Interleukin-4 induces up-regulation of endothelial cell claudin-5 through activation of FoxO1: role in protection from complement-mediated injury.

Injury to endothelial cells (ECs) often results in cell retraction and gap formation. When caused by antigen aggregation or complement, this injury can be prevented by pretreatment of the ECs with IL-4, suggesting that IL-4 modifies the intercellular junction. Therefore, we investigated the effects of IL-4 on expression of intercellular junction proteins and whether such effects are required for IL-4-induced resistance of ECs against complement-mediated injury.

Liver metabolomic changes identify biochemical pathways in hemorrhagic shock.

Background: Despite ongoing advances in treatment, thousands of patients still die annually from complications due to hemorrhagic shock, a condition causing dramatic physiologic and metabolic changes as cells switch to anaerobic metabolism in response to oxygen deprivation. As the shift from aerobic to anaerobic metabolism occurs in the peripheral tissues during shock, the liver must increase production of endogenous glucose as well as process excess lactate produced in the periphery. This places the liver at the center of metabolic regulation in the body during hemorrhagic shock.

Noninvasive tissue oxygen saturation measurements identify supply dependency.

Background: Hemorrhagic shock can lead to multiple organ failure and death. We have previously shown that noninvasive measurement of tissue oxygen saturation (StO(2)) has predictive value for outcomes in patients suffering hemorrhagic shock. Our study objectives were twofold: (1) to compare invasive and noninvasive measurements of local and systemic tissue hemoglobin oxygenation and (2) to compare the effects of various physiologic conditions seen in patients in hemorrhagic shock on tissue hemoglobin oxygenation.

Inhibition of hyaluronan synthases decreases matrix metalloproteinase-7 (MMP-7) expression and activity.

Introduction: Hyaluronan (HA) and its biosynthetic enzymes hyaluronan synthases (HAS2 and HAS3) mediate Matrigel invasion by SW620 colon carcinoma cells. Because matrix metalloproteinases (MMPs) have been implicated in cancer invasion, we hypothesized that changes in HAS expression would alter MMP expression and activity in these cells.

Methods: To determine whether an MMP was involved in invasion, Matrigel invasion assays with SW620 cells were performed in the presence or absence of the MMP inhibitors GM6001 or TIMP2.

The effect of a hyaluronan-carboxymethylcellulose membrane vs. polyglactin 910 mesh on intra-abdominal tumor formation in mice.

Purpose: Hyaluronan mediates growth of SW620 colon cancer cells. Because hyaluronan is the active ingredient in Seprafilm, we hypothesized that Seprafilm would affect intraperitoneal tumor growth in a mouse model of peritoneal seeding.

Methods: Immunodeficient mice underwent laparotomy and intraperitoneal inoculation of 10(5) SW620 cells.

Sp1 elements regulate transcriptional activity within the murine Toll-like receptor 4 promoter.

Background And Purpose: Toll-like receptor 4 (TLR4) mediates the innate immune response to lipopolysaccharide (LPS) by a complex intracellular signaling pathway that activates the transcription factor nuclear factor (NF)-kappaB, with subsequent production of inflammatory cytokines. The precise mechanisms involved have not been delineated. We hypothesized that specific regulatory elements exist within the TLR4 promoter.

Comparison of endotoxin antagonism of linear and cyclized peptides derived from limulus anti-lipopolysaccharide factor.

Background: Limulus anti-lipopolysaccharide (LPS) factor (LALF) is a 102-amino acid LPS-binding protein from the horseshoe crab, Limulus polyphemus. The peptide includes the LPS-binding domain of holoLALF, yet it lacks the loop structure stabilized by disulfide or other covalent bonds that is a common motif in the LPS-binding regions of holo- LALF and several other LPS-binding proteins. Although it neutralizes LPS and is bactericidal against Pseudomonas aeruginosa, the LALF 28-54 portion of LALF is not protective in a murine model of intraperitoneal sepsis compared with holoLALF.

Anti-endotoxin monoclonal antibodies are protective against hepatic ischemia/reperfusion injury in steatotic mice.

Steatotic mice are particularly susceptible to hepatic ischemia/reperfusion injury compared with their lean littermates. We have previously demonstrated that livers of mice having a spontaneous mutation in the leptin gene (ob/ob), resulting in global obesity and liver steatosis, are ATP depleted, are endotoxin sensitive, and do not survive (I/R) injury. We hypothesize that administration of an anti-LPS monoclonal antibody (mAb) prior to initiation of I/R would be protective from that insult.

Structure/function studies of an endotoxin-neutralizing peptide derived from bactericidal/permeability-increasing protein.

Background: Bactericidal/permeability-increasing protein, BPI, has a beta-turn with alternating cationic and hydrophobic residues in its lipopolysaccharide (endotoxin, LPS)-binding domain. A peptide, betapep25, was designed with 9 residues of the LPS-binding domain of BPI flanked by beta-turn-inducing elements. Thereafter, we sought to use single amino acid substitutions to identify residues that are important for the biological activities of betapep25.