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Surfactant proteins (SP)-A and -D are members of the collectin family of host defense proteins that share four distinct structural domains: N[H.sub.2]-terminal oligomerization, collagenous, neck, and carbohydrate recognition (CRD). To determine the specificity of the functions of these domains, the SFTPC promoter was used to express 1) full-length rat (r) Sftpa; 2) N[H.sub.2]-rSftpa/d, consisting of N[H.sub.2]-terminal and collagenous domains of SP-A with neck domain and CRD of SP-D; and 3) rSftpd/a, consisting of N[H.sub.2]-terminal and collagenous domains of SP-D with neck domain and CRD of SP-A, in [Sftpd.sup.-/-] mice. Increased expression of SP-A in [Sftpd.sup.-/-] mice did not correct the increased pulmonary saturated phosphatidylcholine levels, emphysema, or foamy alveolar macrophage and lymphocyte infiltrations characteristic of [Sfipd.sup.-/-] mice, indicating that the decreased SP-A level noted in [Sfipd.sup.-/-] mice does not account for the observed pulmonary abnormalities. The chimeric protein N[H.sub.2]-rSftpa/d was expressed and detected in the airways of transgenic mice, migrating as an SP-A-like oligomer that associated with large aggregate surfactant in a manner similar to that of SP-A rather than SP-D. N[H.sub.2]-rSftpa/d did not correct emphysema, foamy macrophage and lymphocyte infiltration, or the increased lipid accumulations characteristic of [Sftpd.sup.-/-] mice. Thus oligomerization and surfactant lipid association of SP-D requires its N[H.sub.2]-terminal and collagenous domains, which are needed for SP-D-dependent regulation of surfactant homeostasis in vivo. Attempts to express rSftpd/a fusion protein in vivo were unsuccessful. [Mmp9.sup.-/-]/[Sftpd.sup.-/-] and [Mmpl2.sup.-/-]/[Sftpd.sup.-/-] mice developed air space enlargement similar to [Sftpd.sup.-/-] mice, supporting the concept that the increased expression of each metalloproteinase seen in [Sftpd.sup.-/-] lungs is not the major cause of emphysema. [Sftpd.sup.-/-] mice; emphysema; lipid homeostasis; inflammation doi:10.1152/ajplung.00015.2006

The goal of this study was to examine whether IL-6 could directly protect lung resident cells, especially alveolar epithelial cells, from reactive oxygen species (ROS)-induced cell death. ROS induced IL-6 gene expression in organotypic lung slices of wild-type (WT) mice. ROS also induced IL-6 gene expression in mouse primary lung fibroblasts, dose dependently. The organotypic lung slices of WT were more resistant to ROS-induced DNA fragmentation than those of IL-6-deficient (IL-6-/-) mice. WT resistance against ROS was abrogated by treatment with anti-IL-6 antibody. TdT-mediated dUTP nick end labeling stain and electron microscopy revealed that DNA fragmented cells in the IL-6-/- slice included alveolar epithelial cells and endothelial cells. In vitro studies demonstrated that IL-6 reduced ROS-induced A549 alveolar epithelial cell death. Together, these data suggest that IL-6 played an antioxidant role in the lung by protecting lung resident cells, especially alveolar epithelial cells, from ROS-induced cell death. lung slice culture; oxidative stress; diffuse alveolar damage; apoptosis; interleukin-6

Both surfactant protein (SP) D and granulocyte-macrophage colony-stimulating factor (GM-CSF) influence pulmonary surfactant homeostasis, with the deficiency of either protein causing marked accumulation of surfactant phospholipids in lung tissues and in the alveoli. To assess whether the effects of each gene were mediated by distinct or shared mechanisms, surfactant homeostasis and lung morphology were assessed in 1) double-transgenic mice in which both SP-D and GM-CSF genes were ablated [SP-D(-/-),GM(-/-)] and 2) transgenic mice deficient in both SP-D and GM-CSF in which the expression of GM-CSF was increased in the lung. Saturated phosphatidylcholine (Sat PC) pool sizes were markedly increased in SP-D(-/-), GM(-/-) mice, with the effects of each gene deletion on surfactant Sat PC pool sizes being approximately additive. Expression of GM-CSF in lungs of SP-D(-/-),GM(-/-) mice corrected GM-CSF-dependent abnormalities in surfactant catabolism but did not correct lung pathology characteristic of SP-D deletion. In contrast to findings in GM(-/-) mice, degradation of [[sup.3]H]dipalmitoylphosphatidylcholine by alveolar macrophages from the SP-D(-/-) mice was normal. The emphysema and foamy macrophage infiltrates characteristic of SP-D(-/-) mice were similar in the presence or absence of GM-CSF. Taken together, these findings demonstrate the distinct roles of SP-D and GM-CSF in the regulation of surfactant homeostasis and lung structure. phosphatidylcholine; surfactant protein A; pulmonary alveolar proteinosis; emphysema; surfactant protein D; granulocyte-macrophage colony-stimulating factor

Yoshida, Mitsuhiro, Machiko Ikegami, Jacquelyn A. Reed, Zissis C. Chroneos, and Jeffrey A. Whitsett. GM-CSF regulates protein and lipid catabolism by alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 280: L379-L386, 2001.--Metabolism of surfactant protein (SP) A and dipalmitoylphosphatidylcholine (DPPC) was assessed in alveolar macrophages isolated from granulocyte-macrophage colony-stimulated factor (GM-CSF) gene-targeted [GM(-/-)] mice, wild-type mice, and GM(-/-) mice expressing GM-CSF under control of the SP-C promoter element (SP-C-GM). Although binding and uptake of [sup.125]I-SP-A were significantly increased in alveolar macrophages from GM(-/-) compared with wild type or SP-C-GM mice, catabolism of [sup.125]I-SP-A was markedly decreased in GM(-/-) mice. Association of [[sup.3]H]DPPC with alveolar macrophages from GM(-/-), wild-type, and SP-C-GM mice was similar; however, catabolism of DPPC was markedly reduced in cells from GM(-/-) mice. Fluorescence-activated cell sorter analysis demonstrated decreased catabolism of rhodamine-labeled dipalmitoylphosphatidylethanolamine by alveolar macrophages from GM(-/-) mice. GM-CSF deficiency was associated with increased SP-A uptake by alveolar macrophages but with impaired surfactant lipid and SP-A degradation. These findings demonstrate the important role of GM-CSF in the regulation of alveolar macrophage lipid and SP-A catabolism. pulmonary alveolar proteinosis; granulocyte-macrophage colony-stimulating factor

Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo. Am J Physiol Lung Cell Mol Physiol 278: L914-L922, 2000.--Interleukin (IL)-10 has been shown to reduce many inflammatory reactions. We investigated the in vivo effects of IL-10 on a bleomycin-induced lung injury model. Hemagglutinating virus of Japan (HVJ)-liposomes containing a human IL-10 expression vector (hIL10-HVJ) or a balanced salt solution as a control (Cont-HVJ) was intraperitoneally injected into mice on day -3. This was followed by intratracheal instillation of bleomycin (0.8 mg/kg) on day 0. Myeloperoxidase activity of bronchoalveolar lavage fluid and tumor necrosis factor-[Alpha] mRNA expression in bronchoalveolar lavage fluid cells on day 7 and hydroxyproline content of the whole lung on day 21 were inhibited significantly by hILl0-HVJ treatment. However, Cont-HVJ treatment could not suppress any of these parameters. We also examined the in vitro effects of IL-10 on the human lung fibroblast cell line WI-38. IL-10 significantly reduced constitutive and transforming growth factor-[Beta]-stimulated type I collagen mRNA expression. However, IL-10 did not affect the proliferation of WI-38 cells induced by platelet-derived growth factor. These data suggested that exogenous IL-10 may be useful in the treatment of pulmonary fibrosis. transforming growth factor-[Beta]; pulmonary fibrosis; collagen

Surfactant proteins (SP)-A and -D are members of the collectin family of host defense proteins that share four distinct structural domains: NH2-terminal oligomerization, collagenous, neck, and carbohydrate recognition (CRD). To determine the specificity of the functions of these domains, the SFTPC promoter was used to express 1) full-length rat (r) Sftpa; 2) NH2-rSftpa/d, consisting of NH2-terminal and collagenous domains of SP-A with neck domain and CRD of SP-D; and 3) rSftpd/a, consisting of NH2-terminal and collagenous domains of SP-D with neck domain and CRD of SP-A, in Sftpd-/- mice. Increased expression of SP-A in Sftpd-/- mice did not correct the increased pulmonary saturated phosphatidylcholine levels, emphysema, or foamy alveolar macrophage and lymphocyte infiltrations characteristic of Sfipd-/- mice, indicating that the decreased SP-A level noted in Sftpd-/- mice does not account for the observed pulmonary abnormalities. The chimeric protein NH2-rSftpa/d was expressed and detected in the airways of transgenic mice, migrating as an SP-A-like oligomer that associated with large aggregate surfactant in a manner similar to that of SP-A rather than SP-D. NH2-rSftpa/d did not correct emphysema, foamy macrophage and lymphocyte infiltration, or the increased lipid accumulations characteristic of Sftpd-/- mice. Thus oligomerization and surfactant lipid association of SP-D requires its NH2-terminal and collagenous domains, which are needed for SP-D-dependent regulation of surfactant homeostasis in vivo. Attempts to express rSftpd/a fusion protein in vivo were unsuccessful. Mmp9-/-/Sftpd-/- and Mmpl2-/-/Sftpd-/- mice developed air space enlargement similar to Sftpd-/- mice, supporting the concept that the increased expression of each metalloproteinase seen in Sftpd-/- lungs is not the major cause of emphysema. [ABSTRACT FROM AUTHOR]