title: Combined zinc supplementation with proinsulin C-peptide treatment decreases the inflammatory response and mortality in murine polymicrobial sepsis.
abstract: Zinc is a trace element vital for immune function during host response to infection. The proinsulin C-peptide has been shown to exert beneficial effects through activation of the anti-inflammatory peroxisome proliferator-activated receptor γ (PPARγ) in experimental endotoxemia. Some in vitro activities of C-peptide appear dependent on the presence of zinc. We investigated the effect of zinc supplementation before onset of sepsis on the anti-inflammatory properties of C-peptide. Male C57BL/6 mice were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Mice received zinc gluconate (1.3 mg/kg) intraperitoneally (i.p.) for 3 days before CLP. One hour after CLP, animals received C-peptide (280 nmol/kg i.p.) or the antimicrobial agent imipenem (25 mg/kg i.p.). Cecal ligation and puncture was associated with an 11% survival rate, pulmonary leukosequestration, and liver injury. Molecular analysis in lungs of septic mice showed increased nuclear activation of the proinflammatory extracellular signal-regulated kinases 1 and 2 and nuclear factor κB, but decreased PPARγ expression, when compared with sham animals. Combination of zinc supplementation with C-peptide posttreatment significantly improved survival rate (61%) similarly to antibiotic treatment (60%), ameliorated lung architecture and liver function, reduced tissue neutrophil infiltration, and increased bacterial clearance when compared with vehicle, C-peptide, or zinc treatment alone. These beneficial effects were associated with restored lung nuclear expression of PPARγ and reduction of phosphorylated extracellular signal-regulated kinases 1 and 2 and nuclear factor κB activities in comparison to vehicle or single treatment protocols. Our data demonstrate that short-term zinc prophylaxis before the infectious insult is a requisite for the anti-inflammatory properties of C-peptide by facilitating modulation of inflammatory pathways.
authors.affiliation: *Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; and †Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Siarhei
authors.initials: S
authors.lastname: Slinko
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piraino
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hake
authors.forename: John R
authors.initials: JR
authors.lastname: Ledford
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connor
authors.forename: Patrick
authors.initials: P
authors.lastname: Lahni
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Solan
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
mesh_terms: D055371:Acute Lung Injury / Q000517:prevention & control; D000818:Animals; D058491:Bacterial Load / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002096:C-Peptide / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D019587:Dietary Supplements; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008107:Liver Diseases / Q000382:microbiology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D015032:Zinc / Q000627:therapeutic use*
chemical_list: D002096:C-Peptide; D016207:Cytokines; D016328:NF-kappa B; D048049:Extracellular Signal-Regulated MAP Kinases; D015032:Zinc