Effect of liposome-encapsulated hemoglobin resuscitation on proteostasis in small intestinal epithelium after hemorrhagic shock.
Gut barrier dysfunction is the major trigger for multiorgan failure associated with hemorrhagic shock (HS). Although the molecular mediators responsible for this dysfunction are unclear, oxidative stress-induced disruption of proteostasis contributes to the gut pathology in HS. The objective of this study was to investigate whether resuscitation with nanoparticulate liposome-encapsulated hemoglobin (LEH) is able to restore the gut proteostatic mechanisms. Sprague-Dawley rats were recruited in four groups: control, HS, HS+LEH, and HS+saline. HS was induced by withdrawing 45% blood, and isovolemic LEH or saline was administered after 15 min of shock. The rats were euthanized at 6 h to collect plasma and ileum for measurement of the markers of oxidative stress, unfolded protein response (UPR), proteasome function, and autophagy. HS significantly increased the protein and lipid oxidation, trypsin-like proteasome activity, and plasma levels of IFNγ. These effects were prevented by LEH resuscitation. However, saline was not able to reduce protein oxidation and plasma IFNγ in hemorrhaged rats. Saline resuscitation also suppressed the markers of UPR and autophagy below the basal levels; the HS or LEH groups showed no effect on the UPR and autophagy. Histological analysis showed that LEH resuscitation significantly increased the villus height and thickness of the submucosal and muscularis layers compared with the HS and saline groups. Overall, the results showed that LEH resuscitation was effective in normalizing the indicators of proteostasis stress in ileal tissue. On the other hand, saline-resuscitated animals showed a decoupling of oxidative stress and cellular protective mechanisms.
Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and.
Geeta
G
Rao
Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and.
Vivek R
VR
Yadav
Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and.
Shanjana
S
Awasthi
Department of Anesthesiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.
Pamela R
PR
Roberts
Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and vibhudutta-awasthi@ouhsc.edu.
Vibhudutta
V
Awasthi
D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006454:Hemoglobins / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053758:Nanoparticles; D018384:Oxidative Stress / Q000187:drug effects; D010952:Plasma Substitutes / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D054875:Ubiquitination; D056811:Unfolded Protein Response / Q000187:drug effects
D006454:Hemoglobins; D010952:Plasma Substitutes; C000620721:liposome-encapsulated hemoglobin; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex
hemorrhagic shock; liposome-encapsulated hemoglobin; oxidative stress; proteostasis