Biomedical subjects

Laura E Gordon

Publications and source records attributed to Laura E Gordon.

6 recordsLinked to original sources

PubMed2005

Effects of endotoxin administration and cerebral hypoxia-ischemia on complement activity and local transcriptional regulation in neonatal rats.

It is not known whether up-regulation of complement components, either circulating or locally synthesized, contributes to an increased susceptibility to neonatal hypoxic-ischemic (HI) cerebral injury. Therefore, we tested the hypothesis that in neonatal rats subjected to a unilateral HI cerebral insult, prior administration of E. coli lipopolysaccharide (LPS) augments (1) complement-mediated serum hemolytic activity, and (2) C3 mRNA and C9 mRNA levels in hepatic and cerebral tissue. Pregnant rats were injected subcutaneously with sterile normal saline (NS) or 500 microg/kg of LPS on gestational days 18 and 19. Following birth, the pups received intraperitoneal injections of NS or 250 microg/kg of LPS on postnatal days 3 and 5. On postnatal day 7, each animal was subjected to ligation of the right common carotid artery followed by 2.5h of hypoxia (8% O(2)). At 3, 6,18, 24 and 48 h after hypoxia, the complement-mediated hemolytic activity of pooled serum was measured. Hepatic and cerebral C3 mRNA and C9 mRNA were quantified by qRT-PCR at 3, 6, and 18 h after HI. Serum hemolytic activity, hepatic C3 mRNA, and hepatic C9 mRNA were up-regulated after cerebral HI. LPS administration potentiated the effect of HI on serum hemolytic activity and increased cerebral C3 mRNA levels. Cerebral C9 mRNA was not detected and was not affected by HI, with or without the prior LPS administration. These observations support the theory that previously reported C9-mediated neurotoxicity following cerebral HI is induced by circulating, rather than locally synthesized C9.

Animals↗

PubMed2005

The administration of cobra venom factor reduces post-ischemic cerebral injury in adult and neonatal rats.

The role of complement in post-ischemic cerebral injury is incompletely understood. Therefore, experiments were designed to test the effect of complement depletion on cerebral infarct volume in adult rats and cerebral atrophy in neonatal rats. Cerebral infarcts were induced in adult rats by transient filamentous occlusion of the right middle cerebral artery (MCAO). Cerebral atrophy was induced by subjecting 7-day-old rats to ligation of the right common carotid artery followed by 2.5h of hypoxia (8% O2). Forty-eight hours after MCAO, coronal sections of adult brains were obtained and stained with 2,3,5-triphenyl tetrazolium chloride. The infant rat brains were removed for analysis 6 weeks after the hypoxic-ischemic insult. Volumes of infarcts and normal hemispheric parenchyma were quantified by computer-based planimetry. Twenty-four hours prior to MCAO (adults) or hypoxia-ischemia (neonates), each animal received an i.p. injection of either 1 mcg/g body weight cobra venom factor (CVF; adult n=11; neonatal n=20) or normal saline (adult n=12; neonatal n=24). In the neonates, a second dose of CVF or saline was administered 2 days after hypoxia-ischemia. The administration of CVF significantly reduced: (1) post-ischemic cerebral infarct volume in the adults and (2) post-hypoxic-ischemic cerebral atrophy in the neonates. Therefore, complement activation augmented post-ischemic cerebral injury in adult and neonatal rats. Complement depletion induced by CVF significantly reduced post-ischemic cerebral infarct volume and atrophy in adult and neonatal rats.

Animals↗

PubMed2005

Complement component 9 activation, consumption, and neuronal deposition in the post-hypoxic-ischemic central nervous system of human newborn infants.

The role of complement in neonatal hypoxic-ischemic brain injury is not known. Therefore, cerebral spinal fluid (CSF) and post-mortem cerebral tissue were analyzed to determine whether complement is activated and complement component 9 (C9) is deposited on neurons in the central nervous systems (CNS) of newborn infants who developed moderate to severe hypoxic-ischemic encephalopathy (HIE). Control CSF samples were obtained during routine evaluation for possible sepsis from infants who were not depressed at birth. In ELISA assays of CSF obtained from 16 infants with HIE, compared to CSF from 7 control infants, the mean concentration of terminal complement complexes was elevated and the mean C9 concentration was diminished. Immunofluorescence microscopy of post-mortem frozen brain tissue obtained from two infants who expired at 4-5 days of life after severe HIE revealed that activated C9 was deposited on cells in all lobes. Double label immunofluorescence microscopy demonstrated that nearly all of the C9-positive cells were neurons and essentially all of the neurons were C9-positive. Immunoperoxidase immunohistochemistry of formalin-fixed tissue also confirmed the presence of many C9-positive cells, particularly in the hippocampus. The C9-positive cells usually manifested morphology consistent with neurons, most of which contained fragmented nuclei. In summary, complement was activated in the CNS of newborn infants who developed moderate to severe HIE. C9 was deposited on neurons, including morphologically apoptotic neurons. Further investigations into a possible role of complement in the pathogenesis of neonatal hypoxic-ischemic cerebral injury are warranted.

Brain↗

PubMed2004

beta-[H2N(CH2)2NH2]0.5[ZnHPO3], a second modification of ethylenediamine zinc hydrogen phosphite.

The title compound, poly[dizinc(II)-mu-ethylenediamine-di-mu-(hydrogen phosphito)], beta-[H(2)N(CH(2))(2)NH(2)](0.5)[ZnHPO(3)] or [Zn(2)(HPO(3))(2)(C(2)H(8)N(2))](n), is a hybrid organic/inorganic solid built up from ethylenediamine molecules (which lie about inversion centres), Zn(2+) cations (coordinated by three O atoms and one N atom) and HPO(3)(2-) hydrogen phosphite groups. The organic species bond to the Zn atom as unprotonated ligands, acting as bridges between infinite ZnHPO(3) layers that propagate as very buckled (001) sheets. The zincophosphite sheets contain polyhedral four- and eight-membered rings in a 4.8(2) topology. beta-[H(2)N(CH(2))(2)NH(2)](0.5).ZnHPO(3) complements the previously described alpha modification of the same stoichiometry [Rodgers & Harrison (2000). Chem. Commun. pp. 2385-2386].

Journal Article↗

PubMed2004

Amino acid templating of inorganic networks: synthesis and structure of L-asparagine zinc phosphite, C4N2O3H8.ZnHPO3.

C(4)N(2)O(3)H(8).ZnHPO(3) is the first zincophosphite framework to be templated by an amino acid (l-asparagine), which bonds to Zn via a carboxyl O atom. It contains infinite, homochiral, helical 4-ring chains of ZnO(4) and HPO(3) groups, stabilized by intra- and interchain N-H.O hydrogen bonds. Crystal data: C(4)N(2)O(3)H(8).ZnHPO(3), M(r) = 277.49, orthorhombic, P2(1)2(1)2(1) (No. 19), a = 5.0349(2) A, b = 9.4539(4) A, c = 18.6092(8) A, V = 885.79 (6) A(3), Z = 4.

Journal Article↗

PubMed2002

Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes.

BACKGROUND: A systemic inflammatory response (SIR) is seen in approximately 75% of patients with complex blunt liver injuries treated nonoperatively. Many feel this response is caused by blood, bile, and necrotic tissue accumulation in the peritoneal cavity. Our current treatment for these patients is a delayed laparoscopic washout of the peritoneal cavity, resulting in a dramatic resolution of the SIR. Spectrophotometric analysis of the intraperitoneal fluid has confirmed the presence of high concentrations of free hemoglobin (Hb). We hypothesize that free Hb enhances the local peritoneal response by increasing tumor necrosis factor-alpha (TNF-alpha) production by monocytes, contributing to the local inflammatory response and SIR. METHODS: Monocytes from five healthy volunteers were isolated and cultured in RPMI-1640 for 24 hours. Treatment groups included saline controls, lipopolysaccharide ([LPS], 10 ng/mL, from Escherichia coli), human Hb (25 microg/mL), and Hb + LPS. Supernatants were analyzed by enzyme-linked immunosorbent assay. Student's t test with Mann-Whitney posttest was used for statistical analysis with p < or = 0.05 considered significant. RESULTS: Free Hb significantly increased TNF-alpha production 915 +/- 223 pg/mL versus saline (p = 0.02). LPS and Hb + LPS further increased TNF-alpha production (2294 pg/mL and 2501 pg/mL, respectively, p < 0.001) compared with saline controls. CONCLUSION: These data confirm that free Hb is a proinflammatory mediator resulting in the production of significant amounts of TNF-alpha. These in vitro findings support our clinical data in which timely removal of intraperitoneal free hemoglobin helps prevent its deleterious local and systemic inflammatory effects in patients with complex liver injuries managed nonoperatively.

Adult↗