Glucan, a beta-1,3-linked polyglucopyranose isolated from yeast cell walls, is a potent tumor inhibitory and macrophage activating agent. Evidence suggests that macrophages play an important role in glucan-enhanced antitumor activity. The present study was designed to determine: (1) the antitumor activity of resting hepatic, splenic and peritoneal macrophages, (2) the ability of glucan to enhance the in vitro tumoricidal activity of macrophages, (3) the effector cells mediating the antitumor activity of glucan, (4) the ability of resting and glucan activated macrophages to secrete antitumor cytotoxic factors and (5) the functional and physicochemical nature of macrophage derived antitumor secretory products Resting hepatic, splenic and peritoneal macrophages were significantly cytotoxic to adenocarcinoma BW10232 in vitro at target:effector ratios of 1:10 and 1:50. The antitumor activity of hepatic macrophages (Kupffer cells) was depressed on day 1 following a single intravenous (IV) injection of glucan. By day 3 post-glucan injection, the antitumor activity of Kupffer cells had returned to control levels and was enhanced on days 5 and 10. Kupffer cell-mediated cytotoxicity to adenocarcinoma cells returned to control levels by day 14 post injection. Like Kupffer cells, peritoneal macrophage antitumor activity was significantly depressed on day 1 following a single IV injection of glucan and was enhanced on days 3, 5, and 10. Splenic macrophage-mediated tumoricidal activity remained at control levels on days 1 and 3 post-glucan injection and was enhanced on days 5 and 10. Both splenic and peritoneal macrophage-mediated cytotoxicity to adenocarcinoma cells returned to control levels on day 14 post-glucan injection Following multiple IV injections of glucan on days $-5,$ $-3$ and $-1,$ Kupffer cell-mediated antitumor activity was enhanced on days 1 and 4. Peritoneal macrophages exhibited increased antitumor activity on days 1, 4 and 8 following glucan administration on day $-5,$ $-3$ and $-1.$ In order to partially ascertain the mechanisms of macrophage-mediated tumor cell destruction, the ability of macrophages to secrete antitumor cytotoxic factors was evaluated. Resting macrophages secreted significant levels of macrophage cytotoxic factors (MCF). Incubation of macrophages with bacterial endotoxin (LPS) significantly increased the production of MCF. Glucan activated macrophages secreted increased levels of MCF compared to resting and LPS-activated macrophages. (Abstract shortened with permission of author.) / acase@tulane.edu

Correlations between phagocytic alterations induced by colloidal carbon or endotoxin, and the development of liver necrosis has implicated the reticuloendothelial system (RES) in galactosamine (GaIN) induced liver injury. In order to further evaluate this concept, the influence of GaIN on liver function and histology was ascertained in rats in which the RES was either normal, stimulated or depressed. Methyl palmitate or glucan were employed as selective RES suppressant or activating agents, respectively. Biochemical and histological profiles and endotoxemia were studied 24 hours following intraperitoneal administration of GaIN (lg/kg) in either control, glucan or methyl palmitate-treated rats. Biochemical profiles included: serum glucose, phosphorus, total bilirubin, urea nitrogen, uric acid, total protein, albumin, globulin, cholesterol, alkaline phosphatase, glutamic oxalacetic transaminase (SGOT), lactic dehydrogenase (LDH), glutamic pyruvic transaminase (SGPT), creatinine phosphokinase (CPK), triglyceride, plasma electrolytes, and plasma sodium sulfobromphthalein (BSP) retention The Limulus Lysate Gelation Test (LGT) was employed for the quantitative determination of endotoxemia in control, glucan, methyl palmitate and GaIN-treated rats and in rats undergoing combined procedures Administration of GaIN to control rats resulted in significant elevations in SGOT, total bilirubin, urea nitrogen, and profound plasma retention of BSP. Hypoglycemia and hypoglobulinemia were also observed. Histological studies denoted hepatic necrosis with, a polymorphonuclear and, lymphocytic cellular infiltrate in GaIN-treated rats Pretreatment of rats with intravenously administered methyl palmitate (2g/kg) to induce macrophage dysfunction prevented GaIN induced alterations in the serum glucose, SGOT, LDH, and BSP. Liver necrosis and inflammatory reactions were also significantly reduced in methyl palmitate-GaIN-treated animals In contrast, RES activation with intravenously administered glucan (10 mg/kg) on days (-7 & -3), enhanced GaIN-induced alterations in serum bilirubin, glucose, cholesterol, SGOT, SGPT, LDH and BSP. Liver necrosis and inflammation were also significantly enhanced Endotoxemia was not detected in any of the rats regardless of treatment or time following GaIN, methyl palmitate or glucan administration. These composite findings denote that GaIN hepatitis need not be inversely correlated to macrophage functional status, but may be directly correlated when specific macrophage modifying agents such as glucan and methyl palmitate are employed / acase@tulane.edu

Although prostanoids are known to participate in regulating renal function and renal hemodynamics in both physiological and pathophysiological states, increased renal thromboxane production has been demonstrated in response to relatively few stimuli. Even then, it is uncertain whether the thromboxane arises from renal tissue or from invading blood components. In this study data was obtained suggesting that after mild hemorrhage, thromboxane plays a role which is apparently restricted to the control of GFR. After a 10 ml/kg hemorrhage, a vasoconstrictor component preceding the dilation appeared in the response to the AA injection, suggesting formation of a vasoconstrictor metabolite. Administration of the cyclooxygenase inhibitor ibuprofen (5 mg/kg iv) blocked the entire response, indicating that the response was mediated by products of the cyclooxygenase pathway. Since the most likely vasoconstrictor in this pathway is thromboxane A$\sb{2}$, the experiment was repeated and a specific thromboxane synthetase inhibitor was administered after hemorrhage. After administration of the thromboxane synthetase inhibitor OKY-046 or OKY-1581 (2 mg/kg iv) the vasoconstrictor component was blocked. To confirm these findings, the thromboxane receptor antagonist BM 13.177 was used in additional experiments. Removal of this amount of blood from well-hydrated anesthetized dogs reduced both cardiac output (21%) and GFR (25%) compared to pre-hemorrhage values, and increased total peripheral resistance approximately 30%. Renal function parameters that depend on GFR also decreased significantly. After administration of either OKY-046 or BM 13.177, GFR and its dependent parameters returned to pre-hemorrhage levels. Plasma levels of vasopressin, plasma renin activity, and arterial and renal venous norepinephrine levels increased after hemorrhage. Measurements of renal venous thromboxane levels indicated an increase in Tx production in the kidney after hemorrhage, which was returned to control levels or to below control levels by OKY-046, further supporting the conclusion that thromboxane mediated the observed changes in GFR after hemorrhage. Additionally, experiments were conducted in which ibuprofen was administered after hemorrhage and OKY-046 administration, and the effects on renal blood flow and GFR were measured. Both RBF and GFR were significantly reduced after administration of ibuprofen, suggesting that the renal prostaglandins play an important role in the maintenance of renal hemodynamics after hemorrhage. (Abstract shortened with permission of author.) / acase@tulane.edu

acase@tulane.edu

acase@tulane.edu

acase@tulane.edu

acase@tulane.edu

acase@tulane.edu

acase@tulane.edu

acase@tulane.edu