Surfactant metabolism in transgenic mice after granulocyte macrophage-colony stimulating factor ablation

1996 ◽  
Vol 270 (4) ◽  
pp. L650-L658 ◽  
Author(s):  
M. Ikegami ◽  
T. Ueda ◽  
W. Hull ◽  
J. A. Whitsett ◽  
R. C. Mulligan ◽  
...  
Keyword(s):  
Protein A ◽  
Surfactant Protein ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor ◽  
Deficient Mice ◽  
Surfactant Metabolism

Mice made granulocyte macrophage-colony stimulating factor (GM-CSF)-deficient by homologous recombination maintain normal steady-state hematopoiesis but have an alveolar accumulation of surfactant lipids and protein that is similar to pulmonary alveolar proteinosis in humans. We asked how GM-CSF deficiency alters surfactant metabolism and function in mice. Alveolar and lung tissue saturated phosphatidylcholine (Sat PC) were increased six- to eightfold in 7- to 9-wk-old GM-CSF-deficient mice relative to controls. Incorporation of radiolabeled palmitate and choline into Sat PC was higher in GM-CSF deficient mice than control mice, and no loss of labeled Sat PC occurred from the lungs of GM-CSF-deficient mice. Secretion of radiolabeled Sat PC to the alveolus was similar in GM-CSF-deficient and control mice. Labeled Sat PC and surfactant protein A (SP-A) given by tracheal instillation were cleared rapidly in control mice, but there was no measurable loss from the lungs of GM-CSF-deficient mice. The function of the surfactant from GM-CSF-deficient mice was normal when tested in preterm surfactant-deficient rabbits. GM-CSF deficiency results in a catabolic defect for Sat PC and SP-A.

scholarly journals Mice lacking both macrophage- and granulocyte-macrophage colony- stimulating factor have macrophages and coexistent osteopetrosis and severe lung disease

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 27-35 ◽  
Author(s):  
GJ Lieschke ◽  
E Stanley ◽  
D Grail ◽  
G Hodgson ◽  
V Sinickas ◽  
...  
Keyword(s):  
Lung Pathology ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor ◽  
Deficient Mice

Abstract Mice deficient in granulocyte-macrophage colony-stimulating factor (GM- CSF) and macrophage colony-stimulating factor (M-CSF, CSF-1) were generated by interbreeding GM-CSF-deficient mice generated by gene targeting (genotype GM-/-) with M-CSF-deficient osteopetrotic mice (genotype M-/-, op/op). Mice deficient in both GM-CSF and M-CSF (genotype GM-/-M-/-) are viable and have coexistent features corresponding to mice deficient in either factor alone. Like M-CSF- deficient mice, they have osteopetrosis and are toothless because of failure of incisor eruption. Like GM-CSF-deficient mice, they have a characteristic alveolar-proteinosis-like lung pathology, but it is more severe than that of GM-CSF-deficient mice and is often fatal. In particular, in GM-/-M-/- mice the accumulation of lipo-proteinaceous alveolar material is more marked, and bacterial pneumonic infections are more prevalent and more extensive, particularly involving Gram- negative bacteria. Neutrophilia consistently accompanies pulmonary infections, and some older GM-/-M-/- mice have polycythemia. Survival of GM-/-M-/- mice is significantly reduced compared with mice deficient in either factor alone, and all GM-/-M-/- mice have broncho- or lobar- pneumonia at death. These observations indicate that in vivo, M-CSF is involved in modulating the consequences of GM-CSF deficiency in the lung. Interestingly, GM-/-M-/- mice have circulating monocytes at levels comparable with those in M-CSF-deficient mice and the diseased lungs of all GM-/-M-/- mice contain numerous phagocytically active macrophages, indicating that in addition to GM-CSF and M-CSF, other factors can be used for macrophage production and function in vivo.

scholarly journals Mice lacking both macrophage- and granulocyte-macrophage colony- stimulating factor have macrophages and coexistent osteopetrosis and severe lung disease

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 27-35 ◽  
Author(s):  
GJ Lieschke ◽  
E Stanley ◽  
D Grail ◽  
G Hodgson ◽  
V Sinickas ◽  
...  
Keyword(s):  
Lung Pathology ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor ◽  
Deficient Mice

Mice deficient in granulocyte-macrophage colony-stimulating factor (GM- CSF) and macrophage colony-stimulating factor (M-CSF, CSF-1) were generated by interbreeding GM-CSF-deficient mice generated by gene targeting (genotype GM-/-) with M-CSF-deficient osteopetrotic mice (genotype M-/-, op/op). Mice deficient in both GM-CSF and M-CSF (genotype GM-/-M-/-) are viable and have coexistent features corresponding to mice deficient in either factor alone. Like M-CSF- deficient mice, they have osteopetrosis and are toothless because of failure of incisor eruption. Like GM-CSF-deficient mice, they have a characteristic alveolar-proteinosis-like lung pathology, but it is more severe than that of GM-CSF-deficient mice and is often fatal. In particular, in GM-/-M-/- mice the accumulation of lipo-proteinaceous alveolar material is more marked, and bacterial pneumonic infections are more prevalent and more extensive, particularly involving Gram- negative bacteria. Neutrophilia consistently accompanies pulmonary infections, and some older GM-/-M-/- mice have polycythemia. Survival of GM-/-M-/- mice is significantly reduced compared with mice deficient in either factor alone, and all GM-/-M-/- mice have broncho- or lobar- pneumonia at death. These observations indicate that in vivo, M-CSF is involved in modulating the consequences of GM-CSF deficiency in the lung. Interestingly, GM-/-M-/- mice have circulating monocytes at levels comparable with those in M-CSF-deficient mice and the diseased lungs of all GM-/-M-/- mice contain numerous phagocytically active macrophages, indicating that in addition to GM-CSF and M-CSF, other factors can be used for macrophage production and function in vivo.

scholarly journals Impaired response to GM-CSF and G-CSF, and enhanced apoptosis in C/EBPβ-deficient hematopoietic cells

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 2999-3004 ◽  
Author(s):  
Tadayuki Akagi ◽  
Takayuki Saitoh ◽  
James O'Kelly ◽  
Shizuo Akira ◽  
Adrian F. Gombart ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Susceptibility To Infection ◽  
Expression Of Genes ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Deficient Mice

Abstract Transcription factors known as CCAAT enhancer binding proteins (C/EBPs) are involved in hematopoietic differentiation, including myelopoiesis and granulopoiesis. C/EBPβ-deficient mice develop normally; however, they exhibit defective macrophage function, resulting in increased susceptibility to infection. Little is known about the role of C/EBPβ in granulopoiesis; therefore, we examined granulopoiesis in C/EBPβ-deficient mice. Morphology, the number of peripheral blood and bone marrow cells, and the expression of genes specific for the myeloid lineage were normal in C/EBPβ-deficient mice. Interestingly, the hematopoietic progenitor cells of C/EBPβ-deficient mice did not respond normally to granulocyte/macrophage-colony stimulating factor and granulocyte colony stimulating factor. In addition, C/EBPβ-deficient neutrophils displayed enhanced apoptosis compared with wild-type neutrophils. Our present results indicate that C/EBPβ helps regulate survival of neutrophils, downstream of the granulocyte colony stimulating factor receptor.

scholarly journals Granulocyte-macrophage colony-stimulating factor is not responsible for the correction of hematopoietic deficiencies in the maturing op/op mouse

Blood ◽  
1995 ◽  
Vol 86 (1) ◽  
pp. 66-72 ◽  
Author(s):  
SK Nilsson ◽  
GJ Lieschke ◽  
CC Garcia-Wijnen ◽  
B Williams ◽  
D Tzelepis ◽  
...  
Keyword(s):  
Biologically Active ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Marrow Cavity ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Deficient Mice ◽  
Hematopoietic Activity

Osteopetrotic (op/op) mice are characterized by an autosomal recessive inactivating mutation resulting in the absence of biologically active colony-stimulating factor-1 (CSF-1). Consequently, young op/op mice have a severe deficiency of macrophages and osteoclasts resulting in excessive bone formation, occlusion of the marrow cavity, and reduced marrow hematopoietic activity. Recently, we showed that the osteopetrosis and hematopoietic deficiencies evident in young op/op mice are not permanent but are progressively corrected with age. There are increases in osteoclast activity; bone resorption; femoral marrow space; and marrow hematopoietic activity, cellularity, and macrophage content. In the present study we show that CSF-1-/- granulocyte- macrophage colony-stimulating factor (GM-CSF)(-/-)-deficient mice also undergo the same pattern of hematopoietic correction as the op/op mouse. Also, like the op/op mouse, the peritoneal cellularity and macrophage content of CSF-1/GM-CSF-deficient mice remains severely reduced. Our data show that the “knockout” of GM-CSF does not change the op/op phenotype, and that GM-CSF is not essential for the correction of the hematopoietic deficiencies in the op/op mouse. Importantly, the data also show that neither GM-CSF nor CSF-1 is an absolute requirement for the commitment of primitive hematopoietic stem cells to the macrophage lineage or for the differentiation of at least some classes of macrophages. This finding suggests that an alternate regulatory factor can be involved in macrophage and osteoclast commitment, differentiation, and function in vivo.

Overlapping roles for granulocyte-macrophage colony-stimulating factor and interleukin-3 in eosinophil homeostasis and contact hypersensitivity

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 922-928 ◽  
Author(s):  
Silke Gillessen ◽  
Nicolas Mach ◽  
Clayton Small ◽  
Martin Mihm ◽  
Glenn Dranoff
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Contact Hypersensitivity ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Deficient Mice

Abstract Studies of mice rendered deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) have established unique roles for these cytokines in pulmonary homeostasis, resistance to infection, and antigen-specific T- and B-cell responses. In addition to these distinctive properties, however, GM-CSF and IL-3 also stimulate the development and activation of hematopoietic cells in many similar ways, raising the possibility that each factor might partially compensate for the other's absence in singly deficient mice. To test whether endogenous GM-CSF and IL-3 mediate redundant functions in vivo, we generated mice lacking both cytokines through sequential gene targeting experiments in embryonic stem (ES) cells. Surprisingly, doubly deficient animals, but not single knockouts, showed increased numbers of circulating eosinophils. Doubly deficient mice, moreover, developed weaker contact hypersensitivity reactions to haptens applied epicutaneously than mice deficient in either factor alone. Together, these findings delineate overlapping roles for GM-CSF and IL-3 in hematopoiesis and immunity.

Alterations in the vascular extracellular matrix of granulocyte macrophage colony‐stimulating factor (GM‐CSF) ‐deficient mice

2003 ◽  
Vol 17 (11) ◽  
pp. 1451-1457 ◽  
Author(s):  
Gabriele Plenz ◽  
Heike Eschert ◽  
Stefan Beissert ◽  
Volker Arps ◽  
Jürgen R. Sindermann ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Deficient Mice

scholarly journals Expression and function of the human granulocyte-macrophage colony- stimulating factor receptor alpha subunit

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4174-4185 ◽  
Author(s):  
PT Jubinsky ◽  
AS Laurie ◽  
DG Nathan ◽  
J Yetz-Aldepe ◽  
CA Sieff
Keyword(s):  
Bone Marrow ◽  
Normal Bone Marrow ◽  
Colony Stimulating Factor ◽  
Receptor Alpha ◽  
Gm Csf ◽  
Normal Bone ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor

To determine the expression and function of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha chain (GMR alpha) during hematopoiesis and on leukemic cells, monoclonal antibodies were raised by immunizing mice with cells expressing high levels of human GMR alpha. A pool of five antibodies isolated from three different mice was used to characterize GMR alpha. This antibody pool (anti-GMR alpha) immunoprecipitated a protein with the expected molecular weight of GMR alpha from COS cells transiently transfected with the GMR alpha gene. In factor-dependent cells, GMR alpha existed as a phosphoprotein. However, its phosphorylation was not stimulated by the presence of GM- CSF. Anti-GMR alpha inhibited the GM-CSF-dependent growth of cell lines and normal bone marrow cells and inhibited the binding of iodinated GM- CSF to its receptor. Cell surface expression of GMR alpha was examined using anti-GMR alpha and flow cytometry. GMR alpha was readily detectable on both blood monocytes and neutrophils. In adherence- depleted normal bone marrow, two separate populations expressed GMR alpha. The most positive cells were predominantly macrophages, whereas the cells that expressed less GMR alpha were largely myelocytes and metamyelocytes. A small population of lin-CD34+ or CD34+CD38- cells also expressed GMR alpha, but they were not capable of significant growth in colony-forming assays. In contrast, the majority of lin-CD34+ and CD34+CD38- cells were GMR alpha-, yet they produced large numbers of myeloid and erythroid colonies in the same assay. Malignant cells from patients with leukemia were also tested for GMR alpha expression. All of the myeloid leukemias and only rare lymphoid leukemias surveyed tested positive for GMR alpha. These results show that anti-GMR alpha is useful for the functional characterization of the GMR alpha and for the detection of myeloid leukemia and that GMR alpha is expressed on certain lineages throughout hematopoietic development; however, progenitors that express the receptor may have a reduced capacity to proliferate in response to hematopoietic growth factors.

Distinct changes in pulmonary surfactant homeostasis in common β-chain- and GM-CSF-deficient mice

2000 ◽  
Vol 278 (6) ◽  
pp. L1164-L1171 ◽  
Author(s):  
Jacquelyn A. Reed ◽  
Machiko Ikegami ◽  
Lorraine Robb ◽  
C. Glenn Begley ◽  
Gary Ross ◽  
...  
Keyword(s):  
Surfactant Protein ◽  
Wild Type ◽  
Gm Csf ◽  
Adult Mice ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Β Chain ◽  
Stimulating Factor ◽  
Surfactant Metabolism ◽  
Pool Sizes

Pulmonary alveolar proteinosis (PAP) is caused by inactivation of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM receptor common β-chain (βc) genes in mice [GM(−/−), βc(−/−)], demonstrating a critical role of GM-CSF signaling in surfactant homeostasis. To distinguish possible phenotypic differences in GM(−/−) and βc(−/−) mice, surfactant metabolism was compared in βc(−/−), GM(−/−), and wild-type mice. Although lung histology in βc(−/−) and GM(−/−) mice was indistinguishable, distinct differences were observed in surfactant phospholipid and surfactant protein concentrations and clearance from lungs of βc(−/−) and GM(−/−) mice. At 1–2 days of age, lung saturated phosphatidylcholine (Sat PC) pool sizes were higher in wild-type, βc(−/−), and GM(−/−) mice compared with wild-type adult mice. In wild-type mice, Sat PC pool sizes decreased to adult levels by 7 days of age; however, Sat PC increased with advancing age in βc(−/−) and GM(−/−) mice. Postnatal changes in Sat PC pool sizes were different in GM(−/−) compared with βc(−/−) mice. After 7 days of age, the increased lung Sat PC pool sizes remained constant in βc(−/−) mice but continued to increase in GM(−/−) mice, so that by 56 days of age, lung Sat PC pools were increased three- and sixfold, respectively, compared with wild-type controls. After intratracheal injection, the percent recovery of [3H]dipalmitoylphosphatidylcholine and125I-recombinant surfactant protein (SP) C was higher in βc(−/−) compared with wild-type mice, reflecting decreased clearance in the receptor-deficient mice. The defect in clearance was significantly more severe in GM(−/−) than in βc(−/−) mice. The ratio of SP Sat PC to SP-A, -B, and -C was similar in bronchoalveolar lavage fluid (BALF) from adult mice of all genotypes, but the ratio of SP-D to Sat PC was markedly increased in βc(−/−) and GM(−/−) mice (10- and 5-fold, respectively) compared with wild-type mice. GM-CSF concentrations were increased in BALF but not in serum of βc(−/−) mice, consistent with a pulmonary response to the lack of GM-CSF signaling. The observed differences in surfactant metabolism suggest the presence of alternative clearance mechanisms regulating surfactant homeostasis in βc(−/−) and GM(−/−) mice and may provide a molecular basis for the range in severity of PAP symptoms. surfactant metabolism; alveolar macrophage; granulocyte-macrophage colony-stimulating factor

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