ceruletide and Sepsis

Acute pancreatitis (AP) and sepsis are inflammatory disorder varying in magnitude of response to infection or inflammatory stimuli. The specific role of various causative factors in AP, septic shock, current pharmacological treatments, animal models, role of infiltrating cells and novel molecules that play an important role in the disease progression to sepsis are explored. AP is an inflammatory disease of the pancreas. Over the years accumulating evidence suggests numerous molecules as key regulators of the inflammatory signaling cascade such as selectins, chemokine signaling and expression of intergrins on leukocytes facilitate adhesion to vessel walls. Inhibition of any of these molecules has proven to be effective in animal models of AP. Recently, the biochemical role of hydrogen sulfide (H(2)S) and substance P in caerulein induced AP and in cecal ligation and puncture induced sepsis and their role in the pathogenesis of the disease have highlighted the importance of novel molecules as therapeutic targets in addition to the known pro-inflammatory molecules, cytokines and chemoattractant chemokines and their receptors upregulated in AP and sepsis. This review aims to give an overview of the multifaceted complex interactions in a prearranged fashion and their functional role in the inflammatory process that afflict AP and sepsis. The interlinking molecules in AP and sepsis emphasize the similarities in the inflammatory response and the importance of pharmacological agents that reduce or inhibit the progression to chronic stage.

Topics: Animals; Apoptosis; Ceruletide; Chemokines; Female; Humans; Hydrogen Sulfide; Inflammation Mediators; Integrins; Male; Mice; Pancreatitis, Acute Necrotizing; Rats; Selectins; Sepsis; Substance P

Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.

Topics: Animals; Apoptosis; Ceruletide; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreatitis; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Reperfusion Injury; Sepsis; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor alpha-Induced Protein 3

The priming mechanism of macrophages to secrete cytokines in acute pancreatitis is important for remote organ failure following septic complication. The effects of novel carboxamide derivative, IS-741, on neutrophil chemoattractant production by bronchoalveolar macrophages were studied in rats with cerulein-induced pancreatitis complicated by sepsis.. Pancreatitis was induced by four intramuscular injections of cerulein (50 microg/kg at 1-hour intervals). Pancreatitis rats were injected intraperitoneally with 10 mg/kg of lipopolysaccharide (LPS) 6 h following the first cerulein injection as a septic challenge. Pancreatitis rats received a continuous intravenous injection of IS-741 (3 mg/kg/h) 30 min before the septic challenge.. Intense mononuclear cell infiltration and lung hemorrhage occurred in untreated pancreatitis rats complicated with sepsis, but hemorrhage was not seen in septic pancreatitis rats receiving a continuous intravenous injection of IS-741 shortly before sepsis induction. The IS-741-treated rats had lower serum concentrations of cytokine-induced neutrophil chemoattractant (CINC), as well as fewer the pulmonary neutrophils and infiltrates immunoreactive for CINC or Mac-1 (CD11b/CD18).. The novel carboxamide derivative IS-741 reduced CINC production by bronchoalveolar macrophages and effectively prevented pancreatitis-associated lung injury following the septic challenge.

Topics: Animals; CD18 Antigens; Ceruletide; Chemotaxis; Disease Models, Animal; Enzyme Inhibitors; Injections, Intravenous; Interleukin-8; Macrophage-1 Antigen; Macrophages, Alveolar; Male; Neutrophil Infiltration; Pancreatitis; Pyridines; Rats; Rats, Wistar; Sepsis

We investigated the role of platelet-activating factor (PAF) as a priming signal for cytokine-induced neutrophil chemoattractant (CINC) expression by bronchoalveolar macrophages in acute pancreatitis. Pancreatitis was induced by four intramuscular injections of cerulein (50 micrograms/kg at 1-h intervals) in Wistar rats. The animals were injected intraperitoneally with 10 micrograms/kg of lipopolysaccharide (LPS) as a septic challenge. Pancreatitis rats were treated with a bolus intravenous injection of TCV-309 (3 or 30 micrograms/kg) 30 min before the septic challenge. Intense mononuclear cell infiltration and lung hemorrhage occurred in pancreatitis rats complicated with sepsis but were not seen in pancreatitis rats receiving a bolus TCV-309. Pancreatitis rats treated with TCV-309 had lower serum concentrations of CINC after septic challenge and lower levels of CINC messenger RNA (mRNA) in the lung, as well as fewer pulmonary infiltrates immunoreactive for CINC or Mac-1 (CD11b/CD18). In vitro CINC production in response to LPS by bronchoalveolar macrophages obtained from pancreatitis rats 6 h after the first cerulein injection, immediately before septic challenge, was enhanced but was significantly reduced in a TCV-309-sensitive manner. LPS-stimulated in vitro CINC production by naive bronchoalveolar macrophages was significantly enhanced by pretreatment with PAF. TMB-8 (an inhibitor of calcium release from endoplasmic reticulum) or W7 (calmodulin antagonist) completely abrogated the chemoattractant production by bronchoalveolar macrophages pretreated with PAF after LPS stimulation. Altered intracellular calcium, due to Ca2+ efflux from intracellular stores, may be involved in the "priming" of bronchoalveolar macrophages to release CINC after triggering with LPS during acute cerulein-induced pancreatitis. The PAF antagonist TCV-309 effectively prevented hyperactivity of bronchoalveolar macrophages and pancreatitis-associated lung injury after the septic challenge.

Topics: Animals; Ceruletide; Chemokines, CXC; Chemotactic Factors; Growth Inhibitors; Growth Substances; Hemorrhage; Intercellular Signaling Peptides and Proteins; Isoquinolines; Kinetics; Lipopolysaccharides; Lung; Lung Diseases; Macrophages, Alveolar; Male; Pancreatitis; Platelet Activating Factor; Platelet Aggregation Inhibitors; Pyridinium Compounds; Rats; Rats, Wistar; RNA, Messenger; Sepsis; Tetrahydroisoquinolines