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Biomedical subjects

G Hodgson

Publications and source records attributed to G Hodgson.

At least 19 recordsLinked to original sources
PubMed1997

Mice lacking both granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival.

Mice lacking granulocyte colony-stimulating factor (G-CSF) are neutropenic with reduced hematopoietic progenitors in the bone marrow and spleen, whereas those lacking granulocyte-macrophage colony-stimulating factor (GM-CSF) have impaired pulmonary homeostasis and increased splenic hematopoietic progenitors, but unimpaired steady-state hematopoiesis. These contrasting phenotypes establish unique roles for these factors in vivo, but do not exclude the existence of additional redundant functions. To investigate this issue, we generated animals lacking both G-CSF and GM-CSF. In the process of characterizing the phenotype of these animals, we further analyzed G-CSF- and GM-CSF-deficient mice, expanding the recognized spectrum of defects in both. G-CSF-deficient animals have a marked predisposition to spontaneous infections, a reduced long-term survival, and a high incidence of reactive type AA amyloidosis. GM-CSF-deficient mice have a modest impairment of reproductive capacity, a propensity to develop lung and soft-tissue infections, and a similarly reduced survival as in G-CSF-deficient animals. The phenotype of mice lacking both G-CSF and GM-CSF was additive to the features of the constituent genotypes, with three novel additional features: a greater degree of neutropenia among newborn mice than in those lacking G-CSF alone, an increased neonatal mortality rate, and a dominant influence of the lack of G-CSF on splenic hematopoiesis resulting in significantly reduced numbers of splenic progenitors. In contrast to newborn animals, adult mice lacking both G-CSF and GM-CSF exhibited similar neutrophil levels as G-CSF-deficient animals. These findings demonstrate that the additional lack of GM-CSF in G-CSF-deficient animals further impairs steady-state granulopoiesis in vivo selectively during the early postnatal period, expand the recognized roles of both G-CSF and GM-CSF in vivo, and emphasize the utility of studying multiply deficient mouse strains in the investigation of functional redundancy.

Aging↗
PubMed1997

Increased tolerance to endotoxin by granulocyte-macrophage colony-stimulating factor-deficient mice.

The contribution of granulocyte-macrophage CSF (GM-CSF) to endotoxin-mediated septic shock has been assessed by treating GM-CSF-deficient mice with LPS. Hypothermia and loss in body weight were markedly attenuated in LPS-treated GM-CSF-deficient mice compared with similarly treated control mice; moreover, the levels of circulating IFN-gamma, IL-1alpha, and IL-6 were lower in LPS-treated GM-CSF-deficient mice than LPS-treated control mice. Intriguingly, the peak levels of TNF-alpha in response to LPS treatment were the same in the serum of GM-CSF-deficient mice and control mice, although in GM-CSF-deficient mice, TNF-alpha persisted longer. Activation of macrophages by LPS, resulting in expression of cytokines including TNF-alpha and IL-1, is thought to underlie endotoxin-mediated effects. Accordingly, the response of peritoneal macrophages from GM-CSF-deficient mice to LPS was studied in vitro. LPS-stimulated peritoneal macrophages from GM-CSF-deficient mice produced significantly less IL-1alpha and nitric oxide than macrophages from wild-type mice, although there was no difference in TNF-alpha production. Collectively, these observations indicate that GM-CSF contributes to cytokine production in LPS-mediated septic shock, and that the attenuated production of these secondary cytokines (IFN-gamma, IL-1alpha, and IL-6) may contribute to the endotoxin-resistant phenotype of GM-CSF-deficient mice.

Animals↗
PubMed1996

Testing of a GIS Model of Eucalyptus largiflorens Health on a Semiarid, Saline Floodplain

Irrigated agriculture has resulted in substantial changes in water flows to the lower reaches of the River Murray. These changes have led to large-scale occurrences of dieback in Eucalyptus largiflorens (black box) woodlands as well as increased inputs of salt to the river. Management options to address problems of this scale call for the use of spatial data sets via geographic information systems (GIS). A GIS exists for one floodplain of the River Murray at Chowilla, and a simple model predicted six health classes of Eucalyptus largiflorens based on groundwater salinity, flooding frequency, and groundwater depth.To determine the usefulness of the model for vegetation management, the quality of both the model and the GIS data sets were tested. Success of the testing procedure was judged by the degree of spatial matching between the model's predictions of health and that assessed from aerial photographs and by field truthing. Analyses at 80 sites showed that tree health was significantly greater where groundwater salinity was less than 40 dS/m or flooding occurred more frequently than 1 in 10 years or depth to groundwater exceeded 4 m. Testing of the GIS data sets found that vegetation was misclassified at 15% of sites. Association was shown between GIS-predicted values and field-truthed values of groundwater salinity but not groundwater depth. The GIS model of health is a useful starting point for future vegetation management and can be further improved by increasing the quality of the data coverages and further refining of the model to optimize parameters and thresholds.

Journal Article↗
PubMed1995

Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease.

Mice homozygous for a disruption at the Lyn locus display abnormalities associated with the B lymphocyte lineage and in mast cell function. Despite reduced numbers of recirculating B lymphocytes, Lyn-/- mice are immunoglobulin M (IgM) hyperglobulinemic. Immune responses to T-independent and T-dependent antigens are affected. Lyn-/- mice fail to mediate an allergic response to IgE cross-linking, indicating that activation of LYN plays an indispensable role in Fc epsilon RI signaling. Lyn-/- mice have circulating autoreactive antibodies, and many show severe glomerulonephritis caused by the deposition of IgG immune complexes in the kidney, a pathology reminiscent of systemic lupus erythematosus. Collectively, these results implicate LYN as having an indispensable role in immunoglobulin-mediated signaling, particularly in establishing B cell tolerance.

Anaphylaxis↗
PubMed1995

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

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.

Age Factors↗
PubMed1994

Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization.

Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30% of wild-type mice (genotype G-CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophil levels, suggesting a gene-dosage effect. In the marrow of G-CSF-/- mice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells. Despite G-CSF deficiency, mature neutrophils were still present in the blood and marrow, indicating that other factors can support neutrophil production in vivo. G-CSF-/- mice had reduced numbers of neutrophils available for rapid mobilization into the circulation by a single dose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice elevated circulating neutrophil levels to normal, and after 4 days of G-CSF administration, G-CSF+/+ and G-CSF-/- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to control infection with Listeria monocytogenes, with diminished neutrophil and delayed monocyte increases in the blood and reduced infection-driven granulopoiesis. Collectively, these observations indicate that G-CSF is indispensible for maintaining the normal quantitative balance of neutrophil production during "steady-state" granulopoiesis in vivo and also implicate G-CSF in "emergency" granulopoiesis during infections.

Animals↗
PubMed1994

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

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.

Animals↗
PubMed1994

Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology.

Mice homozygous for a disrupted granulocyte/macrophage colony-stimulating factor (GM-CSF) gene develop normally and show no major perturbation of hematopoiesis up to 12 weeks of age. While most GM-CSF-deficient mice are superficially healthy and fertile, all develop abnormal lungs. There is extensive peribronchovascular infiltration with lymphocytes, predominantly B cells. Alveoli contain granular eosinophilic material and lamellar bodies, indicative of surfactant accumulation. There are numerous large intraalveolar phagocytic macrophages. Some mice have subclinical lung infections involving bacterial or fungal organisms, occasionally with focal areas of acute purulent inflammation or lobar pneumonia. Some features of this pathology resemble the human disorder alveolar proteinosis. These observations indicate that GM-CSF is not essential for the maintenance of normal levels of the major types of mature hematopoietic cells and their precursors in blood, marrow, and spleen. However, they implicate GM-CSF as essential for normal pulmonary physiology and resistance to local infection.

Animals↗
PubMed1985

Detection of synergistic factor and interleukin-3 activity in the serum and ascites fluid of mice bearing the WEHI-3 tumour.

Media conditioned (CM) by WEHI-3 cells (a myelomonocytic leukemia cell line) contains a number of haemopoietic growth factors, including synergistic factor (SF) and interleukin-3 (IL3). We have investigated the production of SF and IL3 in vivo in mice bearing the WEHI-3 tumour. SF and IL3 activity were detected in both the sera and ascites fluids of these mice. SF from the ascites fluid was partially purified by a four-step purification schedule consisting of ammonium sulphate fractionation, DEAE-cellulose, hydroxylapatite, and Sephadex G-100 chromatography. This purification sequence resulted in approximately a 250- and 187-fold purification of SF and IL3 respectively on the initial starting material with a yield of 13 and 9.7% respectively of the initial activity. At each stage of purification, the fractions containing SF co-purified with IL3 activity, further supporting our previous report that SF and IL3 are probably identical molecules. The characteristics of the in-vivo derived (sera and ascites fluid) activities were found to be similar to those of the factors produced in vitro in WEHI-3 cell conditioned media. These results support the conclusion that SF and IL3 are produced in vivo in WEHI-3 tumour bearing mice and are not in vitro artifacts.

Animals↗
PubMed1977

Proliferation of erythroid and granulocyte progenitors in the spleen as a function of stem cell dose.

A study of the kinetics of cellular proliferation, in the morphologically unrecongizable haemopoietic progenitor cell compartment, as a function of injected CFU-S dose has been carried out in the spleens of lethally X-irradiated mice using 3H-TdR labelling. Amplification in this proliferating cell compartment was observed to decline as CFU-S dose increased. The number of divisions in the differentiated line arising from CFU-S up to the first appearance of recognizable erythroid precursors were calculated to be 9-2, 12-5, 15 and 17 for the 2, 0-35, 0-05 and 0-007 femur equivalent doses respectively. The growth of cell populations arising from CFU-S was biphasic, with a rapid initial phase having a doubling time of about 6-3 hr, and a slow phase of doubling time around 1 day. Analysis of the rapid phase by the FLM method gave a cycle time of 5-6 hr, Recognizable labelled erythroid precursors were detected at the same time as, or just after, the change in slope of the growth curve. Significant numbers of proliferating (labelled) granulocytes only appeared in the spleens of animals receiving the higher marrow doses (2 and 0-35 femur). The erythroid to granulocyte ratio was also a decreasing function of marrow dose.

Animals↗
PubMed1977

In vivo synchronization of haemopoietic stem cells with hydroxyurea.

Four injections of hydroxyurea 1 mg/g body weight, given to normal mice 31, 24, 10 and 7 h before sampling bone marrow, reduced CFU-S content of femoral marrow to 30% of normal in Balb/c female and to 10% of normal in C57 B1 male mice. Over 80% of the surviving CFU-S were in the S phase of cycle, as judged from their sensitivity to killing by hydroxyurea or ARA-C.

Animals↗