Scopolamine treatment and muscarinic receptor subtype-3 gene ablation augment azoxymethane-induced murine liver injury

Sandeep Khurana, Nirish Shah, Kunrong Cheng, Brian Shiu, Roxana Samimi, Angelica Belo, Jasleen Shant, Cinthia Drachenberg, Jürgen Wess, Jean Pierre Raufman

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Previous work suggests that vagus nerve disruption reduces hepatocyte and oval cell expansion after liver injury. The role of postneuronal receptor activation in response to liver injury has not been ascertained. We investigated the actions of scopolamine, a nonselective muscarinic receptor antagonist, and specific genetic ablation of a key cholinergic receptor, muscarinic subtype-3 (Chrm3), on azoxymethane (AOM)-induced liver injury in mice. Animal weights and survival were measured as was liver injury using both gross and microscopic examination. To assess hepatocyte proliferation and apoptosis, ductular hyperplasia, and oval cell expansion, we used morphometric analysis of 5-bromo-2′-deoxyuridine-, activated caspase-3-, hematoxylin and eosin-, cytokeratin-19-, and epithelial cell adhesion molecule-stained liver sections. Sirius red staining was used as a measure of collagen deposition and its association with oval cell reaction. In AOM-treated mice, both muscarinic receptor blockade with scopolamine and Chrm3 ablation attenuated hepatocyte proliferation and augmented gross liver nodularity, apoptosis, and fibrosis. Compared with control, scopolamine-treated and Chrm3(-/-) AOM-treated mice had augmented oval cell reaction with increased ductular hyperplasia and oval cell expansion. Oval cell reaction correlated robustly with liver fibrosis. No liver injury was observed in scopolamine-treated and Chrm3(-/-) mice that were not treated with AOM. Only AOM-treated Chrm3(-/-) mice developed ascites and had reduced survival compared with AOM-treated wild-type controls. In AOM-induced liver injury, inhibiting postneuronal cholinergic muscarinic receptor activation with either scopolamine treatment or Chrm3 gene ablation results in prominent oval cell reaction. We conclude that Chrm3 plays a critical role in the liver injury response by modulating hepatocyte proliferation and apoptosis.

Original languageEnglish (US)
Pages (from-to)639-649
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume333
Issue number3
DOIs
StatePublished - Jun 1 2010

Fingerprint

Azoxymethane
Scopolamine Hydrobromide
Muscarinic Receptors
Cholinergic Receptors
Cholinergic Agents
Liver
Wounds and Injuries
Genes
Hepatocytes
Apoptosis
Hyperplasia
Keratin-19
Muscarinic Antagonists
Vagus Nerve
Bromodeoxyuridine
Hematoxylin
Eosine Yellowish-(YS)
Ascites
Caspase 3
Liver Cirrhosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Scopolamine treatment and muscarinic receptor subtype-3 gene ablation augment azoxymethane-induced murine liver injury. / Khurana, Sandeep; Shah, Nirish; Cheng, Kunrong; Shiu, Brian; Samimi, Roxana; Belo, Angelica; Shant, Jasleen; Drachenberg, Cinthia; Wess, Jürgen; Raufman, Jean Pierre.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 333, No. 3, 01.06.2010, p. 639-649.

Research output: Contribution to journalArticle

Khurana, S, Shah, N, Cheng, K, Shiu, B, Samimi, R, Belo, A, Shant, J, Drachenberg, C, Wess, J & Raufman, JP 2010, 'Scopolamine treatment and muscarinic receptor subtype-3 gene ablation augment azoxymethane-induced murine liver injury', Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 3, pp. 639-649. https://doi.org/10.1124/jpet.109.165118
Khurana, Sandeep ; Shah, Nirish ; Cheng, Kunrong ; Shiu, Brian ; Samimi, Roxana ; Belo, Angelica ; Shant, Jasleen ; Drachenberg, Cinthia ; Wess, Jürgen ; Raufman, Jean Pierre. / Scopolamine treatment and muscarinic receptor subtype-3 gene ablation augment azoxymethane-induced murine liver injury. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 333, No. 3. pp. 639-649.
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