariestanti, D. M., Ando, H., Hirose, S. & Nakamura, N. 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