• Toxicological Research
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• v.8 no.2
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• pp.343-357
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• 1992

Tumor necrosis factor-${\alpha}$(TNF), a polypeptide hormone secreted primarily by activated macrophages, was originally identified on the basis of its ability to cause hemorrhagic necrosis and tumor regression in vivo. Subsequently, TNF has been shown to be an important component of the host responses to infection and cancer and may mediate the wasting syndrome known as cachexia. These systemic actions of TNF are reflected in its diverse effects on target cells in vitro. TNF initiates its diverse cellular actions by binding to specific cell surface receptors. Although TNF receptors have been identified on most of animal cells, regulation of these receptors and the mechanisms which transduce TNF receptor binding into cellular responses are not well understood. Therefore, in the present study, the mechanisms how TNF receptors are being regulated and how TNF receptor binding is being transduced into cellular responses were investigated in rat liver plasma membranes (PM) and ME-180 human cervical carcinoma cell lines. $^{125}I$-TNF bound to high ($K_d=1.51{\pm}0.35nM$)affinity receptors in rat liver PM. Solubilization of PM with 1% Triton X-100 increased both high affinity (from $0.33{\pm}0.04\;to\;1.67{\pm}0.05$ pmoles/mg protein) and low affinity (from $1.92{\pm}0.16\;to\;7.57{\pm}0.50$ pmoles/mg protein) TNF binding without affecting the affinities for TNF, suggesting the presence of a large latent pool of TNF receptors. Affinity labeling of receptors whether from PM or solubilized PM resulted in cross-linking of $^{125}I$-TNF into $M_r$ 130 kDa, 90 kDa and 66kDa complexes. Thus, the properties of the latent TNF receptors were similar to those initially accessible to TNF. To determine if exposure of latent receptors is regulated by TNF, $^{125}I$-TNF binding to control and TNF-pretreated membranes were assayed. Specific binding was increased by pretreatment with TNF (P<0.05), demonstrating that hepatic PM contains latent TNF receptors whose exposure is promoted by TNF. Homologous up-regulation of TNF receptors may, in part, be responsible for sustained hepatic responsiveness during chronic exposure to TNF. As a next step, the post-receptor events induced by TNF were examined. Although the signal transduction pathways for TNF have not been delineated clearly, the actions of many other hormones are mediated by the reversible phosphorylation of specific enzymes or target proteins. The present study demonstrated that TNF induces phosphorylation of 28 kDa protein (p28). Two dimensional soidum dodecyl sulfate-polyacrylamide gel electrophoresis(SDS-PAGE) resolved the 28kDa phosphoprotein into two isoforms having pIs of 6.2 and 6.1. The pIs and relative molecular weight of p28 were consistent with those of a previously characterized mRNA cap binding protein. mRNA cap binding proteins are a class of translation initiation factors that recognize the 7-methylguanosine cap structure found on the 5' end of eukaryotic mRNAs. In vitro, these proteins are defined by their specific elution from affinity columns composed of 7-methylguanosine 5'-triphosphate($m^7$GTP)-Sepharose. Affinity purification of mRNA cap binding proteins from control and TNF treated ME-180 cells proved that TNF rapidly stimulates phosphorylation of an mRNA cap binding protein. Phosphorylation occurred in several cell types that are important in vitro models of TNF action. The mRNA cap binding protein phosphorylated in response to TNF treatment was purifice, sequenced, and identified as the proto-oncogene product eukaryotic initiation factor-4E(eIF-4E). These data show that phosphorylation of a key component of the cellular translational machinery is a common early event in the diverse cellular actions of TNF.

• Journal of Chest Surgery
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• v.34 no.6
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• pp.477-484
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• 2001

Background: Initial symptoms for esophageal perforation have not been clarified, but when there is no early diagnosis and proper treatment to follow immediately after the diagnosis, it is fatal for the patients. Therefore, this study attempted to discover the factors that influence the prognosis of esophageal perforation to contribute to the improvement of the treatment result. Material and Method: The subjects of this study are 32 patients who came to the hospital with esophageal perforation from October, 1984 to June, 2000. This study examined the items for clinical observation such as patients' sex, age, cause of the perforation, perforation site, the time spent until the beginning of the treatment, symptoms caused by the perforation and its complication, and treatment methods. This study tried to find out the relationship between the survival of patients and each item. Result: There were 24 male and 8 female patients and their mean age was 49.7+16.4. For the causes of perforation, there were 14 cases(43%) of iatrogenic perforation, which ranked first, caused by the medical instrument operation and surgical damage. As for the perforation sites, thoracic esophagus was the most common site(26 cases of 81.2%) and chest pain was the most frequent symptom. The complication caused by esophageal perforation showed the highest cases in the order of mediastinitis, empyema, sepsis and peritonitis. After the treatment, there were 23 cases of survival and 9 cases of mortality. The total mortality rate was 28.1% and the main causes of mortality were sepsis and acute respiratory distress syndrome(ARDS). As for the treatment, 8 cases(25.0%) treated the perforation successfully using conservative treatment only. As for the surgical treatment, there were 5 cases(15.6%) of cervical drainage, 7 cases (21.8%) of primary repair and 12 cases(37.5%) of esophageal reconstruction after performing an exclusion-diversion. There were 18 cases(56.2%) of complete treatment of esophageal perforation at its initial treatment and in 14 cases(43.8%) of treatment failure at its initial treatment, patients were completely cured in the next treatment stage or died during the treatment. The cases of perforation in thoracic esophagus, complication into severe mediastinitis or sepsis and the cases of failure at initial treatment showed a statistically significant mortality rate (p<0.05).