PubMed · 14960798
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A Shah. 2004. Anemia.. https://pubmed.ncbi.nlm.nih.gov/14960798/
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Both polycythemia and the increase in hypoxic ventilatory response (HVR) are considered as important factors of acclimatization to hypoxia. The objective of this study was to characterise the ventilation pattern at different inspired oxygen fraction in a model of chronic anemic mice. These mice have a targeted disruption in the 5' untranslated region of the Epo gene that reduces Epo expression such that the homozygous animal is severely anemic. Ventilation in normoxia in Epo-TAg(h) mice was significantly greater than in wild type, and the difference was mainly due to a higher tidal volume. HVR was higher in Epo-TAg(h) mice at every FIO2 suggesting a higher chemosensitivity. Resting oxygen consumption was maintained in anemic mice. Maximal oxygen consumption was 30% lower while hemoglobin was 60% lower in anemic mice compared to wild type. This small decrease in maximal oxygen consumption is probably due a greater cardiac output and/or a better tissue oxygen extraction and would allow these anemic mice to acclimatize to hypoxia in spite of low oxygen carrying capacity. In conclusion, Epo-TAg(h) anemic mice showed increased ventilation and hypoxic ventilatory response. However, whether these adaptations will contribute to acclimatization in chronic hypoxia remains to be determined.
Darbepoetin alfa (Aranesp), Amgen) is a novel erythropoiesis-stimulating protein with a serum half-life longer than recombinant human erythropoietin (Epo), used in the treatment of cancer-associated anaemia. Anaemia is known to adversely affect prognosis and response to treatment in cancer patients. Solid tumours contain regions of hypoxia due to poor vascular supply and cellular compaction. Although hypoxic stress usually results in cell death, hypoxia-resistant tumour cells are genetically unstable and often acquire a drug-resistant phenotype. Increasing tumour oxygenation and perfusion during treatment could have the doubly beneficial outcome of reducing the fraction of treatment-resistant cells, while increasing drug delivery to previously hypoxic tissue. In this study, we examined the effect of darbepoetin alfa on chemotherapy sensitivity and delivery in an in vivo model of Lewis lung carcinoma, shown here to express the Epo receptor (EpoR). We identified that weekly darbepoetin alfa treatment, commencing 10 days before chemotherapy, resulted in a significant reduction in tumour volume compared to chemotherapy alone. This was mediated by the prevention of anaemia, a reduction in tumour hypoxia and a concomitant increase in drug delivery. Darbepoetin alfa treatment alone did not modulate the growth of the EpoR-expressing tumour cells. This study identifies an important role for darbepoetin alfa in increasing the therapeutic index of chemotherapy.
Infectious salmon anaemia virus (ISAV) is an aquatic orthomyxovirus causing a multisystemic disease in farmed Atlantic salmon (Salmo salar) where disease development, clinical signs, and histopathology vary to a large extent. Here, an experimental trial was designed to determine the effect of variation in viral genes on virus-host interactions, as measured by disease susceptibility and immune responses. The fish were infected using cohabitant transmission, representing a natural route of infection. Variation caused by host factors was minimized using MHC compatible A. salmon half-siblings as experimental fish. Virus isolates were selected according to HE genotype, as European ISAV isolates can be genotyped according to deletion patterns in their hemagglutinin-esterase (HE) surface glycoprotein, and the course of disease they typically induce, classified as acute versus protracted. The different ISAV isolates induced large variations in death prevalence, ranging from 0-47% in the test-group and 3-75% in the cohabitant fish. The use of MHC compatible experimental fish made it possible to determine the relative contribution of humoral versus cellular response in protection against ISA. Ability to induce a strong proliferative response correlated with survival and virus clearance, while induction of a humoral response was less protective.