Chemical chaperone TUDCA prevents apoptosis and improves survival during polymicrobial sepsis in mice.
Sepsis-induced lymphopenia is a major cause of morbidities in intensive care units and in populations with chronic conditions such as renal failure, diabetes, HIV and alcohol abuse. Currently, other than supportive care and antibiotics, there are no treatments for this condition. We developed an in vitro assay to understand the role of the ER-stress-mediated apoptosis process in lymphocyte death during polymicrobial sepsis, which was reproducible in in vivo mouse models. Modulating ER stress using chemical chaperones significantly reduced the induction of the pro-apoptotic protein Bim both in vitro and in mice. Furthermore, in a 'two-hit' pneumonia model in mice, we have been able to demonstrate that administration of the chemical chaperone TUDCA helped to maintain lymphocyte homeostasis by significantly reducing lymphocyte apoptosis and this correlated with four-fold improvement in survival. Our results demonstrate a novel therapeutic opportunity for treating sepsis-induced lymphopenia in humans.
Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Kingsbury Dr. Victoria 3086, Australia.
Marcel
M
Doerflinger
Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Kingsbury Dr. Victoria 3086, Australia.
Jason
J
Glab
Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Kingsbury Dr. Victoria 3086, Australia.
Christina
C
Nedeva
Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Kingsbury Dr. Victoria 3086, Australia.
Irvin
I
Jose
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Ann
A
Lin
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
Lorraine
L
O'Reilly
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
Cody
C
Allison
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
Marc
M
Pellegrini
School of Medicine, Department of Anesthesiology, Washington University, 660 South Euclid, St. Louis, MO 63110, USA.
Richard S
RS
Hotchkiss
Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Kingsbury Dr. Victoria 3086, Australia.
Hamsa
H
Puthalakath
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067996:RAW 264.7 Cells; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D016019:Survival Analysis; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D020298:U937 Cells
D000072224:Bcl-2-Like Protein 11; D002756:Cholagogues and Choleretics; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine
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