TY - JOUR
T1 - Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury
AU - Husain, Kareem D.
AU - Stromberg, Paul E.
AU - Woolsey, Cheryl A.
AU - Turnbull, Isaiah R.
AU - Dunne, W. Michael
AU - Javadi, Pardis
AU - Buchman, Timothy G.
AU - Karl, Irene E.
AU - Hotchkiss, Richard S.
AU - Coopersmith, Craig M.
N1 - Funding Information:
Supported, in part, by grants GM 66202, GM00709, GM08795, GM48095, GM 44118, GM 55194, and P30 DK52574 from the National Institutes of Health, and by Dr. Robert D. Schreiber, Washington University School of Medicine, who generously donated TN3-19 and L2-3D9.
PY - 2005/10
Y1 - 2005/10
N2 - Objectives: 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. Design: Randomized, controlled study. Setting: University research laboratory. Subjects: Genetically inbred mice. Interventions: 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) C57BI/6 mice that received monoclonal anti-tumor necrosis factor-α or control antibody (n = 22); and c) C57BI/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). Measurements and Main 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-α 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 seventy 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.
AB - Objectives: 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. Design: Randomized, controlled study. Setting: University research laboratory. Subjects: Genetically inbred mice. Interventions: 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) C57BI/6 mice that received monoclonal anti-tumor necrosis factor-α or control antibody (n = 22); and c) C57BI/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). Measurements and Main 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-α 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 seventy 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.
KW - Acute lung injury
KW - Apoptosis
KW - Gut
KW - Proliferation
KW - Toll-like receptor 4
KW - Tumor necrosis factor-α
UR - http://www.scopus.com/inward/record.url?scp=26444502973&partnerID=8YFLogxK
U2 - 10.1097/01.CCM.0000182797.89252.A3
DO - 10.1097/01.CCM.0000182797.89252.A3
M3 - Article
C2 - 16215392
AN - SCOPUS:26444502973
SN - 0090-3493
VL - 33
SP - 2350
EP - 2357
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 10
ER -