title: C-peptide, a novel inhibitor of lung inflammation following hemorrhagic shock.
abstract: C-peptide is a 31-amino acid peptide cleaved from proinsulin during insulin synthesis. Initially thought to be inert, C-peptide may modulate the inflammatory response in the setting of endotoxemia and ischemia reperfusion. However, the spectrum of its biological effects is unclear. We hypothesized that exogenous administration of C-peptide would modulate pro- and anti-inflammatory signaling pathways and thereby attenuate lung inflammation in an in vivo model of hemorrhagic shock. Hemorrhagic shock was induced in male Wistar rats (aged 3-4 mo) by withdrawing blood to a mean arterial pressure of 50 mmHg. At 3 h after hemorrhage, rats were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, animals received C-peptide (280 nmol/kg) or vehicle parenterally. Animals were euthanized at 1 and 3 h after resuscitation. C-peptide administration at resuscitation following hemorrhagic shock ameliorated hypotension and blunted the systemic inflammatory response by reducing plasma levels of IL-1, IL-6, macrophage inflammatory protein-1α, and cytokine-induced neutrophil chemoattractant-1. This was associated with a reduction in lung neutrophil infiltration and plasma levels of receptor for advanced glycation end products. Mechanistically, C-peptide treatment was associated with reduced expression of proinflammatory transcription factors activator protein-1 and NF-κB and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor-γ. Our data suggest that C-peptide ameliorates the inflammatory response and lung inflammation following hemorrhagic shock. These effects may be modulated by altering the balance between pro- and anti-inflammatory signaling in the lung.
authors.affiliation: Division of Critical Care Medicine (MLC 2005 Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA. ranjit.chima@cchmc.org
authors.forename: Ranjit S
authors.initials: RS
authors.lastname: Chima
authors.forename: Timberly
authors.initials: T
authors.lastname: LaMontagne
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piraino
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hake
authors.forename: Alvin
authors.initials: A
authors.lastname: Denenberg
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
mesh_terms: D000818:Animals; D002096:C-Peptide / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D011014:Pneumonia / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000188:drug therapy; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D002096:C-Peptide; D016207:Cytokines; D016328:NF-kappa B; D047495:PPAR gamma; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3