Chloroquine attenuates hemorrhagic shock-induced immunosuppression and decreases susceptibility to sepsis.

Hemorrhagic shock causes a severe suppression of cellular immunity and an increased susceptibility to sepsis that may be due to increased release of prostaglandin E2 by macrophages. Since chloroquine inhibits the secretion of prostaglandin E2 by macrophages in vitro, the effects of chloroquine administration in vivo following hemorrhagic shock on macrophage prostaglandin E2 secretion and on depressed cellular immunity were examined. Inbred C3H/HeN male mice, aged 6 to 8 weeks, were bled to a mean blood pressure of 35 mm Hg, which was maintained for 60 minutes, and adequately, resuscitated. Mice then received intramuscular injections of either saline (vehicle) or chloroquine (10 mg/kg of body weight). Prostaglandin E2 in macrophage supernatants (radioimmunoassay) concanavalin A-dependent splenocyte proliferation, and interleukin 2 in splenocyte supernatants (CTLL 20 interleukin 2-dependent proliferation) were determined 2 or 24 hours later. Hemorrhage caused a significant decrease of splenocyte proliferation (47%) and interleukin 2 release (49%) at 24 hours, while prostaglandin E2 secretion from macrophages was elevated at 2 hours. Chloroquine treatment attenuated depression of splenocyte functions and reduced prostaglandin E2 release. Furthermore, chloroquine treatment decreased the mortality of septic mice after hemorrhage to levels comparable with those of sham-operated mice. Thus, chloroquine may be a useful adjunct in the clinical setting for the treatment of shock-induced immunodepression and increased susceptibility to sepsis following hemorrhage.     

The immune-enhancing effect of perioperative thymopentin administration in elderly patients undergoing major surgery

The effects of perioperative administration of thymopentin (TP-5) on in vivo and in vitro measurements of cell-mediated immunity in elderly patients undergoing major surgery were investigated. A placebo-controlled study was conducted in 25 patients (mean age, 67 years) with congenital or acquired heart disease undergoing surgery with cardiopulmonary bypass. Patients were divided into three groups: Group 1 patients were given 50 mg of TP-5 subcutaneously two hours preoperatively. Group 2 patients were given 50 mg of TP-5 subcutaneously two hours preoperatively and 48 hours postoperatively. Group 3 patients were given placebo at corresponding times. Cell-mediated immunity measurements were the in vivo delayed-type hypersensitivity (DTH) response on day 0 and on day 7 to an antigen skin test battery. The in vitro studies included antigen cocktail-induced lymphocyte proliferation of peripheral blood mononuclear cells. The DTH response on day 7 after surgery was significantly suppressed in group 3 patients compared with the preoperative baseline value, while it remained unaltered in group 1 and 2 patients. There was a considerable difference of DTH measurements (number of positive antigen responses and sum of their mean diameters) between group 2 and 3 patients. Antigen cocktail-induced lymphocyte proliferation, following initial suppression in the majority of patients, was significantly different between the placebo group and patients in group 2 on day 7 after surgery. The data indicate that perioperative administration of TP-5 might be of considerable clinical utility in preventing a defective cellular immune response.     

Modulation of guanylate cyclase and phosphodiesterase by monovalent cations and nucleoside triphosphates in light-sensitive excised patches of rod outer segments

Excised inside-out patches of vertebrate rod outer segment can support phototransduction. I have examined how ionic and metabolic conditions influence the functional properties of light-sensitive patches fromGekko gekko. I find that such patches retain a variable level of basal phosphodiesterase activity, which lowers the cyclic guanosine monophosphate (cGMP) concentration reaching the channels and reduces the dark current. The dose/response relationship for channel opening by cGMP varies among patches and this variability is only reduced by working in darkness with the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX), suggesting that it is only partially due to phosphodiesterase activity. MgATP or MgGTP, but not Mg or ATP separately, increase this activity but a kinase does not appear to be involved. Intracellular monovalent cations also influence dark current intensity and light response kinetics. With 5 mM MgGTP, 1 mM IBMX, and 144 mM Li⁺, Na⁺, K⁺, or Rb⁺, dark current intensity and recovery time follow the respective sequences K⁺>Rb⁺>Na⁺>Li⁺ and K⁺<Rb⁺<Li⁺<Na⁺. Without IBMX, a dark current develops with K⁺ but not with Na⁺. These effects are not due to altered channel permeability (P) = 0.841.00 1.011.090.42], or differential Mg²⁺ block, but to modulation of guanylate cyclase, which overcomes phosphodiesterase when the major cation is K⁺ but not when it is Na⁺.