Sepsis from Pseudomonas aeruginosa pneumonia decreases intestinal proliferation and induces gut epithelial cell cycle arrest.
OBJECTIVE
To evaluate whether the up-regulation in sepsis-induced gut epithelial apoptosis is balanced by an increase in intestinal proliferation and to assess mechanisms affecting the gut's regenerative response to overwhelming infection.


METHODS
Prospective, randomized, controlled study.


METHODS
Animal laboratory in a university medical center.


METHODS
Mice were subjected to intratracheal injection of Pseudomonas aeruginosa and killed between 1.5 and 24 hrs after induction of pneumonia-induced sepsis to assess for gut epithelial proliferation and cell division and for apoptosis. Animals were compared with sham-operation controls, septic transgenic mice that overexpress Bcl-2 throughout their small intestinal epithelium, and septic p53-/- mice.


RESULTS
Proliferation and cell division were assessed by measuring S-phase and M-phase cells in intestinal crypts. The number of S-phase cells showed a progressive decline at all time points measured, with a 5-fold decrease in proliferation between control animals and septic mice 24 hrs after intratracheal injection of pathogenic bacteria (p <.0001). In contrast, cells in M-phase remained constant for the first 12 hrs after the onset of sepsis, but increased nearly 50% at 24 hrs after instillation of P. aeruginosa (p <.005). Both the decrease in S-phase cells and the increase in M-phase cells were partially suppressible in Bcl-2 overexpressors, but cellular proliferation and division were similar between septic p53-/- and p53+/+ mice. Crypt apoptosis was increased at all time points, with maximal death occurring between 12 and 24 hrs.


CONCLUSIONS
Sepsis from P. aeruginosa pneumonia induces a p53-independent decrease in gut epithelial proliferation. Despite an increase in sepsis-induced intestinal apoptosis, there is no compensatory increase in intestinal epithelial proliferation, and there is evidence of a cell cycle block with an accumulation of cells in M-phase. Decreasing gut apoptosis by overexpression of Bcl-2 is associated with a partial reversal of the effect of sepsis on the cell cycle.
Coopersmith
Craig M
CM
Department of Surgery, Washiongton University School of Medicine, St. Louis, MO, USA.
Stromberg
Paul E
PE
Davis
Christopher G
CG
Dunne
W Michael
WM
Amiot
Daniel M
DM
Karl
Irene E
IE
Hotchkiss
Richard S
RS
Buchman
Timothy G
TG
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008822:Mice, Transgenic; D018410:Pneumonia, Bacterial; D011552:Pseudomonas Infections / Q000503:physiopathology*; D011897:Random Allocation; D018805:Sepsis / Q000382:microbiology / Q000503:physiopathology*; D015854:Up-Regulation