Liver cirrhosis reversion is improved in hamsters with a neurointermediate pituitary lobectomy

Quintanar‐Stephano, Andrés; Ventura‐Juárez, Javier; Sánchez-Alemán, Esperanza; Aldaba‐Muruato, Liseth Rubí; Cervantes‐García, Daniel; González-Blas, Daniel; Muñoz‐Ortega, Martín Humberto

doi:10.1016/j.etp.2017.04.006

Cited by 5 publications

(9 citation statements)

References 32 publications

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“…Simultaneously, the AVP deficiency activates cell signaling pathways associated with an anti-inflammatoryantifibrotic state (IL-10 and MMP-13), thus favoring a decreased liver inflammatory response and less activation of the HSCs and fibrosis, favoring liver recovery. This possibility is supported by our previous work on NIL-cirrhotic hamsters, in which both overexpression of MMP-13 and decreased expression level of TIMP-2 were accompanied by a significant regression in liver cirrhosis [33].…”

Section: Discussionsupporting

confidence: 61%

“…Profibrogenic properties of AVP on the heart, liver, and kidney have been demonstrated [ 28 – 32 ]. In addition, we have reported that AVP deficiency promotes the reduction of collagen deposits in a CCl 4 cirrhosis hamster model and restores the balance between metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) [ 33 ]. All this evidence supports that AVP is a major player in the regulation of immune responses and fibrosis; however, less is known on cell and molecular mechanisms through AVP deficiency may modulate the immune responses.…”

Section: Introductionmentioning

confidence: 99%

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Recovery from Liver Failure and Fibrosis in a Rat Portacaval Anastomosis Model after Neurointermediate Pituitary Lobectomy

Muñoz‐Ortega

Macías-Segura

Ventura‐Juárez

et al. 2021

Journal of Immunology Research

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Liver diseases, including cirrhosis, viral hepatitis, and hepatocellular carcinoma, account for approximately two million annual deaths worldwide. They place a huge burden on the global healthcare systems, compelling researchers to find effective treatment for liver fibrosis-cirrhosis. Portacaval anastomosis (PCA) is a model of liver damage and fibrosis. Arginine vasopressin (AVP) has been implicated as a proinflammatory-profibrotic hormone. In rats, neurointermediate pituitary lobectomy (NIL) induces a permanent drop (80%) in AVP serum levels. We hypothesized that AVP deficiency (NIL-induced) may decrease liver damage and fibrosis in a rat PCA model. Male Wistar rats were divided into intact control (IC), NIL, PCA, and PCA+NIL groups. Liver function tests, liver gene relative expressions (IL-1, IL-10, TGF-β, COLL-I, MMP-9, and MMP-13), and histopathological assessments were performed. In comparison with those in the IC and PCA groups, bilirubin, protein serum, and liver glycogen levels were restored in the PCA+NIL group. NIL in the PCA animals also decreased the gene expression levels of IL-1 and COLL-I, while increasing those of IL-10, TGF-β, and MMP-13. Histopathology of this group also showed significantly decreased signs of liver damage with lower extent of collagen deposition and fibrosis. Low AVP serum levels were not enough to fully activate the AVP receptors resulting in the decreased activation of cell signaling pathways associated with proinflammatory-profibrotic responses, while activating cell molecular signaling pathways associated with an anti-inflammatory-fibrotic state. Thus, partial reversion of liver damage and fibrosis was observed. The study supports the crucial role of AVP in the inflammatory-fibrotic processes and maintenance of immune competence. The success of the AVP deficiency strategy suggests that blocking AVP receptors may be therapeutically useful to treat inflammatory-fibrotic liver diseases.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Recovery from Liver Failure and Fibrosis in a Rat Portacaval Anastomosis Model after Neurointermediate Pituitary Lobectomy

Muñoz‐Ortega

Macías-Segura

Ventura‐Juárez

et al. 2021

Journal of Immunology Research

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“…Regarding the possible mechanism of the highly fibrotic response produced by DdAVP administration, we considered the possibility that this could be induced indirectly by increased production of TGF-β, a potent fibrogenic and immunosuppressing cytokine related to poor protection against infection. It has been previously reported that VP promotes collagen synthesis and proliferation of fibroblasts through TGF-β, modifying fibrotic responses (42, 43). In this regard, mice treated with DdAVP showed higher TGF-β immunostaining after 60 days of treatment (Figure 2E, images), which correlated with relative increase in its gene expression (Figure 2F).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, it has been reported that VP disturbances occur in the pathophysiology of inflammatory diseases (24, 39); nevertheless, the anti-inflammatory effect of this hormone in the lungs has also been described, through the inhibition in the production of IL-6 (37). In addition, in heart, liver, and in fibroblasts, VP is an inducer of fibrosis, a mechanism partially dependent on TGF-β (42, 43, 57). To study the possible pathogenic effect in TB, experiments were carried out using vasopressinergic manipulation, with the synthetic agonist DdAVP, because its half-life is longer than VP, and CVP was used as a non-selective antagonist for the V1a and V2 receptors.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Vasopressin in the Pathogenesis of Pulmonary Tuberculosis: A New Therapeutic Target?

et al. 2019

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Tuberculosis (TB) is a highly complex infectious disease caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb). It is characterized by chronic granulomatous inflammation of the lung and systemic immune–neuroendocrine responses that have been associated with pathophysiology and disease outcome. Vasopressin (VP), a neurohypophysial hormone with immunomodulatory effects, is abnormally high in plasma of some patients with pulmonary TB, and is apparently produced ectopically. In this study, a BALB/c mouse model of progressive pulmonary TB was used to determine whether VP may play a role in TB pathophysiology. Our results show that VP gene is expressed in the lung since early infection, increasing as the infection progressed, and localized mainly in macrophages, which are key cells in mycobacterial elimination. Pharmacologic manipulation using agonist and antagonist compounds showed that high and sustained stimulation of VPR resulted in increased bacillary burdens and fibrosis at lungs, while blockade of VP receptors reduced bacterial loads. Accordingly, treatment of infected alveolar macrophages with VP in cell cultures resulted in high numbers of intracellular Mtb and impaired cytokine production. Thus, we show that VP is ectopically produced in the tuberculous lungs, with macrophages being its most possible target cell. Further, it seems that chronic vasopressinergic stimulation during active late disease causes anti-inflammatory and tissue reparative effects, which could be deleterious while its pharmacologic suppression reactivates protective immunity and contributes to shorten conventional chemotherapy, which could be a new possible form of immune-endocrine therapy.

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“…22 In CCl 4 -induced cirrhotic hamsters with AVP deficiency [neurointermediate pituitary lobectomy (NIL)induced], we found a significant reduction in alkaline phosphatase serum levels, clear signs of liver histopathological reversion, diminution in type I collagen deposits, increased gene expression of matrix metalloproteinase-13 (MMP-13) and decreased expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). 23 In a recent experiment, we also determined that NIL surgery in PCA rats induced a significant improvement in liver clinical symptoms and histophysiology, as well as changes in the expression of genes involved in the pathophysiology of liver disease, including a decrease in pro-inflammatory interleukin-1 (IL-1) and collagen type I (COLL-I), while genes related to the anti-inflammatory anti-fibrotic response [interleukin-10 (IL-10) and MMP -13] were increased. 24 Taken together, these accumulated data support the view that AVP is a pro-inflammatory hormone and that its deficiency decreases immune responses and improves liver function and fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Arginine vasopressin deficiency and conivaptan (a V1a–V2 receptor antagonist) treatment reverses liver damage and fibrosis in rats with chronic portocaval anastomosis

Navarro‐Gonzalez

Ventura‐Juárez

Muñoz‐Ortega

et al. 2023

Int J Experimental Path

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Arginine vasopressin (AVP) is a naturally occurring hormone synthesized in the hypothalamus. AVP demonstrates pro-fibrotic effects as it stimulates hepatic stellate cells to secrete transforming growth factor-β (TGF-β) and collagen. Previous work in liver cirrhotic (CCL 4 -induced) hamsters demonstrated that AVP deficiency induced by neurointermediate pituitary lobectomy (NIL) can restore liver function. Therefore, we hypothesized that liver fibrosis would decrease in portocaval anastomosis (PCA) rats, which model chronic liver diseases, when they are treated with the V1a-V2 AVP receptor antagonist conivaptan (CV). In this study, changes in liver histology and gene expression were analysed in five experimental groups: control, PCA, NIL, PCA + NIL and PCA + CV, with NIL surgery or CV treatment administered 8 weeks after PCA surgery. Body weight gain was assessed on a weekly basis, and serum liver function, liver weight and liver glycogen content were assessed following euthanasia. Most PCA-induced phenotypes were reverted to normal levels following AVP-modelled deficiency, though hypoglycemia and ammonium levels remained elevated in the PCA + CV group. Liver histopathological findings showed a significant reversal in collagen content, less fibrosis in the triad and liver septa and increased regenerative nodules. Molecular analyses showed that the expression of fibrogenic genes (TGF-β and collagen type I) decreased in the PCA + CV group. Our findings strongly suggest that chronic NIL or CV treatment can induce a favourable microenvironment to decrease liver fibrosis and support CV as an alternative treatment for liver fibrosis.

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Liver cirrhosis reversion is improved in hamsters with a neurointermediate pituitary lobectomy

Cited by 5 publications

References 32 publications

Recovery from Liver Failure and Fibrosis in a Rat Portacaval Anastomosis Model after Neurointermediate Pituitary Lobectomy

Recovery from Liver Failure and Fibrosis in a Rat Portacaval Anastomosis Model after Neurointermediate Pituitary Lobectomy

Involvement of Vasopressin in the Pathogenesis of Pulmonary Tuberculosis: A New Therapeutic Target?

Arginine vasopressin deficiency and conivaptan (a V1a–V2 receptor antagonist) treatment reverses liver damage and fibrosis in rats with chronic portocaval anastomosis

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