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PubMed1990

Effect of age at the start of iron chelation therapy on gonadal function in beta-thalassemia major.

BACKGROUND: Patients with transfusion-dependent thalassemia major tend to have abnormal growth and sexual maturation at puberty, presumably as a result of pituitary iron overload. This study was designed to determine whether chelation therapy with deferoxamine before the age of puberty would ameliorate this problem. METHODS: We examined 40 patients over 14 years of age with transfusion-dependent thalassemia major. The 19 patients in group A (mean [+/- SD] age at study, 17.0 +/- 1.5 years) had begun nightly treatment with subcutaneous deferoxamine before the age of 10 (mean age at start of treatment, 7.5 +/- 1.8 years). The 21 patients in group B (mean age, 24.1 +/- 3.8 years) had begun treatment after the age of 10 (mean age at start of treatment, 14.4 +/- 4.7 years). RESULTS: The abnormal findings were essentially confined to sexual development. The final height did not differ between groups or from the mean parental height in each group. Ninety percent of the patients in group A had normal sexual development, as compared with 38 percent of those in group B (P = 0.001). Outcomes were correlated with indexes of iron overload; the patients in group A had lower serum ferritin levels before chelation treatment (P = 0.01) and lower average serum ferritin levels during treatment (P = 0.005). CONCLUSIONS: Beginning chelation treatment with deferoxamine before the age of puberty can help children with transfusion-dependent thalassemia major to attain normal sexual maturation.

Adolescent↗
PubMed1998

Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major.

BACKGROUND: Deferiprone is an orally active iron-chelating agent that is being evaluated as a treatment for iron overload in thalassemia major. Studies in an animal model showed that prolonged treatment is associated with a decline in the effectiveness of deferiprone and exacerbation of hepatic fibrosis. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens, magnetic susceptometry, or both. Three hepatopathologists who were unaware of the patients' clinical status, the time at which the specimens were obtained, and the iron content of the specimens examined 72 biopsy specimens from 19 patients treated with deferiprone for more than one year. For comparison, 48 liver-biopsy specimens obtained from 20 patients treated with parenteral deferoxamine for more than one year were similarly reviewed. RESULTS: Of the 19 patients treated with deferiprone, 18 had received the drug continuously for a mean (+/-SE) of 4.6+/-0.3 years. At the final analysis, 7 of the 18 had hepatic iron concentrations of at least 80 micromol per gram of liver, wet weight (the value above which there is an increased risk of cardiac disease and early death in patients with thalassemia major). Of 19 patients in whom multiple biopsies were performed over a period of more than one year, 14 could be evaluated for progression of hepatic fibrosis; of the 20 deferoxamine-treated patients, 12 could be evaluated for progression. Five deferiprone-treated patients had progression of fibrosis, as compared with none of those given deferoxamine (P=0.04). By the life-table method, we estimated that the median time to progression of fibrosis was 3.2 years in deferiprone-treated patients. After adjustment for the initial hepatic iron concentration, the estimated odds of progression of fibrosis increased by a factor of 5.8 (95 percent confidence interval, 1.1 to 29.6) with each additional year of deferiprone treatment. CONCLUSIONS: Deferiprone does not adequately control body iron burden in patients with thalassemia and may worsen hepatic fibrosis.

Adolescent↗
PubMed1993

Hexamethylenebisacetamide-induced erythroleukemia cell differentiation involves modulation of events required for cell cycle progression through G1.

Hexamethylenebisacetamide (HMBA), a potent inducer of differentiation of transformed cells such as murine erythroleukemia cells, causes a prolongation of the G1 phase of the cell cycle during which commitment to terminal differentiation is first detected. Removal of HMBA prior to the G1 phase aborts commitment. To further define the relationship between the G1 phase and commitment to differentiation, we used two inhibitors of cell cycle progression: aphidicolin, which blocks cells at the G1/S interphase, and deferoxamine, which blocks cells at an earlier stage during G1. HMBA-induced prolongation of G1 is associated with the accumulation of underphosphorylated retinoblastoma protein, decrease in cyclin A protein levels, and commitment to differentiation. G1 arrest of murine erythroleukemia cells induced by aphidicolin or deferoxamine is not associated with accumulation of under-phosphorylated retinoblastoma protein, suppression of cyclin A protein, or commitment of cells to terminal differentiation. Neither of the cell cycle inhibitors alters the effect of HMBA in inducing the G1-associated changes or commitment to differentiation. Taken together, the present findings indicate that the site of action of HMBA which leads to commitment is in a stage of the G1 phase prior to the point of cell cycle block caused by deferoxamine or aphidicolin. HMBA appears to cause cell differentiation with suppression of cell cycle progression by an action that affects events required for cell progression through G1, including accumulation of underphosphorylated retinoblastoma protein and changes in regulation of cyclin levels.

Acetamides↗
PubMed1998

The effect of Gingko biloba extract (Egb 761) as a free radical scavenger on the survival of skin flaps in rats. A comparative study.

Free radicals may have a role in pedicle flap necrosis. We undertook this study to compare the effect of various antioxidants and scavengers of free radicals such as vitamin E, vitamin C, deferoxamine, and Gingko biloba extract (Egb 761) on McFarlane caudal-based dorsal rat flaps. Fifty rats were divided into five groups of 10 animals each. One group served as a control (saline) group. The remaining four groups were given vitamin C 340 mg/kg, deferoxamine 150 mg/kg, Egb 761 100 mg/kg, and vitamin E 20 mg/kg. The necrosed area of flap was significantly reduced in the deferoxamine (p < 0.001), Egb 761 (p < 0.001), and vitamin C (p < 0.05) groups compared with the control group. Vitamin E had no effect on distal flap necrosis (p = 0.20).

Animals↗
PubMed1992

Assessment of renal osteodystrophy in hemodialysis patients.

We performed a prospective study of 30 patients undergoing chronic hemodialysis to determine which of 6 generally available diagnostic procedures provided the most useful information for the assessment of bone disease in hemodialysis patients. The 6 procedures were: routine biochemical measurements, N-terminal parathyroid hormone (N-PTH), radiographic analysis of hands and clavicles, bone density determination by dual photon absorptiometry (DPA), deferoxamine stimulation test, and iliac crest bone biopsy. Serum N-PTH was elevated in 83% of patients but was not significantly associated with abnormalities of other biochemical parameters. No significant relationship was demonstrated between biochemical data and radiographic findings or between biochemical data and bone density by DPA. All patients with abnormal DPA had an elevation of N-PTH; therefore, DPA did not reveal any unsuspected disease. Bone biopsies were done in 20 patients and findings in each were consistent with uremic osteodystrophy, including osteitis fibrosa cystica in 11 patients and aluminum-associated bone disease in 2 patients. Six patients had mixed disease, and 1 patient had osteoporosis. Despite 11 positive deferoxamine tests, bone biopsy revealed aluminum deposition in only 7 of these patients, suggesting extraosseous aluminum accumulation in the remaining 4. Evaluation of the positive and negative predictive accuracies of DPA, x-ray analysis, N-PTH levels, and aluminum bone deposition revealed that normal DPA or x-ray findings do not exclude bone disease, that N-PTH level is a good marker for secondary hyperparathyroidism, and that a negative deferoxamine test excludes aluminum-associated bone disease. Discriminant analysis also reinforced these conclusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1987

A role for iron in oxidant-mediated ischemic injury to intestinal microvasculature.

Recent reports in the literature suggest that iron plays an important role in free radical-mediated injury in biological systems. To assess the role of iron-catalyzed oxidant production in ischemia-reperfusion injury, we examined the influence of deferoxamine (an iron chelator) and apotransferrin (iron transporting protein) on the increased intestinal vascular permeability produced by 1 h of ischemia and reperfusion. Both agents were administered intravascularly as a constant infusion, beginning 5 min before reperfusion. Capillary osmotic reflection coefficients were derived from the relationship between lymph-to-plasma protein concentration ratio and lymph flow in the feline small bowel. Vascular permeability in control intestinal preparations was 0.08 +/- 0.005, however it increased significantly to 0.40 +/- 0.03 in preparations subjected to 1 h of ischemia and 30 min of reperfusion. Vascular permeability in the deferoxamine-(0.15 +/- 0.009) and apotransferrin- (0.17 +/- 0.002) treated animals were significantly lower (P less than 0.01) than in the untreated group. Treatment with iron-loaded deferoxamine or transferrin did not offer any protection against ischemic injury. These findings support the hypothesis that iron plays an important role in the formation of hydroxyl radicals after reperfusion of the ischemic bowel.

Animals↗
PubMed1991

Platelet-activating factor-induced mucosal dysfunction: role of oxidants and granulocytes.

We tested the possibility that platelet-activating factor (PAF) exerts some of its actions on the microvascular and mucosal membranes by stimulating the production of reactive O2 metabolites. Two series of experiments were performed using autoperfused segments of cat ileum pretreated with human recombinant superoxide dismutase (hSOD), catalase (H2O2 scavenger), or deferoxamine (an iron chelator). In the first series, we examined the effects of PAF infusion on mucosal permeability (blood-to-lumen clearance) to 51Cr-EDTA. PAF induced a 4-, 25-, and 20-fold increase in 51Cr-EDTA clearance at 4, 20, and 40 ng/min, respectively, and the increase was positively correlated with luminal fluid flux. hSOD, catalase, and deferoxamine reduced the 51Cr-EDTA clearance at each PAF dose and eliminated the dependence of 51Cr-EDTA clearance on transmucosal fluid flux. To determine whether mucosal granulocytes were the source of the reactive O2 metabolites, the mucosa was depleted of myeloperoxidase-positive cells using an antibody against the leukocyte integrin CD11/CD18. Mucosal granulocyte depletion resulted in a greatly reduced clearance of 51Cr-EDTA, suggesting that resident granulocytes may be the source of the reactive O2 metabolites. In a second series of studies, we examined the influence of hSOD, catalase, and deferoxamine on the increased transcapillary fluid and protein fluxes induced by intra-arterial PAF infusion. These agents attenuated the enhanced transvascular fluid and protein filtration by greater than 50% at the low dose but had no effect at the higher doses. We conclude that the PAF-induced increase in mucosal permeability to 51Cr-EDTA is mediated by reactive O2 metabolites produced by resident phagocytic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Iron chelation and a free radical scavenger suppress angiotensin II-induced upregulation of TGF-beta1 in the heart.

Long-term administration of angiotensin II causes myocardial loss and cardiac fibrosis. We previously found iron deposition in the heart of the angiotensin II-infused rat, which may promote angiotensin II-induced cardiac damage. In the present study, we have investigated whether an iron chelator (deferoxamine) and a free radical scavenger (T-0970) affect the angiotensin II-induced upregulation of transforming growth factor-beta1 (TGF-beta1). Angiotensin II infusion for 7 days caused a robust increase in TGF-beta1 mRNA expression in vascular smooth muscle cells, myofibroblast-like cells, and migrated monocytes/macrophages. T-0970 and deferoxamine suppressed the upregulation of TGF-beta1 mRNA and reduced the extent of cardiac fibrosis in the heart of rats treated with angiotensin II. These agents blocked the angiotensin II-induced upregulation of heme oxygenase-1, a potent oxidative and cellular stress-responsive gene, but they did not significantly affect systolic blood pressure or plasma levels of aldosterone. In addition, T-0970 and deferoxamine suppressed the angiotensin II-induced upregulation of monocyte chemoattractant protein-1 in the heart. These results collectively suggest that iron and the iron-mediated generation of reactive oxygen species may contribute to angiotensin II-induced upregulation of profibrotic and proinflammatory genes, such as TGF-beta1 and monocyte chemoattractant protein-1.

Aldosterone↗
PubMed1989

Xanthine oxidase-induced injury to endothelium: role of intracellular iron and hydroxyl radical.

The major objective of the present study was to characterize the sequence of events leading to endothelial cytotoxicity induced by oxidants generated extracellularly by xanthine oxidase. 51Cr-labeled monolayers of calf pulmonary artery endothelial cells were exposed to a reaction mixture containing hypoxanthine, xanthine oxidase, and chelated iron (HX/XO) and endothelial cell injury was quantitated as 51Cr release into the media. Catalase, but not mannitol or superoxide dismutase, prevented endothelial cell injury induced by HX/XO, indicating that H2O2 was the mediator of the cytotoxicity. Pretreatment of the cells with free deferoxamine (an iron chelator), but not with deferoxamine bound to dextran (mol wt 40,000), prevented endothelial cell injury induced by HX/XO or H2O2. Of the membrane-permeant hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea, only dimethylthiourea prevented 1) HX/XO or H2O2-induced endothelial cytotoxicity and 2) deoxyribose degradation by hydroxyl radicals (.OH) generated by an iron-catalyzed reaction on the sugar (site-specific reaction). The concentration of ferritin required to produce significant quantities of .OH was much greater than that present in endothelial cells, and ferritin-catalyzed .OH formation was not affected by deferoxamine, indicating that ferritin-bound iron is most likely not the physiologically active catalyst. We conclude that extracellularly generated H2O2 can enter the cell and interact with nonferritin iron to produce the cytotoxic .OH via a site-specific reaction.

Animals↗
PubMed1992

Toxicity of tubule fluid iron in the nephrotic syndrome.

This study was carried out in rats with nephrotoxic serum nephritis after autologous phase proteinuria was well established to determine the effect of tubule fluid iron chelation on the course of this disease. Deferoxamine administration caused a reduction in urinary iron potentially capable of catalyzing hydroxyl radical (.OH) formation and kidney iron uptake (224 +/- 60 vs. 398 +/- 152 mg/kg). This was associated with a decrease rate of progression of renal failure over the 21-day study period (creatinine clearance -0. 199 +/- 0.152 vs. -0.509 +/- 0.336 ml/min, P < 0.05) and improved survival (8/8 vs. 4/8, P < 0.05). In addition deferoxamine caused a reduction in urinary transferrin excretion (32 +/- 15 vs. 74 +/- 16 mg/day) and fractional excretion of transferrin (2.01 +/- 1 vs. 5.9 +/- 3.7%) and an increase in serum transferrin levels (229 +/- 36 vs. 139 +/- 45 mg/dl, all P < 0.05). It is suggested that iron presented to the tubule fluid as a result of the glomerular leak for transferrin is dissociated from transferrin. In turn the iron is available in a form capable of catalyzing .OH formation, resulting in lipid peroxidation of tubule cell membranes. Deferoxamine chelation of tubule fluid iron retards the development of both tubulointerstitial injury and superimposed glomerular sclerosis in this model of membranous nephropathy.

Animals↗
PubMed2005

Gene expression profiling of hypoxia signaling in human hepatocellular carcinoma cells.

Cellular, local, and organismal responses to low O2 availability occur during processes such as anaerobic metabolism and wound healing and pathological conditions such as stroke and cancer. These responses include increases in glycolytic activity, vascularization, breathing, and red blood cell production. These responses are mediated in part by the hypoxia-inducible factors (HIFs), which receive information on O2 levels from a group of iron- and O2-dependent hydroxylases. Hypoxia mimics, such as cobalt chloride, nickel chloride, and deferoxamine, act to simulate hypoxia by altering the iron status of these hydroxylases. To determine whether these mimics are appropriate substitutes for the lower O2 tension evoked naturally, we compared transcriptional responses of a Hep3B cell line using high-density oligonucleotide arrays. A battery of core genes was identified that was shared by all four treatments (hypoxia, cobalt, nickel, and deferoxamine) including glycolytic enzymes, cell cycle regulators, and apoptotic genes. Importantly, cobalt, nickel, and deferoxamine influenced transcription of distinct sets of genes that were not affected by cellular hypoxia. These global responses to hypoxia indicate a balancing act between adaptation and programmed cell death and suggest caution in the use of hypoxia mimics as substitutes for the low O2 tension that occurs in vivo.

Algorithms↗
PubMed2000

Hypoxia induces transcription of the plasminogen activator inhibitor-1 gene through genistein-sensitive tyrosine kinase pathways in vascular endothelial cells.

A decline in oxygen concentration perturbs endothelial function, which promotes local thrombosis. In this study, we determined whether hypoxia in the range of that observed in pathophysiological hypoxic states stimulates plasminogen activator inhibitor-1 (PAI-1) production in bovine aortic endothelial cells. PAI-1 production, measured by ELISA, was increased by 4.7-fold (P<0.05 versus normoxic control, n=4) at 12 hours after hypoxic stimulation. Northern blot analysis showed the progressive time-dependent increase in the steady-state level of PAI-1 mRNA expression by hypoxia, which reached a 7.5-fold increase (P<0.05 versus control, n=4) at 12 hours. Deferoxamine, which has been known to bind heme protein and to reproduce the hypoxic response, induced PAI-1 production at both the mRNA and protein levels. The half-life of PAI-1 mRNA, as determined by a standard decay assay, was not affected by hypoxia, suggesting that induction of PAI-1 mRNA was regulated mainly at the transcriptional level. Transient transfection assays of the human PAI-1 promoter-luciferase construct indicates that a hypoxia-responsive region lies between -414 and -107 relative to the transcription start site, where no putative hypoxia response element is found. The hypoxia-mediated increase in PAI-1 mRNA levels was attenuated by the tyrosine kinase inhibitors genistein (50 micromol/L) and herbimycin A (1 micromol/L), whereas PD98059 (50 micromol/L, MEK1 inhibitor), SB203580 (10 micromol/L, p38 mitogen-activated protein kinase inhibitor), and calphostin C (1 micromol/L, protein kinase C inhibitor) had no effect on the induction of PAI-1 expression by hypoxia and deferoxamine. Genistein but not daidzein blocked the production of hypoxia- and deferoxamine-induced PAI-1 protein. Thus, we conclude that hypoxia stimulates PAI-1 gene transcription and protein production through a signaling pathway involving genistein-sensitive tyrosine kinases in vascular endothelial cells.

Animals↗
PubMed1992

Antioxidants attenuate microvascular changes in the early phase of experimental pneumococcal meningitis in rats.

BACKGROUND AND PURPOSE: We tested in a rat meningitis model 1) whether pneumococcal cell wall components are capable of producing changes in regional cerebral blood flow, brain water content, and intracranial pressure similar to those we have already observed after intracisternal inoculation of live pneumococci and 2) whether antioxidants would modulate these alterations in the early phase of meningitis. METHODS: Regional cerebral blood flow as measured by laser Doppler flowmetry and intracranial pressure were monitored continuously for 4 hours after intracisternal challenge. Brain edema formation was assessed by brain water content determinations. We investigated the following groups: rats challenged intracisternally with the whole intact pneumococcal cell wall (n = 7) or the pneumococcal cell wall hydrolyzed by the M1-muramidase (n = 7); rats injected intracisternally with phosphate-buffered saline (n = 6); rats pretreated intravenously with superoxide dismutase conjugated with polyethylene glycol (10,000 units/kg) and injected intracisternally with cell wall components (n = 5) or phosphate-buffered saline (n = 6); rats injected intracisternally with phosphate-buffered saline and pretreated intravenously with polyethylene glycol (10% solution, 1.2 ml/kg, n = 5) or continuously treated with intravenous free superoxide dismutase (22,000 units/kg per hour, n = 6); and rats continuously treated intravenously with deferoxamine mesylate (10 mg/kg per hour) and injected intracisternally with cell wall components (n = 6) or phosphate-buffered saline (n = 7). RESULTS: Both pneumococcal cell wall preparations produced a significant increase in regional cerebral blood flow, intracranial pressure, and brain water content. Conjugated superoxide dismutase as well as deferoxamine prevented the increase in intracranial pressure and brain water content. In addition, the increase in regional cerebral blood flow as observed in untreated, cell wall-challenged rats (baseline, 100%; 183.1 +/- 12.3% after 4 hours, mean +/- SEM) was significantly attenuated by administration of both conjugated superoxide dismutase (136.6 +/- 14.1%) and deferoxamine (149.8 +/- 8.2%) (p < 0.05). Polyethylene glycol-conjugated superoxide dismutase alone produced an increase in regional cerebral blood flow (125.6 +/- 8.7% after 4 hours). We found that polyethylene glycol per se accounts for this action. CONCLUSIONS: These data show that pneumococcal cell wall components containing teichoic acid produce changes in regional cerebral blood flow, intracranial pressure, and brain water content and that oxygen radicals contribute to these pathophysiological alterations in the early phase of experimental pneumococcal meningitis.

Animals↗
PubMed2003

Air pollution particles produce airway wall remodeling in rat tracheal explants.

There is evidence that chronic exposure to high levels of ambient particulate pollutants (PM) is associated with chronic airflow obstruction, but how this occurs is not known. We exposed rat tracheal explants to Ottawa urban air particles (ECH93) or diesel exhaust particles. After 7 d in air organ culture, both types of PM increased explant procollagen and transforming growth factor (TGF)-beta 1 gene expression, and markedly increased tissue hydroxyproline. For both types of particle, nuclear factor-kappa B inhibitor SN50 completely blocked increased gene expression. With EHC93, procollagen expression was inhibited by the oxidant scavenger, tetramethylthiourea, and by the iron chelator, deferoxamine, but TGF-beta1 expression was not inhibited by deferoxamine. Inhibitors of extracellular signal regulated kinase and p38 kinase did not affect EHC93-induced gene expression. With diesel exhaust particles, tetramethylthiourea and deferoxamine had no effect, but extracellular signal regulated kinase and p38 inhibitors completely blocked effects on procollagen and TGF-beta 1. Fetuin, an inhibitor of TGF-beta receptor binding, prevented increases in procollagen gene expression. We conclude that two common types of PM can directly induce expression of genes involved in fibrogenesis and actual airway wall fibrosis through nuclear factor-kappa B- and TGF-beta-mediated mechanisms. PM-induced airway wall remodeling may play an important role in producing airflow obstruction in individuals living in high PM regions.

Air Pollution↗
PubMed2006

New chelation therapies and emerging chelating drugs for the treatment of iron overload.

Iron chelation therapy using deferoxamine or deferiprone (L1) is effective for the treatment of most transfused iron-loaded patients. The combination administration of deferiprone in the daytime and deferoxamine in the night appears to be universally effective in rapidly achieving negative iron balance. The cardiac iron removal effect of deferiprone increases the prospects of longer survival in beta-thalassaemia patients. New chelators have reached the stage of clinical development such as deferitrin, 1-allyl-2-methyl-3-hydroxypyrid-4-one (L1NAll) and the starch deferoxamine polymers. Deferasirox has received a conditional approval in the US under the FDA-accelerated approval regulations, but needs further verification of its efficacy and safety. Future iron chelation therapies are likely to be based on combinations of chelating drugs.

Carboxylic Acids↗
PubMed1987

Fatal iron intoxication in late pregnancy.

A case of intoxication with 5 g of elemental iron (25 g of ferrous sulfate) in a 30-year old woman at 36 weeks gestation is reported. Deferoxamine treatment was given with a delay of 26 hours after ingestion. A healthy infant was delivered by cesarean section 31 hours following ingestion. Subsequently, the patient developed hepatic necrosis, coma and hemostatic dysfunction and expired in cardiac failure after two weeks. The fatal outcome supports the view that the potential lethal dose of iron is lower for adults than for children. This case also demonstrates that major hepatic dysfunction can be a prominent feature of adult cases of iron intoxication. It is not unequivocal that early institution of deferoxamine treatment would have had a significant influence on the outcome. However, taking into account the well-documented efficacy of the drug in children and that no major adverse fetal effects have been associated with deferoxamine treatment in pregnancy, we suggest such antidote therapy to be considered for prompt institution in similar cases.

Adult↗
PubMed1995

Conservative management of patients with moderately elevated serum iron levels.

For the four year period 1990-1993, we retrospectively reviewed all cases of iron ingestion reported to a regional poison control center that had serum iron levels in the 300-500 micrograms/dL range and did not receive deferoxamine. A total of 32 patients did not undergo deferoxamine therapy or challenge testing. The mean age was 6.7 years (range five months to 21 years). The mean serum iron level was 372.8 micrograms/dL (range 301-487 micrograms/dL). Ten patients (31.3%) were asymptomatic. Symptoms included vomiting in 18 (56.3%), diarrhea in six (18.8%), lethargy in one (3.1%), and transient hypotension in one patient (3.1%). No patients presented with grossly bloody emesis or stool. Fifteen patients (46.9%) were hospitalized for at least one day. Seventeen (53.1%) were treated and released from the emergency department. All 32 patients recovered without sequelae. A conservative approach without deferoxamine therapy or challenge should be considered when serum iron levels are in the 300-500 micrograms/dL range in asymptomatic patients, as well as in those with self-limited, non-bloody emesis or diarrhea without other symptoms.

Adolescent↗
PubMed2005

Antioxidants to prevent bovine neutrophil-induced mammary epithelial cell damage.

Activated neutrophils are able to produce a large quantity of bactericidal molecules such as reactive oxygen species that have been associated with tissue damage in several inflammation models. The protective effects of antioxidants in a context of neutrophil-induced damage to mammary epithelial cells were first evaluated in vitro using a coculture model of activated bovine neutrophils and a bovine mammary epithelial cell line (MAC-T cells). Cell damage was determined by quantifying the release of lactate dehydrogenase by MAC-T cells in culture medium. Morphological observation of cells stained with acridine orange was used to visualize the extent of cell damage. When incubated with neutrophils activated by lipopolysaccharides and phorbol 12-myristate 13-acetate, MAC-T cells released large amounts of lactate dehydrogenase indicating significant cell damage. The addition of dimethylthiourea or bathocuproine disulfonic acid did not reduce the damage whereas catechin, deferoxamine or glutathione ethyl ester significantly reduced neutrophil-induced cytotoxicity in a dose-dependent manner. The effect of deferoxamine, an iron chelator, on the growth of Escherichia coli and the ability of bovine neutrophils to phagocytose these bacteria were then assessed in vitro. Our data showed that deferoxamine did not interfere with the phagocytic activity of neutrophils but inhibited growth of the bacteria. Overall, our results suggest that antioxidants may be effective tools for protecting mammary tissue against neutrophil-induced oxidative stress during bovine mastitis.

Animals↗