Shigeyuki Itai

Significance of 2-3 and 2-6 sialylation of lewis A antigen in pancreas cancer

Distributions of sialylated derivatives of Lewis a (Lea) antigen in cancer tissue of the human pancreas and in the sera of patients with pancreas diseases have been studied; the significance of 2‐3 and 2‐6 sialylation of Lea antigens in pancreas cancer have been investigated using specific monoclonal antibodies. In most pancreas cancer tissue the 2‐3 sialylated Lea antigen was found to be specifically distributed in cancer cells as determined by immunohistologic techniques, while a significantly smaller amount of the antigen was detected in surrounding nonmalignant pancreas tissue, which was infiltrated by cancer cells. Conversely, the 2‐6 sialylated Lea antigen was abundantly present in nonmalignant pancreas tissue, while it was less frequently present in pancreas cancer cells. When the sera of 66 patients with pancreas diseases were examined for these sialylated Lea antigens, correlation studies showed that the levels of 2‐3 sialylated Lea tended to be 44.1 times more than the levels of 2‐6 sialylated Lea in the sera of cancer patients. The average ratio of 2‐3 sialylated Lea to 2‐6 sialylated Lea was 0.23 in the sera of patients with pancreatitis. These data collectively indicate that the 2‐3 sialylation of Lea is remarkably enhanced, and the 2‐6 sialylation of Lea antigen is suppressed in pancreas cancer. The determination of the 2‐3 sialylated Lea to 2‐6 sialylated Lea ratio in patients with pancreas diseases may be helpful for the differential diagnosis of pancreas cancer and nonmalignant pancreatic disorders.

Tissue distribution of 2‐3 and 2‐6 sialyl lewis A antigens and significance of the ratio of two antigens for the differential diagnosis of malignant and benign disorders of the digestive tract

The authors investigated the tissue distribution of two kinds of sialylated derivatives of Lewis A (Lea) antigen in patients with cancers of the digestive system using specific monoclonal antibodies, and evaluated the significance of determining the 2‐3 and 2‐6 sialylated Lea antigen levels for the diagnosis of cancer. In most specimens from patients with cancers of the pancreas, biliary tract, stomach, and colon, the 2‐3 sialylated Lea antigen was strongly expressed in cancer cells. However, 2‐6 sialylated Lea antigen was less frequently expressed in cancer cells. The former is therefore more specific to cancer than the latter. Also, the serum level of the 2‐3 sialylated Lea antigen was significantly higher than that of the 2‐6 counterpart in patients with cancers of pancreas, biliary tract, stomach, and colon. The resulting ratio of serum 2‐3/2‐6 sialylated Lea antigens was frequently high in patients with malignancy and was low in patients with benign disorders of these digestive organs. Therefore, the 2‐3/2‐6 sialylated Lea antigen ratio is a useful for the differential diagnosis of malignant disorders in these organs. However, liver disorders were found to be exceptional in that both antigens were mostly absent in hepatocellular carcinoma (HCC) cells in immunohistologic examination, as well as in nonmalignant parenchymal liver cells. Only the epithelial cells of the intrahepatic bile ducts expressed the 2‐6 sialylated Lea antigen strongly, and expressed the 2‐3 sialylated Lea antigen moderately. The levels of both antigens were sometimes high in patients with liver disorders, but the ratio always remained low in patients with HCC as well as benign liver disorders such as cirrhosis or chronic hepatitis. The sialylated Lea antigens, which sometimes accumulate in the sera of patients with HCC, were concluded to originate from the epithelial cells of the proliferating small bile ducts, and those serum antigens cannot be considered as evidence for the presence of liver cancer cells.

Enhancement of hepatic macrophages in septic rats and their inhibitory effect on hepatocyte function

In the present study, the function of hepatic macrophages and the modulation of hepatocytes by sepsis-elicited hepatic macrophages were investigated in rats with induced sepsis. The functional state of hepatic macrophages was determined by the following indicators: phagocytic index, protein-synthesizing capacity, and superoxide (O2-) producing capacity. These indices of changes in hepatic macrophages were much higher in rats with sepsis than in healthy controls. Moreover, the activated hepatic macrophages had some biological properties which were different from those of the resident Kupffer cells. It was found that protein synthesis by cultured hepatocytes was inhibited in the co-culture system of hepatocytes and sepsis-elicited hepatic macrophages, and that the supernatant of hepatic macrophages from rats with sepsis also reduced the protein-synthesizing capacity of cultured hepatocytes. Thus, activated hepatic macrophages may play a role in inducing hepatic dysfunction in sepsis.

Depressed function of Kupffer cells in rats with CCl4-induced liver cirrhosis.

SummaryIn the present study, the Kupffer cell function of rats with CCl4-induced liver cirrhosis was tested by analyzing the changes in the host defense system. In rats without liver cirrhosis injected with CCl4 for 3 weeks concomitant with the high opsonic activity the endocytic index was significantly increased. Rats treated for 9 and 13 weeks developed cirrhosis, and their endocytic indices were not increased despite the rise in their opsonic activity. Particularly, the endocytic index of 13-week-treated rats with advanced liver cirrhosis was significantly lower than that of the other groups. The organic distribution of 51Cr-endotoxin injected intravenously exhibited characteristic changes in 9-week- and 13-week-treated rats: decreased hepatic uptake and increased splenic uptake. In contrast, pulmonary uptake was increased in all CCl4-treated rats. The superoxide production by Kupffer cells from 13-week-treated rats was greatly reduced, accompanied by the decreased superoxide dismutase activity of liver homogenate. Thus, results of this study suggest that Kupffer cell dysfunction is one of the main factors affecting host defenses in liver cirrhosis.

The three different phases of reticuloendothelial system phagocytic function in rats with liver injury

In the present study, reticuloendothelial system (RES) phagocytic function of rats with partial hepatectomy or experimentally induced liver cirrhosis was investigated by determining the phagocytic index, the opsonic index, and uptake rate in liver, spleen, and lung of a 51Cr-labeled endotoxin-injected rat. In both the partially hepatectomized and the cirrhotic rats, all three indicators varied markedly according to the elapsed period since liver injury. The changes in RES phagocytic function were classified into three different phases: compromised, compensatory, and enhanced. The compromised phase, consisting of a decrease in the phagocytic index, was observed during the first 24 hr after 67% hepatectomy and in advanced liver cirrhosis. This represented the failure of RES phagocytic function. The compensatory phase, in which the phagocytic index was maintained at nearly normal levels mainly by a compensatory enhancement in the opsonic index, was seen during the first to second postoperative day and in moderate liver cirrhosis. The enhanced phase, with a high phagocytic index, was observed from Day 4 to approximately Day 14 after surgery, and in the cases of mild liver damage. In the compromised and compensatory phases, the liver uptake rate was significantly decreased compared with the control. However, the uptake in the spleen and lung were markedly increased. In conclusion, the phagocytic function of the RES was significantly affected to a degree which changed with the extent of liver damage.

Enhancement and hepatocyte-modulating effect of chemical mediators and monokines produced by hepatic macrophages in rats with induced sepsis.

SummaryWe investigated the production of chemical mediators by hepatic macrophages from rats with sepsis and the modulation of hepatocyte function by these hepatic macrophages. The chemical mediators we measured were superoxide (O2−), TNF, IL-1, and PGE2. Production of these mediators by hepatic macrophages from rats with sepsis was significantly increased. Furthermore, protein synthesis by cultured hepatocytes was inhibited in a co-culture system of hepatocytes and hepatic macrophages from rats with sepsis, and it was even inhibited by the supernatant of cultured hepatic macrophages from septic rats. These results demonstrate that hepatic macrophages are activated in sepsis and may play a role in inducing hepatic dysfunction in sepsis.

Enhancement of rat hepatic macrophages by treatment with interleukin-2 and streptococcal preparation OK432, with reference to antitumor activity, soluble factor production and Ia expression

SummaryThe effect of biological response modifiers, such as interleukin-2 (IL-2) and streptococcal preparation OK432, on the functions of hepatic macrophages was investigated. The macrophages, even with no exogenous stimulation, produced superoxide anion (O2-) and tumor necrosis factor (TNF), displayed cytotoxicity against K562 cells and cytostasis against P815 cells and expressed immune-region-associated antigen (Ia). IL-2 administered in vitro or in vivo enhanced O2- production by hepatic macrophages and the intravenous injection of OK432 also enhanced O2- production. Furthermore, IL-2 added to the culture medium of hepatic macrophages isolated from OK432-injected rats augmented O2- production even more. The TNF production and Ia expression of the macrophages were also increased by the intravenous injection of OK432. As with O2- production, the cytotoxicity of the cells was enhanced by OK432 injection or by IL-2 added to the culture medium and the combination of OK432 and IL-2 augmented their cytotoxicity even more. Thus, the present study suggested that IL-2 and OK432 induce the augmentation of the antitumor activity of hepatic macrophages, partly as a result of the increase in production of O2- and TNF and Ia expression.