title: Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.
abstract: BACKGROUND
  Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis.
  
  
  METHODS
  Aged (20-24 months) Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival.
  
  
  RESULTS
  In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005). Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice.
  
  
  CONCLUSIONS
  Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.
authors.affiliation: Emory Center for Critical Care and Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Basic Sciences, Bastyr University California, San Diego, California, United States of America.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Dominguez
authors.affiliation: Emory Center for Critical Care and Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Elise R
authors.initials: ER
authors.lastname: Breed
authors.affiliation: Emory Center for Critical Care and Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Benyam P
authors.initials: BP
authors.lastname: Yoseph
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Burd
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Davidson
authors.affiliation: Emory Center for Critical Care and Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics*; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D055786:Gene Knockout Techniques; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000276:immunology; D008168:Lung / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity; D009195:Peroxidase / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000502:physiology; D018805:Sepsis / Q000378:metabolism / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology*; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol; D009195:Peroxidase