Intestinal Ischemia-Reperfusion-Induced Acute Lung Injury and Oncotic Cell Death in Multiple Organs

Abstract

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.

Effect of N-acetylcysteine on pulmonary cell death in a controlled hemorrhagic shock model in rats

“…RL and RL+NAC groups, despite being HS-induced, did not exhibit caspase-3 expression, similarly to CG. These data corroborate Mura et al 25 findings in a model of extra pulmonary I/R injury. The authors evidenced cell death in the lung, by TUNEL, in an experimental model of MODS, but not observed an increase of cellular expression of caspase 3.…”

“…They performed electron microscopy with showed that structural changes in lung tissue were compatible with oncotic cell death 25 .…”

XB130, a Novel Adaptor Protein, Promotes Thyroid Tumor Growth

“…20 After deparaffinization, dehydration, and permeabilization with 20 g/ml proteinase K in 10 mmol/L Tris/HCl (pH 7.4 to 8) for 15 minutes, tetramethylrhodamine red-labeled nucleotides were detected under a fluorescence microscope. The nuclei were counterstained with Hoechst 33258 (Pierce, Rockford, IL) at a dilution of 1:5000 for 10 minutes.…”

Milk Fat Globule Epidermal Growth Factor 8 Attenuates Acute Lung Injury in Mice after Intestinal Ischemia and Reperfusion

“…Only a limited number pharmacologic treatment options have been found that provide some benefit in I/R and ALI, most of them targeting inflammatory mediators and oxidative stress pathways (7). A key aspect of I/R injury is the increased occurrence of apoptotic cell death of intestinal and bronchial epithelial cells and of type II alveolar epithelial cells (2,(8)(9)(10)(11). Apoptosis is associated with a marked up-regulation of Fas and Fas-ligand and the activation of caspase-3 in lung epithelial cells (12,13).…”