title: Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion.
abstract: Epidermal growth factor (EGF) is a cytoprotective protein that improves survival in preclinical models of sepsis through its beneficial effects on intestinal integrity. Alcohol use disorder worsens intestinal integrity and is associated with increased morbidity and mortality in critical illness. We sought to determine whether chronic alcohol ingestion alters the host response to systemic administration of EGF in sepsis. Six-week-old FVB/N mice were randomized to receive 20% alcohol or water for 12 weeks. All mice then underwent cecal ligation and puncture to induce polymicrobial sepsis. Mice were then randomized to receive either intraperitoneal injection of EGF (150 μg/kg/day) or normal saline. Water-fed mice given EGF had decreased 7-day mortality compared with water-fed mice (18% vs. 55%). Alcohol-fed mice given EGF also had decreased 7-day mortality compared with alcohol-fed mice (48% vs. 79%). Notably, while systemic EGF improved absolute survival to a similar degree in both water-fed and alcohol-fed mice, mortality was significantly higher in alcohol+EGF mice compared with water+EGF mice. Compared with water-fed septic mice, alcohol-fed septic mice had worsened intestinal integrity with intestinal hyperpermeability, increased intestinal epithelial apoptosis, decreased proliferation and shorter villus length. Systemic administration of EGF to septic alcohol-fed mice decreased intestinal permeability compared with septic alcohol-fed mice given vehicle, with increased levels of the tight junction mediators claudin-5 and JAM-A. Systemic administration of EGF to septic alcohol-fed mice also decreased intestinal apoptosis with an improvement in the Bax/Bcl-2 ratio. EGF also improved both crypt proliferation and villus length in septic alcohol-fed mice. EGF administration resulted in lower levels of both pro- and anti-inflammatory cytokines monocyte chemoattractant protein-1, tumor necrosis factor, and interleukin 10 in alcohol-fed mice. EGF is therefore effective at improving both intestinal integrity and mortality following sepsis in mice with chronic alcohol ingestion. However, the efficacy of EGF in sepsis is blunted in the setting of chronic alcohol ingestion, as intestinal integrity and mortality in alcohol-fed mice given EGF improves animals to levels seen in water-fed mice given vehicle but does not approach levels seen in water-fed mice given EGF.
authors.affiliation: *Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia †Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia ‡Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia §Department of Internal Medicine and Emory Alcohol and Lung Biology Center, Emory University School of Medicine, Atlanta, Georgia ||Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Klingensmith
authors.forename: Benyam P
authors.initials: BP
authors.lastname: Yoseph
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liang
authors.forename: John D
authors.initials: JD
authors.lastname: Lyons
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Burd
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Margoles
authors.forename: Michael
authors.initials: M
authors.lastname: Koval
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D008297:Male; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D062507:Claudin-5; C498686:F11r protein, mouse; D011956:Receptors, Cell Surface; D051028:bcl-2-Associated X Protein; D016753:Interleukin-10; D004815:Epidermal Growth Factor