Sympathetic nervous system regulation of liver repair

Abstract

This chapter reviews recent evidence that the sympathetic nervous system (SNS) regulates liver repair by modulating the phenotypes of hepatic stellate cells (HSCs), the liver's principal fibrogenic cells, and hepatic epithelial progenitors, i.e., oval cells. SNS nerve fibers touch HSCs and these cells express adrenoceptors, suggesting that HSCs may be targets for SNS neurotransmitters. HSCs also contain catecholamine biosynthetic enzymes, release norepinephrine (NE), and are growth-inhibited by adrenoceptor antagonists. In addition, HSCs from mice with reduced levels of NE grow poorly in culture and exhibit inhibited activation during liver injury. Finally, growth and injury-related fibrogenic responses are rescued by adrenoceptor agonists. Thus, certain SNS inhibitors (SNSIs) protect experimental animals from cirrhosis. Conversely, SNSIs enhance the hepatic accumulation of oval cells (OCs) in injured livers. This response is associated with improved liver injury. Because SNSIs do not affect the expression of cytokines, growth factors, or growth factor receptors that are known to regulate OCs, and OCs express adrenoceptors, it is conceivable that catecholamines influence OCs by direct interaction with OC adrenoceptors. Given evidence that the SNS regulates the viability and activation of HSCs and OCs differentially, SNSIs may be novel therapies to improve the repair of damaged livers.

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

“…We propose an inhibition of the fibrogenic properties in fibroblasts involved in sclerosing cholangitis because fibroblasts of different tissues were shown to express the whole subset of b-adrenoceptors. 33,34 Therefore, fibroblasts may be directly affected by the inhibition of b-adrenoceptors in a manner similar to that recently described for HSC by Oben et al 10 As vagotomy has been shown to reduce bile flow, whereas elevated levels of neuropeptide Y increase the bile flow, improvement after b-adrenoceptor inhibition could also be a matter of altered bile composition or reduced bile flow. 35 In addition, an indirect effect on fibrosis is also suggested because the RAS is highly controlled by the SNS.…”

“…Additionally, HSCs are able to biosynthesize catecholamines because of their subset of metabolizing enzymes. 10 The inhibition of fibrogenic features of HSCs by blockade of the adrenoceptors was supported by studies of Dubuisson et al These authors demonstrated that sympathectomy after 6-hydroxydopamine application leads to 60% reduction of fibrosis after CCL4 intoxication. 25 Our studies using the Mdr2 À/À model now proves that the blockade of b-adrenoceptors by propranolol results in a significant deceleration of fibrosis progression.…”

“…5,6 Furthermore, in vitro studies demonstrated that blocking of the angiotensin pathway not only reduces the expression of collagens but also the secretion of the crucial fibrogenic mediator TGF-b. 7 Oben et al demonstrated that the sympathetic nervous system (SNS) also affects collagen synthesis and proliferation of HSCs in vitro 8,10 and in vivo. 11,12 Moreover, Dubuisson et al 13 were able to show that chemical sympathectomy leads to attenuated fibrosis in a CCl 4 -induced sinusoidal fibrosis model.…”

Role for Hedgehog signaling in hepatic stellate cell activation and viability

“…5 However, these cells also exhibit many neuroendocrine features, including the expression of synaptophysin, glial fibrillary acidic protein (GFAP), neural cell adhesion molecule, nestin, 6 neurotrophins, 7 dopamine-b-hydroxylase (DBH), and tyrosine hydroxylase. 8 Like neuroendocrine cells, HSC synthesize a variety of catecholamines and express adrenoreceptors, 9 as well as receptors for other neurohumoral factors, such as acetylcholine, 10 neuropeptide Y, 11 angiotensin, 12 somatostatin, 13 and leptin. 14 These features have prompted speculation that HSC might be derived from neural precursors during development.…”

Purinergic signalling in the liver in health and disease

“…It is interesting that the sympathetic nervous system has been implicated in the regulation of liver repair (see [191]). Since ATP is now well established as a cotransmitter with NA in sympathetic nerves, it may be a source of ATP involved in liver regeneration.…”