title: Ghrelin decreases microvascular leak during inflammation.
abstract: BACKGROUND
  Obesity is a risk factor for poor outcomes after trauma, and circulating levels of ghrelin are decreased in obese patients. We hypothesized that ghrelin modifies microvascular permeability. The purposes of this study were to determine (1) the effect of ghrelin on microvascular permeability, (2) the effect of ghrelin on microvascular permeability during lipopolysaccharide (LPS)-induced inflammation, (3) the involvement of the growth hormone secretagogue receptor (GHS-R1a) cell receptor, and (4) the involvement of nuclear factor kappa B (NF-kappaB).
  
  
  METHODS
  Hydraulic permeability (Lp), a measure of transendothelial fluid leak, was measured in rat mesenteric postcapillary venules. Lp was measured during continuous administration of (1) ghrelin (3 micromol/L), (2) ghrelin and systemic LPS (10 mg/kg), (3) the GHS-R1a receptor antagonist, (D-Arg1 D-Phe5 D-Trp7,9 Leu11)-substance P (9 micromol/L) plus ghrelin and LPS, and (4) an NF-kappaB inhibitor, parthenolide (10 micromol/L) plus ghrelin and LPS.
  
  
  RESULTS
  Ghrelin alone had no effect (p > 0.7). Compared with LPS alone, ghrelin plus LPS decreased Lp (Lp: ghrelin + LPS = 1.60 +/- 0.16 vs. LPS = 2.27 +/- 0.14, p < 0.006). The GHS-R1a ghrelin receptor antagonist blunted the effect of ghrelin by 86% during LPS-induced inflammation (Lp: ghrelin + LPS = 1.60 +/- 0.16 vs. ghrelin antagonist + ghrelin + LPS = 2.17 +/- 0.27, p < 0.018). NF-kappaB inhibition did not influence the initial increased microvascular leak effect of ghrelin (p > 0.8).
  
  
  CONCLUSIONS
  Although ghrelin has no effect on basal microvascular permeability, it has a biphasic effect with an overall decrease in microvascular permeability during LPS-induced inflammation through the GHS-R1a receptor, independent of NF-kappaB. Ghrelin is a key mediator of inflammation and may contribute to the increased morbidity and mortality in obese trauma patients.
authors.affiliation: Department of Surgery, University of California, San Francisco-East Bay, Alameda County Medical Center, Oakland, California 94610, USA.
authors.forename: Rita O
authors.initials: RO
authors.lastname: Kwan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cureton
authors.forename: Kristopher
authors.initials: K
authors.lastname: Dozier
authors.forename: Brian
authors.initials: B
authors.lastname: Curran
authors.forename: Javid
authors.initials: J
authors.lastname: Sadjadi
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Victorino
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D054439:Ghrelin / Q000502:physiology*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008643:Mesentery / Q000098:blood supply; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D009765:Obesity / Q000150:complications / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000502:physiology; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000378:metabolism; D014699:Venules; D014947:Wounds and Injuries / Q000150:complications / Q000378:metabolism
chemical_list: D054439:Ghrelin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D054440:Receptors, Ghrelin; D012717:Sesquiterpenes; C002669:parthenolide; D013373:Substance P; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-