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Microparticles mediate hepatic ischemia-reperfusion injury and are the targets of Diannexin (ASP8597).
PLoS One. 2014; 9(9):e104376.Plos

Abstract

BACKGROUND & AIMS

Ischemia-reperfusion injury (IRI) can cause hepatic failure after liver surgery or transplantation. IRI causes oxidative stress, which injures sinusoidal endothelial cells (SECs), leading to recruitment and activation of Kupffer cells, platelets and microcirculatory impairment. We investigated whether injured SECs and other cell types release microparticles during post-ischemic reperfusion, and whether such microparticles have pro-inflammatory, platelet-activating and pro-injurious effects that could contribute to IRI pathogenesis.

METHODS

C57BL6 mice underwent 60 min of partial hepatic ischemia followed by 15 min-24 hrs of reperfusion. We collected blood and liver samples, isolated circulating microparticles, and determined protein and lipid content. To establish mechanism for microparticle production, we subjected murine primary hepatocytes to hypoxia-reoxygenation. Because microparticles express everted phosphatidylserine residues that are the target of annexin V, we analyzed the effects of an annexin V-homodimer (Diannexin or ASP8597) on post-ischemia microparticle production and function.

RESULTS

Microparticles were detected in the circulation 15-30 min after post-ischemic reperfusion, and contained markers of SECs, platelets, natural killer T cells, and CD8+ cells; 4 hrs later, they contained markers of macrophages. Microparticles contained F2-isoprostanes, indicating oxidative damage to membrane lipids. Injection of mice with TNF-α increased microparticle formation, whereas Diannexin substantially reduced microparticle release and prevented IRI. Hypoxia-re-oxygenation generated microparticles from primary hepatocytes by processes that involved oxidative stress. Exposing cultured hepatocytes to preparations of microparticles isolated from the circulation during IRI caused injury involving mitochondrial membrane permeability transition. Microparticles also activated platelets and induced neutrophil migration in vitro. The inflammatory properties of microparticles involved activation of NF-κB and JNK, increased expression of E-selectin, P-selectin, ICAM-1 and VCAM-1. All these processes were blocked by coating microparticles with Diannexin.

CONCLUSIONS

Following hepatic IRI, microparticles circulate and can be taken up by hepatocytes, where they activate signaling pathways that mediate inflammation and hepatocyte injury. Diannexin prevents microparticle formation and subsequent inflammation.

Authors+Show Affiliations

Australian National University Medical School at The Canberra Hospital, Canberra, ACT, Australia.Australian National University Medical School at The Canberra Hospital, Canberra, ACT, Australia.Australian National University Medical School at The Canberra Hospital, Canberra, ACT, Australia.School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.Alavita Inc, Palo Alto, California, United States of America.Australian National University Medical School at The Canberra Hospital, Canberra, ACT, Australia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25222287

Citation

Teoh, Narci C., et al. "Microparticles Mediate Hepatic Ischemia-reperfusion Injury and Are the Targets of Diannexin (ASP8597)." PloS One, vol. 9, no. 9, 2014, pp. e104376.
Teoh NC, Ajamieh H, Wong HJ, et al. Microparticles mediate hepatic ischemia-reperfusion injury and are the targets of Diannexin (ASP8597). PLoS One. 2014;9(9):e104376.
Teoh, N. C., Ajamieh, H., Wong, H. J., Croft, K., Mori, T., Allison, A. C., & Farrell, G. C. (2014). Microparticles mediate hepatic ischemia-reperfusion injury and are the targets of Diannexin (ASP8597). PloS One, 9(9), e104376. https://doi.org/10.1371/journal.pone.0104376
Teoh NC, et al. Microparticles Mediate Hepatic Ischemia-reperfusion Injury and Are the Targets of Diannexin (ASP8597). PLoS One. 2014;9(9):e104376. PubMed PMID: 25222287.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Microparticles mediate hepatic ischemia-reperfusion injury and are the targets of Diannexin (ASP8597). AU - Teoh,Narci C, AU - Ajamieh,Hussam, AU - Wong,Heng Jian, AU - Croft,Kevin, AU - Mori,Trevor, AU - Allison,Anthony C, AU - Farrell,Geoffrey C, Y1 - 2014/09/15/ PY - 2014/03/31/received PY - 2014/06/30/accepted PY - 2014/9/16/entrez PY - 2014/9/16/pubmed PY - 2015/5/29/medline SP - e104376 EP - e104376 JF - PloS one JO - PLoS One VL - 9 IS - 9 N2 - BACKGROUND & AIMS: Ischemia-reperfusion injury (IRI) can cause hepatic failure after liver surgery or transplantation. IRI causes oxidative stress, which injures sinusoidal endothelial cells (SECs), leading to recruitment and activation of Kupffer cells, platelets and microcirculatory impairment. We investigated whether injured SECs and other cell types release microparticles during post-ischemic reperfusion, and whether such microparticles have pro-inflammatory, platelet-activating and pro-injurious effects that could contribute to IRI pathogenesis. METHODS: C57BL6 mice underwent 60 min of partial hepatic ischemia followed by 15 min-24 hrs of reperfusion. We collected blood and liver samples, isolated circulating microparticles, and determined protein and lipid content. To establish mechanism for microparticle production, we subjected murine primary hepatocytes to hypoxia-reoxygenation. Because microparticles express everted phosphatidylserine residues that are the target of annexin V, we analyzed the effects of an annexin V-homodimer (Diannexin or ASP8597) on post-ischemia microparticle production and function. RESULTS: Microparticles were detected in the circulation 15-30 min after post-ischemic reperfusion, and contained markers of SECs, platelets, natural killer T cells, and CD8+ cells; 4 hrs later, they contained markers of macrophages. Microparticles contained F2-isoprostanes, indicating oxidative damage to membrane lipids. Injection of mice with TNF-α increased microparticle formation, whereas Diannexin substantially reduced microparticle release and prevented IRI. Hypoxia-re-oxygenation generated microparticles from primary hepatocytes by processes that involved oxidative stress. Exposing cultured hepatocytes to preparations of microparticles isolated from the circulation during IRI caused injury involving mitochondrial membrane permeability transition. Microparticles also activated platelets and induced neutrophil migration in vitro. The inflammatory properties of microparticles involved activation of NF-κB and JNK, increased expression of E-selectin, P-selectin, ICAM-1 and VCAM-1. All these processes were blocked by coating microparticles with Diannexin. CONCLUSIONS: Following hepatic IRI, microparticles circulate and can be taken up by hepatocytes, where they activate signaling pathways that mediate inflammation and hepatocyte injury. Diannexin prevents microparticle formation and subsequent inflammation. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/25222287/Microparticles_mediate_hepatic_ischemia_reperfusion_injury_and_are_the_targets_of_Diannexin__ASP8597__ L2 - https://dx.plos.org/10.1371/journal.pone.0104376 DB - PRIME DP - Unbound Medicine ER -