The Inflammatory and Cytotoxic Effects of a Nitric Oxide Releasing Cream on Normal Skin

Ormerod, Anthony; Copeland, Paul M.; Hay, Isabelle; Husain, Akhtar; Ewen, S. W. B.

doi:10.1046/j.1523-1747.1999.00692.x

Cited by 68 publications

(59 citation statements)

References 44 publications

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“…In the present study there was a significant increase in apoptotic cells in the centrilobular and midzonal regions at 4 and 24 h ( Figure 1, Table 2), which confirmed a heterogenous spread of liver damage as previously reported (9). Positive ApopTag staining of the liver seen in Figure 1 may be indicative of cells undergoing repair or apoptosis (37), as the DNA is stained in the damaged nuclei of affected cells (38). In addition, significantly increased levels of ALT were seen at 4 and 24 h, indicating extensive liver damage caused by I/R injury.…”

Section: Discussionsupporting

confidence: 90%

Effects of Long-Term Hepatic Ischemia-Reperfusion Injury on the Function of P-glycoprotein in vivo in Rats

Thorling¹,

Roberts²,

Liu³

et al. 2014

J Pharm Pharm Sci

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-PURPOSE: Ischemia-reperfusion injury is a common complication in liver surgery with oxidative stress related graft failure as a potential complication. The oxidative stress could affect hepatic drug transporters such as P-glycoprotein, which is crucial in the hepatic clearance of certain immunosuppressant drugs. Thus,, it is important to study its function after ischemia-reperfusion injury in vivo. Rhodamine 123 is a fluorescent substrate of P-glycoprotein and its hepatic disposition can be visualized using multiphoton microscopy in vivo using anaesthetized animals. The aim of this study was to investigate the effect of long-term ischemia-reperfusion injury on P-glycoprotein function in hepatocytes using in vivo multiphoton microscopy. METHODS: Localized ischemia was induced for 1 hour in rats. The liver was reperfused for 4, 24, 48 hours or 1 week, where-after rhodamine 123 was injected intravenously. Multiphoton microscopy imaged the liver and bile was collected continuously up to 6 hours following drug administration. The liver was harvested for histology andprotein expression of Pglycoprotein. RESULTS: Ischemia-reperfusion injury resulted in extensive liver damage, inflammatory cell infiltration and apoptosis in the midzonal and centrilobular regions of the liver acinus. P-glycoprotein protein expression decreased. Cellular concentration of rhodamine 123 increased as visualized by multiphoton microscopy, which was confirmed with decreased excretion of rhodamine 123 in collected bile. CONCLUSIONS: This study showed reduced function of P-glycoprotein in ischemia-reperfusion injury as reflected by decreased biliary excretion of Rhodamine 123, as well as reduced protein expression of the transporter. Multiphoton microscopy could be used to visualize and quantitate the intracellular levels of rhodamine 123. These findings stipulate the importance of using multiphoton microscopy to understand transmembrane drug flux and reflect on careful drug dosing after hepatic surgery.

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Section: Discussionsupporting

confidence: 90%

Effects of Long-Term Hepatic Ischemia-Reperfusion Injury on the Function of P-glycoprotein in vivo in Rats

Thorling¹,

Roberts²,

Liu³

et al. 2014

J Pharm Pharm Sci

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“…To confirm the heterogenic spread in the damage the harvested livers were histopathologically analyzed. ApopTag stained cells, staining DNA damaged nuclei, 47 were significantly increased in the centrilobular and midzonal regions, but not in the periportal region. Early ischemia reperfusion injury induces a burst of free radicals, 42 which in turn cause DNA strand breaks in the nuclei of the cells.…”

Section: Discussionmentioning

confidence: 84%

Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats

et al. 2011

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Abstract. Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery. In orthotopic transplantation, the donor liver is exposed to periods of ischemia and when oxygenated blood is reintroduced to the liver, oxidative stress may develop and lead to graft failure. The aim of this project was to investigate whether noninvasive multiphoton and fluorescence lifetime imaging microscopy, without external markers, were useful in detecting early liver damage caused by I/R injury. Localized hepatic ischemia was induced in rats for 1 h followed by 4 h reperfusion. Multiphoton and fluorescence lifetime imaging microscopy was conducted prior to ischemia and up to 4 h of reperfusion and compared to morphological and biochemical assessment of liver damage. Liver function was significantly impaired at 2 and 4 h of reperfusion. Multiphoton microscopy detected liver damage at 1 h of reperfusion, manifested by vacuolated cells and heterogeneous spread of damage over the liver. The damage was mainly localized in the midzonal region of the liver acinus. In addition, fluorescence lifetime imaging showed a decrease in cellular metabolic activity. Multiphoton and fluorescence lifetime imaging microscopy detected evidence of early I/R injury both structurally and functionally. This provides a simple noninvasive technique useful for following progressive liver injury without external markers. C 2011 Society of Photo-Optical Instrumentation Engineers (SPIE).

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“…69 Again, it has been suggested that this effect may be partly because of the induction of apoptosis in infiltrating cells. In a human model similar to sunburn and psoriasis, Ormerod et al 68 described a cytotoxic effect of high concentrations of topically administered NO to immunocompetent cells, which was not seen with low concentrations. Aminoguanidine, an inhibitor of iNOS, prevented the impairment of renal vascular bed responses and reduced urine nitrate levels and apoptotic mononuclear cells in a rat model of experimental nephropathy.…”

Section: In Vivo Effects Of No and Its Therapeutic Potentialmentioning

confidence: 99%

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

et al. 2003

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Apoptosis of inflammatory cells is a critical event in the resolution of inflammation, as failure to undergo this form of cell death leads to increased tissue damage and exacerbation of the inflammatory response. Many factors are able to influence the rate of apoptosis in neutrophils, eosinophils, monocytes and macrophages. Among these is the signalling molecule nitric oxide (NO), which possesses both anti-and proapoptotic properties, depending on the concentration and flux of NO, and also the source from which NO is derived. This review summarises the differential effects of NO on inflammatory cell apoptosis and outlines potential mechanisms that have been proposed to explain such actions.

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The Inflammatory and Cytotoxic Effects of a Nitric Oxide Releasing Cream on Normal Skin

Cited by 68 publications

References 44 publications

Effects of Long-Term Hepatic Ischemia-Reperfusion Injury on the Function of P-glycoprotein in vivo in Rats

Effects of Long-Term Hepatic Ischemia-Reperfusion Injury on the Function of P-glycoprotein in vivo in Rats

Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

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