HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Miyake, Y. Articles by Tanaka, M. Search for Related Content PubMed PubMed Citation Articles by Miyake, Y. Articles by Tanaka, M.

Protective Role of Macrophages in Noninflammatory Lung Injury Caused by Selective Ablation of Alveolar Epithelial Type II Cells¹

Yasunobu Miyake^*, Hitomi Kaise^*, Kyo-ichi Isono, Haruhiko Koseki, Kenji Kohno and Masato Tanaka^2,*

^* Laboratory for Innate Cellular Immunity, and Developmental Genetics Group, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan; and Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan

Macrophages have a wide variety of activities and it is largely unknown how the diverse phenotypes of macrophages contribute to pathological conditions in the different types of tissue injury in vivo. In this study we established a novel animal model of acute respiratory distress syndrome caused by the dysfunction of alveolar epithelial type II (AE2) cells and examined the roles of alveolar macrophages in the acute lung injury. The human diphtheria toxin (DT) receptor (DTR), heparin-binding epidermal growth factor-like growth factor (HB-EGF), was expressed under the control of the lysozyme M (LysM) gene promoter in the mice. When DT was administrated to the mice they suffered from acute lung injury and died within 4 days. Immunohistochemical examination revealed that AE2 cells as well as alveolar macrophages were deleted via apoptosis in the mice treated with DT. Consistent with the deletion of AE2 cells, the amount of surfactant proteins in bronchoalveolar lavage fluid was greatly reduced in the DT-treated transgenic mice. When bone marrow from wild-type mice was transplanted into irradiated LysM-DTR mice, the alveolar macrophages became resistant to DT but the mice still suffered from acute lung injury by DT administration. Compared with the mice in which both AE2 cells and macrophages were deleted by DT administration, the DT-treated LysM-DTR mice with DT-resistant macrophages showed less severe lung injury with a reduced amount of hepatocyte growth factor in bronchoalveolar lavage fluid. These results indicate that macrophages play a protective role in noninflammatory lung injury caused by the selective ablation of AE2 cells.

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.

¹ This work was supported in a part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology in Japan, the Uehara Foundation, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research.

² Address correspondence and reprint requests to Dr. Masato Tanaka, Laboratory for Innate Cellular Immunity, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa, Japan. E-mail address: mtanaka{at}rcai.riken.jp

³ Abbreviations used in this paper: DT, diphtheria toxin; AE1, alveolar epithelial type I; AE2, alveolar epithelial type II; ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; DIG, digoxygenin; DTR, DT receptor; ES, embryonic stem; FasL, Fas ligand; HB-EGF, heparin-binding epidermal growth factor-like growth factor; HGF, hepatocyte growth factor; LysM, lysozyme M; SP, surfactant protein.