Susceptibility of murine periportal hepatocytes to hypoxia-reoxygenation: Role for NO and Kupffer cell–derived oxidants
✍ Scribed by Hisashi Taniai; Ian N. Hines; Sulaiman Bharwani; Ronald E. Maloney; Yuji Nimura; Bifeng Gao; Sonia C. Flores; Joe M. McCord; Matthew B. Grisham; Tak Yee Aw
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 901 KB
- Volume
- 39
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
Ischemia/reperfusion (I/R) is an important problem in liver resection and transplantation that is associated with hepatocellular dysfunction and injury. This study was designed to investigate whether a difference in hepatocyte susceptibility occurs in the periportal (PP) and/or perivenous (PV) zones in response to hypoxia/reoxygenation (H/R), and to delineate the mechanisms underlying this susceptibility. H/R was induced in an in situ perfused mouse liver model with deoxygenated Krebs-Henseleit buffer followed by oxygenated buffer. Selective destruction of PP or PV sites was achieved by digitonin perfusion into the portal or inferior vena cava , and was confirmed by histological evaluations and zone-specific enzymes. Hepatocellular injury was assessed by alanine aminotransferase (ALT) release. In whole liver, H/R significantly increased perfusate ALT. H/R of PP-enriched zones caused ALT release that was similar to that of whole liver (80 ؉ 10 vs. 70 ؉ 12 U/mg protein), consistent with significant PP hepatocyte injury. Minimal ALT release occurred in PV zones (10 ؉ 5 U/mg protein). Administration of N-acetyl L-cysteine or a chimeric superoxide dismutase (SOD)-SOD2/3, a genetically engineered SOD-abrogated ALT release in H/Rperfused PP zones, implicating a role for superoxide (O 2 ؊ ). This elevated ALT release was attenuated by gadolinium chloride pretreatment, indicating that Kupffer cells are the O 2 ؊ source. Enzymatic inhibition of cellular nitric oxide synthase (NOS) or genetic depletion of endothelial nitric oxide synthase (eNOS) aggravated hypoxia injury while exogenous NO and inducible nitric oxide synthase (iNOS) deficiency abolished reoxygenation injury. In conclusion, PP hepatocytes are more vulnerable to H/R; this injury is mediated directly or indirectly by Kupffer cell derived O 2 ؊ and is limited by eNOS-derived NO. (HEPATOLOGY 2004;39:1544 -1552.)
P revious studies in animal models show that ischemia/reperfusion (I/R) injury to the liver occurs in 2 distinct phases. The early reperfusion injury response occurs between 1 and 6 hours, and reactive oxygen species (ROS), such as superoxide (O 2 Ϫ ), hydrogen peroxide, and/or hydroxyl radical produced during reperfusion, [1][2][3][4][5] have been implicated in this acute hepatic injury process that is independent of leukocyte involvement. Because hepatic proliferation, which is an important determinant of a patient's survival after major hepatic resection, occurs from the periportal (PP) to perivenous (PV) zones, 6 an understanding of the differential vulnerability of hepatic zones to postischemic injury would provide an important basis for preventing liver failure caused by alcoholic addiction or after major hepatectomy and liver transplantation. Given that metabolic heterogeneity of hepatic parenchymal cells occurs along the sinusoids in the acinus wherein zonal differences have been described for gradients of oxygen, hormones, and xenobiotic detox-