title: Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II Cells.
abstract: 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.
authors.affiliation: Laboratory for Innate Cellular Immunity, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Miyake
authors.forename: Hitomi
authors.initials: H
authors.lastname: Kaise
authors.forename: Kyo-Ichi
authors.initials: K
authors.lastname: Isono
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.forename: Masato
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004167:Diphtheria Toxin / Q000633:toxicity; D066257:Heparin-binding EGF-like Growth Factor; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000473:pathology; D016676:Macrophages, Alveolar / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics; D011650:Pulmonary Alveoli / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000502:physiology; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000517:prevention & control*
chemical_list: D016207:Cytokines; D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D017228:Hepatocyte Growth Factor; D009113:Muramidase; C472450:lysozyme M, mouse