Circulatory shock最新文献

Tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and endotoxin (LPS) are potent pro-inflammatory mediators which induce multiple and diverse biological responses in a wide variety of cell types. However, these pro-inflammatory mediators also have significant overlap and redundancy in their biological effects. This suggests that there is significant diversity in second messenger signal transduction systems induced by these stimuli to explain the diversity in biological responses, as well as significant redundancy. Here we show that one such second messenger common to several proinflammatory stimuli may be phosphatidic acid (PA). Intracellular PA species, which may have intracellular signaling functions, are rapidly induced in P388 monocytic leukemia cells by TNF alpha, IL-1 beta, or LPS. These PA species vary according to the bond type (i.e., sn-1 ester vs. ether vs. vinyl ether), acyl chain length, and the degree of saturation in the sn-1 and sn-2 positions. Although PA itself may have direct second messenger activities, many of the PA species induced are converted to diacylglycerol species (DG), which are structurally distinct from the DGs generated by phosphatidylcholine-specific phospholipase C (PC-PLC). Lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine; LSF] selectively inhibits generation of selected species of PA in P388 cells induced by TNF alpha, IL-1 beta or LPS. TNF alpha-induced sphingomyelin hydrolysis, PLC-mediated PC hydrolysis, and DG kinase-mediated PA formation or TNF alpha-induced NF-kappa B activation and apoptosis are not inhibited by LSF. LSF has a marked protective effect in a variety of acute inflammatory animal models that may be due to inhibition of this shared second messenger pathway involving PA.

Clinical trials of anticytokines in sepsis have not been as straightforward as had been anticipated from results in animal models of sepsis and the role of cytokines in sepsis is now in question. Retrospective analysis of the results of a phase III trial of interleukin-1 (IL-1) receptor antagonist suggests that sepsis-induced adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), renal dysfunction, and shock are valuable markers of patients in whom IL-1 is a pathogenic mediator and in whom IL-1ra can reduce mortality. A re-examination of the effects of IL-1ra in animal models of sepsis supports the validity of this analysis. A new phase III clinical trial will confirm or disprove the hypothesis that IL-1 is a mediator of pathology, and IL-1ra is a valuable therapy for sepsis complicated by ARDS, DIC, renal dysfunction, or shock.

Recent studies have led to the re-discovery of the protein originally described as macrophage-migration inhibitory factor (MIF) to be both a pituitary hormone and a pro-inflammatory, macrophage cytokine. MIF is a pivotal mediator in endotoxic shock and may serve as a pituitary "stress" hormone that regulates systemic inflammatory responses.

The enhancement of tumor metastasis by concurrent inflammatory processes is mainly due to the cytokines TNF and IL-1. In the case of TNF this effect is not restricted to metastasis models as measured by in vivo colony formation but also found in experimental model systems of spontaneous metastasis. Direct effects on the tumor cells or interference with the host NK cell system did not seem to account for the observed TNF effect. Experimental evidence from different test systems rather points to TNF- or IL-1-induced enhanced adhesion of tumor cells to the endothelial cell layer as the underlying mechanism. Blocking of integrin-matrix interactions with monoclonal antibodies or competing peptides inhibited tumor cell adhesion to endothelioma cells in vitro and lung colony formation of tumor cells in vivo.

Intravital video microscopy was used to monitor and quantify leukocyte-endothelial cell adherence, leukocyte emigration, venular shear rate, and leukocyte rolling velocity in cat mesenteric venules exposed to E. coli endotoxin lipopolysaccharides (LPS). LPS induced a steady decrease in venular shear rate and leukocyte rolling velocity while increasing leukocyte adherence and emigration. The molecular determinants and chemical mediators of LPS-induced leukocyte-endothelial cell adhesion were investigated using monoclonal antibodies (MAbs) against the adhesion glycoproteins CD11/CD18 on leukocytes (MAb IB4) and ICAM-1 (MAb RR1/1) on endothelial cells as well as superoxide dismutase (SOD) and a platelet-activating factor receptor antagonist (WEB 2086). Leukocyte adherence was significantly (P < .05) reduced by administration of either the CD11/CD18 MAb or SOD, while the PAF receptor antagonist and ICAM-1 MAb had no effect. None of the four agents studied significantly altered LPS-induced leukocyte emigration, venular shear rate, or leukocyte rolling velocity. These results indicate that the leukocyte adherence induced by LPS is dependent on the adhesion glycoprotein CD11/CD18 and superoxide, and that an endothelial cell ligand other than ICAM-1 participates in this adhesion process.

The interstitial lactate concentration in rat skeletal muscle and liver was measured using a microdialysis method during the early stage of endotoxemia and during lactic acid infusion. The lactate concentration in the muscle and liver interstitium never exceeded the blood lactate concentration throughout the 180 min period after endotoxin administration. The present findings also showed that the muscle and liver interstitial lactate concentration gradually increased in endotoxin-infused animals compared to that in lactic-acid infused animals, although the blood lactate concentration in lactic acid-infused animals was the same as that in endotoxin-infused animals. These findings suggest that the skeletal muscle and liver may consume lactate in an endotoxemic condition. However, the capacity of lactate consumption in the skeletal muscle might gradually decrease after endotoxin administration, although that in liver might be well preserved.

Isolated perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response compared with 52% after ILP with melphalan alone. Leakage and release of nanograms levels of TNF alpha in the systemic circulation can be abrogated in most patients by low pump flow, continuous leak monitoring, extensive washout, and limb massage. In case of unavoidable leakage, appropriate intensive care results in minimal toxicity. The ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in humans.

Rheumatoid arthritis (RA) is an autoimmune disease with inflammatory manifestations in the peripheral synovial joints, which are infiltrated by activated T cells, macrophages, and plasma cells. We have investigated the role of cytokines in RA and have proposed that tumour necrosis factor has a pivotal role in the pathogenesis of this disease. This chapter describes those studies, which led to the first clinical trial in RA patients using a chimeric anti TNF alpha antibody. In addition to pro-inflammatory cytokine production, at sites of inflammation such as the RA synovial joint, there is also evidence for homeostatic immunoregulatory mechanisms which include the production of cytokine inhibitors, such as soluble TNF-R and the IL-1 receptor antagonist, and cytokines with immunoregulatory properties like IL-10. The evidence for these inhibitors in RA is presented, and the relevance of this homeostatic mechanism in relation to chronic inflammatory diseases is discussed.