Expression of nitric oxide synthase isoforms and arginase in normal human skin and chronic venous leg ulcers

Abd-El-Aleem, Seham A.; Ferguson, Mark W. J.; Appleton, Ian; Kairsingh, Sadeo; Jude, Edward B.; Jones, Katherine R.; McCollum, Charles; Ireland, Grenham W.

doi:10.1002/1096-9896(2000)9999:9999<::aid-path654>3.0.co;2-s

Cited by 84 publications

(72 citation statements)

References 53 publications

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“…Immunostaining for iNOS and ecNOS was absent from the negative control in which the primary antibodies were omitted (Figures 3C and 4F). This indicates the specificity of the antibodies used for iNOS and ecNOS, which was also confirmed in previous studies by pre‐adsorption with immune serum 12, 13. Results were consistent in both the normal controls and the cirrhotic livers for both antibodies.…”

Section: Resultssupporting

confidence: 88%

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Expression of nitric oxide synthase isoforms in human liver cirrhosis

Mohammed

El-Aleem

Appleton

et al. 2003

The Journal of Pathology

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Several mediators of systemic vasodilatation in liver cirrhosis have been reported. Among these is nitric oxide (NO), which has been proposed as one of the main mediators. In this study, sera and liver biopsies were analysed from 15 patients with clinically and pathologically diagnosed liver cirrhosis. In addition, sera from seven and liver biopsies from three healthy controls were used. Serum levels of nitrite (the end product of NO) were measured using the Griess reaction and the expression of the inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (ecNOS) proteins was investigated using immunohistochemistry. This study shows that serum nitrite levels (94 +/- 9.8 micro mol/l) in cirrhotic patients were significantly (p < 0.05) increased in comparison with the controls (36.6 +/- 11.03 micro mol/l). iNOS was completely absent from the control group but was highly expressed in the livers from the cirrhotic group. iNOS was seen mainly in the inflammatory cells infiltrating the portal tracts, blood monocyte-like cells, hepatocytes, sinusoidal cells, and endothelial cells. However, expression of ecNOS was only seen in the vascular endothelial cells of both the control and the cirrhotic groups, but was much higher in the latter. It is therefore clear that NO is augmented in cirrhotic patients and it is mainly produced by induction of iNOS. Moreover, NO up-regulation is dependent on the inflammatory stage of liver cirrhosis. ecNOS production could be a normal chronic adaptation mechanism of the endothelium to the chronically increased splanchnic blood flow secondary to portal hypertension. In the near future, the appropriate inhibition of NO activity by using NOS-active agents may provide a novel strategy for the treatment of patients with liver cirrhosis.

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Section: Resultssupporting

confidence: 88%

“…Haematoxylin was used as a counterstain to delineate the nuclei. Previous studies from our group have confirmed the specificity of the iNOS and ecNOS antibodies by the use of positive controls and the finding of negativity using pre‐adsorption with immune serum 12, 13.…”

Section: Methodssupporting

confidence: 62%

Expression of nitric oxide synthase isoforms in human liver cirrhosis

Mohammed

El-Aleem

Appleton

et al. 2003

The Journal of Pathology

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“…Both aspects are widely considered a biologic advantage because while binding iron, it avoids ROS production via the Fenton and Haber-Weiss reactions. 23,24 The main finding of our study is the demonstration of the increased release of iron in the serum of patients affected by severe CVD. This latter condition is readily visible, for example, in patients affected by liver hemochromatosis, but it causes nothing more than a mild dermal atrophy.…”

Section: Discussionmentioning

confidence: 65%

“…23,24 NO is known to combine with hydroxyl free radicals, forming peroxynitrite, a potent free radical that causes tissue destruction. 23,24 NO is known to combine with hydroxyl free radicals, forming peroxynitrite, a potent free radical that causes tissue destruction.…”

Section: Discussionmentioning

confidence: 99%

Serum Iron and Matrix Metalloproteinase-9 Variations in Limbs Affected by Chronic Venous Disease and Venous Leg Ulcers

Zamboni

Scapoli

Lanzara

et al. 2005

Dermatologic Surgery

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BACKGROUND. Severe chronic venous disease (CVD) is characterized by both dermal hemosiderin accumulation and matrix metalloproteinase (MMP) hyperactivation. The iron-driven pathway is one of the recognized mechanisms of MMP hyperactivation. OBJECTIVE. To investigate the potential consequences of leg hemosiderin deposits on both iron metabolism and activation of MMPs.METHODS. We contemporaneously assessed the following in the serum of the arm and ankle veins of 30 patients (C4-6) with CVD and 14 normal subjects: ferritin, transferrin, iron, percentage of transferrin iron binding capacity (%TIBC), and MMP-9. Optical microscopy examinations with Perls' staining of chronic wounds were also performed. RESULTS. Histology consistently revealed iron deposits. Serum ferritin, iron, and %TIBC were significantly increased in the legs affected by severe CVD compared with the arm of the same subjects or the controls. In addition, iron and %TIBC were significantly elevated in the legs of ulcer patients. The rate of activation of MMP-9 was significantly elevated in CVD.CONCLUSIONS. The increased iron deposition in legs affected by CVD seems to be more instable in ulcer patients, leading to iron release in the serum of the affected leg. Our data suggest the iron-driven pathway as a further mechanism for MMP hyperexpression leading to tissue lesion.

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“…It is our contention the effects observed in this case series is not surprising in light of the mechanism by which HWDS increases microcirculation in rat experiments [7]. Moreover, nitric oxide is profoundly involved with wound healing by virtue of its effects to control blood flow to tissues and anti-inflammatory effects to influence pain [11]. Interestingly, wound healing represents a particularly challenging clinical problem to which no efficacious treatment regimens currently exist.…”

Section: Discussionmentioning

confidence: 88%

Healing enhancement of chronic venous stasis ulcers utilizing H-WAVE®device therapy: a case series

Blum

Chen

et al. 2010

Cases Journal

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IntroductionApproximately 15% (more than 2 million individuals, based on these estimates) of all people with diabetes will develop a lower-extremity ulcer during the course of the disease. Ultimately, between 14% and 20% of patients with lower-extremity diabetic ulcers will require amputation of the affected limb. Analysis of the 1995 Medicare claims revealed that lower-extremity ulcer care accounted for $1.45 billion in Medicare costs. Therapies that promote rapid and complete healing and reduce the need for expensive surgical procedures would impact these costs substantially. One such example is the electrotherapeutic modality utilizing the H-Wave® device therapy and program.It has been recently shown in acute animal experiments that the H-Wave® device stimulation induces a nitric oxide-dependent increase in microcirculation of the rat Cremaster skeletal muscle. Moreover, chronic H-wave® device stimulation of rat hind limbs not only increases blood flow but induces measured angiogenesis. Coupling these findings strongly suggests that H-Wave® device stimulation promotes rapid and complete healing without need of expensive surgical procedures.Case presentationWe decided to do a preliminary evaluation of the H-Wave® device therapy and program in three seriously afflicted diabetic patients. Patient 1 had chronic venous stasis for 6 years. Patient 2 had chronic recurrent leg ulcerations. Patient 3 had a chronic venous stasis ulcer for 2 years. All were dispensed a home H-Wave® unit. Patient 1 had no other treatment, patient 2 had H-Wave® therapy along with traditional compressive therapy, and patient 3 had no other therapy.For patient 1, following treatment the ulcer completely healed with the H-Wave® device and program after 3 months. For patient 2, by one month complete ulcer closure occurred. Patient 3 had a completely healed ulcer after 9 months.ConclusionsWhile most diabetic ulcers can be treated successfully on an outpatient basis, a significant proportion will persist and become infected. Based on this preliminary case series investigation we found that three patients prescribed H-Wave® home treatment demonstrate accelerated healing with excellent results. While these results are encouraging, additional large scale investigation is warranted before any interpretation is given to these interesting outcomes.

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Expression of nitric oxide synthase isoforms and arginase in normal human skin and chronic venous leg ulcers

Cited by 84 publications

References 53 publications

Expression of nitric oxide synthase isoforms in human liver cirrhosis

Expression of nitric oxide synthase isoforms in human liver cirrhosis

Serum Iron and Matrix Metalloproteinase-9 Variations in Limbs Affected by Chronic Venous Disease and Venous Leg Ulcers

Healing enhancement of chronic venous stasis ulcers utilizing H-WAVE®device therapy: a case series

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