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This study graded the severity of necroinflammatory activity in chronic liver disease in dogs using a modification of Ishak\u2019s grading scheme for human chronic liver disease and examined the association of grade score with hepatocellular apoptosis, regeneration, nitric oxide synthase isoform expression, copper and iron accumulation, and indicators of oxidative stress. Formalin-fixed, paraffin-embedded hematoxylin and eosin (HE)\u2013stained liver biopsies from 45 dogs with chronic liver disease and 55 healthy control dogs were graded for various morphologic components of liver injury and response. The cumulative score for grade of necroinflammatory activity was strongly and significantly correlated with immunoreactive labels for hepatocellular proliferation (Ki-67); apoptosis (cleaved caspase-3); inducible nitric oxide synthase (iNOS) in lobular, portal, and septal stromal cells; endothelial nitric oxide synthase (eNOS) in hepatocytes and lobular, portal, and septal stromal cells; and total stainable hepatic iron. A weaker significant correlation was found between grade and accumulation of hepatocellular copper. No significant correlation was found between grade and immunoreactivity for malondialdehyde-protein adducts. These results document a method for grading of the severity of necroinflammatory disease in canine liver biopsies and show an association with increased iNOS and eNOS expression.<\/jats:p>","DOI":"10.1177\/0300985813513041","type":"journal-article","created":{"date-parts":[[2013,12,14]],"date-time":"2013-12-14T00:30:36Z","timestamp":1386981036000},"page":"932-945","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":17,"title":["Hepatic Injury Correlates With Apoptosis, Regeneration, and Nitric Oxide Synthase Expression in Canine Chronic Liver Disease"],"prefix":"10.1177","volume":"51","author":[{"given":"A. R.","family":"Vince","sequence":"first","affiliation":[{"name":"Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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