title: Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury.
abstract: OBJECTIVE
  The aim of this study was to determine the effects of acute lung injury on the gut epithelium and examine mechanisms underlying changes in crypt proliferation and apoptosis. The relationship between severity and timing of lung injury to intestinal pathology was also examined.
  
  
  METHODS
  Randomized, controlled study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Genetically inbred mice.
  
  
  METHODS
  Following induction of acute lung injury, gut epithelial proliferation and apoptosis were assessed in a) C3H/HeN wild-type and C3H/HeJ mice, which lack functional Toll-like receptor 4 (n = 17); b) C57Bl/6 mice that received monoclonal anti-tumor necrosis factor-alpha or control antibody (n = 22); and c) C57Bl/6 wild-type and transgenic mice that overexpress Bcl-2 in their gut epithelium (n = 21). Intestinal epithelial proliferation and death were also examined in animals with differing degrees of lung inflammation (n = 24) as well as in a time course analysis following a fixed injury (n = 18).
  
  
  RESULTS
  Acute lung injury caused decreased proliferation and increased apoptosis in crypt epithelial cells in all animals studied. C3H/HeJ mice had higher levels of proliferation than C3H/HeN animals without additional changes in apoptosis. Anti-tumor necrosis factor-alpha antibody had no effect on gut epithelial proliferation or death. Overexpression of Bcl-2 did not change proliferation despite decreasing gut apoptosis. Proliferation and apoptosis were not correlated to severity of lung injury, as gut alterations were lost in mice with more severe acute lung injury. Changes in both gut epithelial proliferation and death were apparent within 12 hrs, but proliferation was decreased 36 hrs following acute lung injury while apoptosis returned to normal.
  
  
  CONCLUSIONS
  Acute lung injury causes disparate effects on crypt proliferation and apoptosis, which occur, at least in part, through differing mechanisms involving Toll-like receptor 4 and Bcl-2. Severity of lung injury does not correlate with perturbations in proliferation or death in the gut epithelium, and acute lung injury-induced changes in intestinal epithelial proliferation persist longer than those in apoptosis.
authors.affiliation: Departments of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Kareem D
authors.initials: KD
authors.lastname: Husain
authors.forename: Paul E
authors.initials: PE
authors.lastname: Stromberg
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Woolsey
authors.forename: Isaiah R
authors.initials: IR
authors.lastname: Turnbull
authors.forename: W Michael
authors.initials: WM
authors.lastname: Dunne
authors.forename: Pardis
authors.initials: P
authors.lastname: Javadi
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Buchman
authors.forename: Irene E
authors.initials: IE
authors.lastname: Karl
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology*; D007421:Intestine, Small / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000503:physiopathology*; D012720:Severity of Illness Index; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha