Hepatic Ischemia/Reperfusion in Rats Induces iNOS Gene Transcription by Activation of NF-κB

Hur, Gang Min; Ryu, Young Sue; Yun, Hyo Yung; Jeon, Byeong Hwa; Kim, Yong Man; Seok, Jeong Ho; Lee, Jae Heun

doi:10.1006/bbrc.1999.1143

Cited by 127 publications

(92 citation statements)

References 17 publications

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“…Early activation of NF-B after I/R, similar to the first peak of NF-B activation seen in this study, has been well documented in both warm (23,40,49) and cold (6,7,19) I/R injury. In an effort to examine the role of NF-B activation after I/R, several studies attempted to inhibit early NF-B binding activity using antioxidant/anti-NF-B reagents (e.g., diethyldithiocarbamate) (9,23,31,32), double-stranded DNA with a specific affinity for NF-B (35), or IB superrepressor (6).…”

Section: Discussionsupporting

confidence: 86%

Role of NF-κB on liver cold ischemia-reperfusion injury

Takahashi¹,

Ganster²,

Gambotto³

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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The role of NF-κB, the rapid-response transcription factor for multiple genes, in cold ischemia-reperfusion (I/R) injury was examined after syngeneic transplantation of liver grafts. Lewis rat recipients were killed 1–48 h after reperfusion of three different liver grafts: 1) uninfected control, 2) infected ex vivo with control adenoviral vector (AdEGFP), and 3) infected ex vivo with AdIκB. In uninfected control livers, NF-κB was activated biphasically at 1–3 and 12 h after reperfusion with aspartate transaminase (AST) levels of 4,244 ± 691 IU/l. The first peak of NF-κB activation associated with an increase of mRNA for TNF-α, IL-1β, and IL-10. AdEGFP transfection resulted in similar outcomes. Interestingly, AdIκB-transfected liver grafts suffered more severe I/R injury (AST >9,000 IU/l). Transfected IκB was detected in transplanted livers as early as 6 h, and this correlated with the abrogation of the second, but not the first, peak of NF-κB activation at 12–48 h and increased apoptosis. Thus inhibition of the second wave of NF-κB activation in IκB-transfected livers resulted in an increase of liver injury, suggesting that NF-κB may have a dual role during liver I/R injury.

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Section: Discussionsupporting

confidence: 86%

Role of NF-κB on liver cold ischemia-reperfusion injury

Takahashi¹,

Ganster²,

Gambotto³

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…However, we anticipated that iNOS would be detectable immediately after birth due to the relative hepatic hypoxia seen during this time period in accordance with previous studies have shown that ischemia-reperfusion leads to an increase in expression of hepatic iNOS (37). Absence of detectable iNOS expression immediately after birth may be explained by a relatively minor hypoxia that may result in a lesser stimulus than true ischemia reperfusion.…”

supporting

confidence: 73%

Developmental Expression of Endothelial Nitric Oxide Synthase (eNOS) in the Rat Liver

et al. 2003

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Transition from fetal to postnatal life requires significant changes in cardiac, pulmonary, and hepatic blood flow. As such, there must be changes in vascular control in these vascular systems. Vascular resistance, a major contributor to blood flow, is mediated in the ductus arteriosus and pulmonary vasculature by endothelial nitric oxide synthase (eNOS). This study was conducted to determine the ontogeny of hepatic eNOS expression and activity. Additionally, the expression and activity of inducible nitric oxide synthase (iNOS) was measured to determine whether perinatal hypoxia resulted in detectable levels. NOS mRNA and proteins were determined by reverse transcription PCR assay and semiquantitative Western blot analysis, respectively. NOS activity was measured by the formation of [ 14 C]-citrulline from [14 C]-arginine. Localization of eNOS within the liver was determined by immunohistochemistry. eNOS mRNA was detectable at low levels at 18-d gestation and increased after birth, reaching a maximum level (4.5-fold increase) at 20 d of life. Parallel patterns for eNOS protein and activity were seen, with 6.9-fold and 16.1-fold increases, respectively. In the prenatal rat, eNOS was localized to areas of extramedullary hematopoiesis, with little signal in the sinusoids. Postnatally, there was a decrease in staining in the hematopoietic cells and a gradual increase in the staining of the endothelium of the sinusoids and central veins. iNOS mRNA and protein could not be detected at any age. eNOS expression and activity are developmentally regulated, increasing after birth coincident with an initial relative hypoxia and an increase in shear forces upon closure of the ductus venosus. NO is a short-lived free radical that influences physiologic processes in essentially every organ and tissue. Some of the roles of NO include neuromodulator, prevention of clotting, mediation of bactericidal and tumoricidal activity of macrophages, and regulation of blood pressure. NO is enzymatically synthesized from L-arginine by three known NOS isoforms: constitutively expressed eNOS (or NOS-3), nNOS (or NOS-1), iNOS (or NOS-2) (1-3). NO production by eNOS is primarily regulated by fluctuations in intracellular calcium levels. In the liver under normal conditions, only eNOS is present, produced by the sinusoidal endothelial cells (4, 5). The resulting low level of NO production is a major contributor of the basal vascular tone in the normal liver (4, 5).eNOS plays a role in control of vascular tone in most vascular beds (6). eNOS participates in the control of vascular tone during the transition from fetal circulation to postnatal circulation in the ductus arteriosus (7) and lung (8). The role of eNOS in control of the ductus arteriosus is age dependent. The effects of eNOS are more pronounced in determining vascular tone of the ductus arteriosus in the preterm animal than in the near-term or adult animal (7, 9). During the transition period, blood flow to the lungs is increased by a number of factors, including closure of the ductus ...

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“…However, the influence of iNOS and its true contribution in conferring liver protection deserves additional studies. In a rat model of liver IRI, iNOS expression was significantly increased as per increases in iNOS RNA at 1 and 5 hrs (Hur et al, 1999). This is consistent with other studies measuring iNOS expression of conditions of liver IRI.…”

Section: The Influence Of Endogenous No On Liver Irisupporting

confidence: 90%