title: Heat stress induces intestinal injury through lysosome- and mitochondria-dependent pathway in vivo and in vitro.
abstract: Damage to the small intestine secondary to heat stroke is a major factor in heat stroke-related morbidity and mortality. However, the underlying mechanisms by which heat stroke causes small intestinal lesions and dysfunction remain unclear. To explore the pathogenesis of small intestinal tissue and epithelial cell injury, the SW480 cell heat stress model and the mice heat stroke model were established to mimic heat stroke. Morphologic changes in intestinal tissue and increased TUNEL-positive index were induced by heat stress in vivo. Heat stress activated the lysosomal-mitochondrial apoptotic pathway in SW480 cells, increasing intracellular reactive oxygen species and causing lysosomal membrane permeabilization with subsequent release of cathepsin B to the cytosol, mitochondrial depolarization, and cytochrome C release to cytosol. An increase in the Bax/Bcl2 ratio, caspase-9 and caspase-3 were observed. N-Acetyl-L-Cysteine was shown to inhibit ROS generation, suppress permeabilization of lysosomal membranes, decrease levels of cathepsin B and cytochrome C in the cytosol, and inhibit Bax/Bcl2 ratio, caspase-9 and caspase-3 activity both in vitro and in vivo. Mitochondrial damage was alleviated when the models were pre-treated with CA-074 Me both in vitro and in vivo, decreasing cathepsin B and cytochrome C levels in the cytosol, Bax/Bcl2 ratio, caspase-9 and caspase-3 activity. In our models, heat stress-induced apoptosis of small intestinal tissue and epithelial cells through accumulation of ROS and activation of the lysosomal-mitochondrial apoptotic pathway involved the release of cathepsin B. These findings may offer potentially pharmaceutical targets and strategies to repair intestinal injury caused by heat stroke.
authors.affiliation: Southern Medical University, Guangzhou, 510515, P.R. China.|The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, P.R. China.
authors.forename: Gao
authors.initials: G
authors.lastname: Yi
authors.affiliation: Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, P.R. China.|Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou 510515, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, P.R. China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Luo
authors.affiliation: Southern Medical University, Guangzhou, 510515, P.R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: He
authors.affiliation: Southern Medical University, Guangzhou, 510515, P.R. China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, P.R. China.|Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou 510515, P.R. China.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Southern Medical University, Guangzhou, 510515, P.R. China.|Department of Intensive Care Unit, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, 510010, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Su
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002401:Cathepsin B / Q000378:metabolism; D045744:Cell Line, Tumor; D018882:Heat Stress Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006358:Hot Temperature; D006801:Humans; D007410:Intestinal Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D002401:Cathepsin B
keywords: apoptosis; cathepsin B; heat stress; lysosomal membrane permeabilization; mitochondrial