Intestinal ischemia-reperfusion-induced acute lung injury and oncotic cell death in multiple organs.
Most acute respiratory distress syndrome studies have been focused on the lung injury. Little is known about other organs during the development of acute respiratory distress syndrome. Herein, we investigated the injury and cell death in multiple organs after intestinal ischemia-reperfusion (IIR) in C57BL/6 mice. Terminal transferase dUTP nick end labeling staining was used as a marker of cell death. Caspase 3 and cathepsin B activation as markers of caspase-dependent and caspase-independent apoptosis, respectively, and electron microscopy for ultimate characterization of cell death were used. In comparison with control and sham-operated mice, the IIR group showed interstitial inflammatory infiltrates in the lung and significant increases of lung injury parameters and plasma lactate dehydrogenase and aspartate aminotransferase levels. Terminal transferase dUTP nick end labeling-positive cells and immunostaining for hemeoxygenase 1, an enzyme induced by inflammatory stimuli, were increased in the lung, heart, and kidney, but not in the liver. The number of hemeoxygenase 1-positive cells positively and significantly correlated to the number of terminal transferase dUTP nick end labeling-positive cells. Cell death was not associated with caspase 3 or cathepsin B activation. Electron microscopy showed morphological features compatible with oncotic rather than apoptotic cell death or necrosis, including mitochondrial swelling and cytoplasm disorganization in pulmonary and renal epithelial cells, lung and cardiac endothelial cells, and myocytes. These results indicate that, although lung injury is the most significant manifestation after IIR, oncotic cell death occurs in the lung, heart, and kidney, which may be related to ischemia and inflammation.
Thoracic Surgery Research Laboratories, Toronto General Hospital, University Health Network, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Canada.
Marco
M
Mura
Cristiano F
CF
Andrade
Bing
B
Han
Rashmi
R
Seth
Yu
Y
Zhang
Xiao-Hui
XH
Bai
Thomas K
TK
Waddell
David
D
Hwang
Shaf
S
Keshavjee
Mingyao
M
Liu
D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D007422:Intestines / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000473:pathology*; D009336:Necrosis; D015427:Reperfusion Injury / Q000473:pathology*; D012128:Respiratory Distress Syndrome / Q000473:pathology*