Decreased constitutive hepatic nitric oxide synthase expression in secondary biliary fibrosis and its changes after Roux-en-Y choledocho-jejunostomy in the rat
Abstract
Background/aims Inducible nitric oxide synthase (iNOS) in the liver has been shown to increase after stimulation by different compounds. Its exact role in cirrhosis is unclear, but it is thought to be an important factor in the development of the hyperdynamic state. In contrast, little is known about the constitutive form of nitric oxide synthase (cNOS) in the liver, and in particular in liver disease. We therefore investigated immunohistochemical expression of endothelial NOS (cNOS) and, in addition, of macrophage NOS (iNOS), a constitutive and inducible form of NOS, in secondary biliary fibrosis and after reversing these changes by biliodigestive anastomosis.Methods Sprague-Dawley rats were allocated to one of seven groups: sham-operated controls (CTR), bile duct ligation for 3 weeks (BDL) and BDL followed by Roux-en-Y choledochojejunostomy (RY); the latter group was studied after 1, 2, 3, 7 and 45 days (RY1, RY2, RY3, RY7, and RY45). cNOS-positive hepatocytes were stained with a monoclonal antibody specifically recognizing this isoenzyme, and quantitated stereologically.Results Virtually all hepatocytes were positive for cNOS in CTR (99.9 +/- 0.2%); this was markedly reduced in BDL (73.7 +/- 9.8%; p < 0.05). After RY, cNOS positive hepatocytes increased to reach normal levels (99.7 +/- 0.5%) in RY45. In contrast to cNOS, there was no iNOS positive staining with a monoclonal macrophage NOS antibody for this isoenzyme, which was confirmed by determining total iNOS protein concentration by Western blot. Serum nitrite/nitrate concentrations mirrored these findings and decreased from 7.9 +/- 3.7 mol/l in CTR to 2.1 +/- 0.4 mol/l in BDL. After RY, nitrite/nitrate concentration increased to 22.7 +/- 30.1, 32.4 +/- 21.4 and 44.6 +/- 32.7 mol/l in RY1, RY2 and RY3, respectively; in RY45, serum nitrite/nitrate concentration was normal averaging 6.1 +/- 1.2 mol/l.Conclusions The present investigation shows that, in secondary biliary fibrosis, endothelial nitric oxide synthase is decreased in hepatocytes, macrophage nitric oxide synthase is not increased, and that-in contrast to current thinking-nitrate/nitrate production is diminished.
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NOS3 is expressed at highest relative abundance in vascular endothelium, but is also found in neurons, epithelial cells, cardiomyocytes, adipocytes, and hepatocytes.
“NOS3 (commonly called endothelial NOS or eNOS) is expressed to highest relative abundance in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67, 68] and hepatocytes [69-71].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [71]
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Regulation of obesity and insulin resistance by nitric oxide
Sansbury, B. E., & Hill, B. G. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.05.016 · Cited by 274 · see citing works
“most abundant in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67,68] and hepatocytes [69–71].”
Background
- Authors
- Zimmermann, H., Kurzen, P., Klossner, W., Renner, E. L., & Marti, U.
- Affiliations
- University of Bern (CH)
- Corresponding author
- Zimmermann, Heinz
- ORCID
- Zimmermann, Heinz
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 1996-10
- Volume
- 25
- Issue
- 4
- Pages
- 567-573
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2103885578
- Cited by
- 35
- References
- 10
- Citations by year
- 2021: 1 · 2017: 1 · 2015: 1 · 2014: 3
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- constitutive nitric oxide synthase, endothelial nitric oxide synthase, inducible nitric oxide synthase, Roux-en-Y choledochojejunostomy, bile duct ligation, liver cirrhosis, nitrite/nitrate, hepatic macrophages, hepatic blood flow, liver regeneration
- MeSH terms
- Anastomosis, Roux-en-Y, Animals, Choledochostomy, Immunohistochemistry, Ligation, Liver Cirrhosis, Biliary, Male, Blotting, Western, Rats, Sprague-Dawley, Nitric Oxide Synthase, Rats
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