Prior induction of an endoplasmic reticulum stress response has been associated with an increased tolerance to cellular toxins in in vitro systems, primarily involving renal and neuronal cells. Reactive intermediates are involved in toxicity in many tissues, therefore, we wished to determine if cytoprotection after induction of an endoplasmic reticulum stress response was a general phenomenon in other cell types. A stress response was induced by tunicamycin in a human hepatocyte cell line (HepG2), a rat hepatocyte cell line (H4IIE), a porcine kidney cell line (LLC-PK1), and a human lymphocyte cell line (K562). Induction of the endoplasmic reticulum stress proteins GRP78, GRP94, calreticulin and protein disulfide isomerase was assessed by immunoblotting. Cytotoxicity was assessed 24 hr after a 3 hr exposure to iodoacetamide, tert-butylhydrogenperoxide, menadione, or sulfamethoxazole hydroxylamine, or after a 2 hr exposure to N-acetyl-p-benzoquinoneimine, the reactive metabolite of acetaminophen. Induction of endoplasmic reticulum stress proteins in LLC-PK1 cells resulted in a 2-6 times increase in the concentration of all the cytotoxins required to cause a 50% decrease in cell viability at 24 hr. In contrast, tunicamycin pretreatment only resulted in a 1.7-times increase for iodoacetamide in HepG2 cells and a 2.2-times increase for N-acetyl-p-benzoquinoneimine in the H4IIE cells, but had no effect on the other toxins tested. Induction of endoplasmic reticulum stress proteins in K562 cells did not alter susceptibility to any toxins tested. Our results indicate that protection afforded by the induction of an endoplasmic reticulum stress response is dependent on the cell type and may be toxin specific. These results suggest that either the molecular pathways of cell death for individual toxins are different between cell types and toxins, or that the function of endoplasmic reticulum stress proteins are dependent on the cell type.
Corticosteroids may produce mood changes. This could account for improvement in patients with chronic airflow limitation following trials of oral corticosteroid treatment as mood elevation might improve performance in objective measurements. This proposition was tested in 21 patients with chronic airflow limitation, who underwent detailed psychological assessment during a randomised controlled double blind crossover trial of the effect of prednisolone 40 mg daily compared with that of a placebo. Self rating visual analogue scales for various qualities of mood were completed before the study and after each phase in addition to depression and psychological symptom questionnaires. After treatment with the placebo, patients showed increases in cheerfulness (p < 0.01) and sociability (p < 0.01) and a decrease in depression (p <0.01). After treatment with prednisolone there were increases in cheerfulness (p < 0.01), optimism (p < 0.01), activity (p < 0.05), and sociability (p < 0.02) and there was a decrease in depression (p < 0.01). When placebo and prednisolone values were compared, however, there were no significant differences. Some patients showed improvements (>20%) in peak expiratory flow, FEV, or forced vital capacity (FVC) after prednisolone, but nearly all had improvements in at least one psychological test. There were no detectable associations between changes in objective measurements and changes in psychological test ratings. This study suggests that in patients with chronic obstructive lung disease significant psychological changes are no more likely to follow treatment with a corticosteroid than treatment with a placebo and that physiological improvement after corticosteroid treatment is not tied to psychological changes.
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