A Protective Role of Interleukin 11 on Hepatic Injury in Acute Endotoxemia

Maeshima, Kyoichiro; Takahashi, Toru; Nakahira, Kiichi; Shimizu, Hiroko; Fujii, Hiromi; Katayama, Hiroshi; Yokoyama, Masataka; Morita, Kiyoshi; Akagi, Reiko; Sassa, Shigeru

doi:10.1097/01.shk.0000103386.98235.f6

Cited by 39 publications

(33 citation statements)

References 25 publications

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“…This effect on serum transaminases has been previously described after LPS administration (29,39) and in situations in which liver injury was induced by injection of LPS plus a bacillus (21,67). LPS injections increased serum nitrites/nitrates and TNF-␣ mRNA in the liver.…”

Section: Discussionmentioning

confidence: 76%

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GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia

Granado¹,

Martín²,

López-Menduiña³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Granado M, Martín AI, López-Menduiñ a M, López-Calderón A, Villanú a MA. GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia. Am J Physiol Endocrinol Metab 294: E131-E141, 2008. First published November 6, 2007 doi:10.1152/ajpendo.00308.2007.-It has been reported that growth hormone (GH)-releasing peptide-2 (GHRP-2), a ghrelin receptor agonist, has an anti-inflammatory effect. We investigated whether this GH secretagogue attenuates liver injury in LPS-treated rats. Wistar rats were simultaneously injected (ip) with LPS (1 mg/kg) and/or GHRP-2 (100 g/kg). Serum levels of aspartate and alanine transaminases were measured as an index of liver damage. Circulating nitrites/ nitrates and hepatic IGF-I and TNF-␣ were evaluated as possible mediators of GHRP-2 actions. LPS increased serum levels of transaminases and nitrites/nitrates. Moreover, LPS increased hepatic TNF-␣ and decreased hepatic IGF-I mRNAs. GHRP-2 administration attenuated the effects of LPS on transaminases, nitrites/nitrates, TNF-␣, and IGF-I in vivo. This GHRP-2 effect does not seem to be due to modifications in food intake, since fasting did not modify serum levels of transaminases, serum nitrites/nitrates, and hepatic TNF-␣ mRNA both in vehicle rats and in LPS-injected rats. To elucidate whether GHRP-2 is acting directly on the liver, cocultures of hepatocytes and nonparenchymal cells and monocultures of isolated hepatocytes were incubated with LPS and GHRP-2. The ghrelin receptor agonist prevented an endotoxin-induced increase in transaminases and nitrite/nitrate release as well as in TNF-␣ mRNA and increased IGF-I mRNA from cocultures of hepatocytes and nonparenchymal cells, but not from monocultures. In summary, these data indicate that GHRP-2 has a protective effect on the liver in LPSinjected rats that seems to be mediated by IGF-I, TNF-␣, and nitric oxide. Our data also suggest that the anti-inflammatory effect of GHRP-2 in the liver is exerted on nonparenchymal cells. transaminases; insulin-like growth factor I; nitrites/nitrates; tumor necrosis factor-␣; growth hormone-releasing peptide-2 CATABOLISM AND GROWTH IMPAIRMENT are complications of several situations such as sepsis and inflammatory diseases. Inflammatory response can be induced experimentally by administering lipopolysaccharide (LPS), a component of the wall of gram-negative bacteria. The liver plays a central role in the inflammatory response to LPS, since it clears LPS and also responds to LPS with production of cytokines (38) and reactive oxygen intermediates (1). Most of the toxicities of LPS, both in liver and in systemic circulation, have been related to the release of these inflammatory cytokines and mediators (24, 61). Nitric oxide (NO) and tumor necrosis factor (TNF) are believed to be involved in hepatic dysfunction in sepsis (5, 57). As potent producers of inflammatory cytokines such as TNF-␣, Kupffer cells have been implicated in the pathway leading to liver injury (60). In many models of liver injury, elevated TNF-␣ levels are pres...

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Section: Discussionmentioning

confidence: 76%

“…*P Ͻ 0.05 vs. vehicle-ad libitum fed (2-way ANOVA and Student's t-test). inducible NO synthase (iNOS) and TNF-␣ mRNAs after LPS have been previously reported (39,43). The increased TNF-␣ and NO can contribute to liver damage, as previously described (22,36).…”

Section: Discussionmentioning

confidence: 77%

GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia

Granado¹,

Martín²,

López-Menduiña³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…These studies highlighted impressive effects of IL-11 on platelets, which is the basis for the approval of IL-11 by the U.S. Food and Drug Administration as a treatment that fosters platelet reconstitution after bone marrow ablative therapy (17,18). They also defined the ability of recombinant and transgenic IL-11 to confer cytoprotection and inhibit inflammation during states of mucosal/tissue injury (27,28,33,(41)(42)(43). These studies did not, however, address in detail the roles of endogenous IL-11 and IL-11 signaling in the generation of tissue inflammatory and extraosseous remodeling responses.…”

Section: Discussionmentioning

confidence: 99%

IL-11 Receptor α in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

Chen

Rabach

Noble

et al. 2005

The Journal of Immunology

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IL-13 is a major stimulator of inflammation and tissue remodeling at sites of Th2 inflammation. In Th2-dominant inflammatory disorders such as asthma, IL-11 is simultaneously induced. However, the relationship(s) between IL-11 and IL-13 in these responses has not been defined, and the role(s) of IL-11 in the genesis of the tissue effects of IL-13 has not been evaluated. We hypothesized that IL-11, signaling via the IL-11Rα-gp130 receptor complex, plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of IL-11, IL-11Rα, and gp130 in lungs from wild-type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of IL-11Rα on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11Rα. They also demonstrate that IL-13 is a potent stimulator of inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure and death in mice with wild-type IL-11Rα loci and that these alterations are ameliorated in the absence of IL-11Rα. Lastly, they provide insight into the mechanisms of these processes by demonstrating that IL-13 stimulates CC chemokines, matrix metalloproteinases, mucin genes, and gob-5 and stimulates and activates TGF-β1 via IL-11Rα-dependent pathways. When viewed in combination, these studies demonstrate that IL-11Rα plays a key role in the pathogenesis of IL-13-induced inflammation and remodeling.

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“…LPS also induces hepatic injury as revealed by increases in serum ALT and aspartate transaminase (AST) activities, TNF-mRNA, iNOS mRNA, and DNAbinding activity of NF-κB, and extensive hepatocyte necrosis. However, induction of HO-1 by rhIL-11 ameliorated the LPS-induced hepatic injury and decreased LPS-induced mortality (Maeshima et al, 2004) In an animal model, the cytoprotective effects of HO-1 against oxidative stress were also shown in other organs (Maeshima et al, 2005, Barreiro et al, 2002, Shimizu et al, 2000, Poole et al, 2005, Yu et al, 2009). …”

Section: Animal Studiesmentioning

confidence: 99%

“…Patients with acute liver failure show increased HO-1 and decreased ALAS-1. These may indicate an increase in free heme concentration, resulting in altered heme metabolism and liver function (Fujii et al, 2004). In liver transplantation, which induces oxidative stress through I/R, a donor HO-1 genotype that modulates HO-1 induction levels is associated with outcomes, such as serum ALT and AST levels and early graft survival.…”

Section: Human Studiesmentioning

confidence: 99%