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J. Biol. Chem., Vol. 281, Issue 47, 36420-36433, November 24, 2006

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Transgenic Expression of Group V, but Not Group X, Secreted Phospholipase A₂ in Mice Leads to Neonatal Lethality because of Lung Dysfunction^*

Mitsuhiro Ohtsuki, Yoshitaka Taketomi, Satoru Arata, Seiko Masuda^¶||1, Yukio Ishikawa^**, Toshiharu Ishii^**, Yasukazu Takanezawa, Junken Aoki, Hiroyuki Arai, Kei Yamamoto^¶, Ichiro Kudo, and Makoto Murakami^¶2

From the Department of Health Chemistry, School of Pharmaceutical Sciences and Center for Biotechnology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, ^¶Biomembrane Signaling Project, Tokyo Metropolitan Institute of Medical Sciences, Bunkyo-ku, Tokyo 113-8613, the ^**Department of Pathology, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ohta-ku, Tokyo 143-8540, Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, ^||Japan Society for the Promotion of Science, 1-8 Chiyoda-ku, Tokyo 102-8472, and PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan

In an effort to elucidate the functions of secreted phospholipase A₂ (sPLA₂) enzymes in vivo, we generated transgenic (Tg) mice for group V sPLA₂ (sPLA₂-V) and group X sPLA₂ (sPLA₂-X), which act potently on phosphatidylcholine in vitro.We found that sPLA₂-V Tg mice died in the neonatal period because of respiratory failure. The lungs of sPLA₂-V Tg mice exhibited atelectasis with thickened alveolar walls and narrow air spaces, accompanied by infiltration of macrophages and only modest changes in eicosanoid levels. This severe pulmonary defect in sPLA₂-V Tg mice was attributable to marked reduction of the lung surfactant phospholipids, phosphatidylcholine and phosphatidylglycerol. Given that the expression of sPLA₂-V is greatly elevated in human lungs with severe inflammation, our present results raise the intriguing possibility that this isozyme may contribute to ongoing surfactant hydrolysis often observed in the lungs of patients with respiratory distress syndrome. In contrast, sPLA₂-X Tg neonates displayed minimal abnormality of the respiratory tract with normal alveolar architecture and surfactant composition. This unexpected result was likely because sPLA₂-X protein existed as an inactive zymogen in most tissues. The active form of sPLA₂-X was detected in tissues with inflammatory granulation in sPLA₂-X Tg mice. These results suggest that sPLA₂-X mostly remains inactive under physiological conditions and that its proteolytic activation occurs during inflammation or other as yet unidentified circumstances in vivo.

Received for publication, August 21, 2006 , and in revised form, September 25, 2006.

^* This work was supported in part by grants-in aid for scientific research from the Ministry of Education, Science, Culture, Sports and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5.

¹ Research fellow supported by the Japan Society for the Promotion of Science.

² Supported by PRESTO from the Japan Science and Technology Agency, the Naito Foundation, the ONO Medical Research Foundation, the Tokyo Biochemical Research Foundation, and the Astellas Foundation for Research on Metabolic Disorders. To whom correspondence should be addressed. Tel./Fax: 81-3-3823-5280; E-mail: mako{at}rinshoken.or.jp.

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