Critical role of CXC chemokines in endotoxemic liver injury in mice

Jaeschke, Hartmut; Bajt, Mary Lynn

doi:10.1189/jlb.0504309

Cited by 17 publications

(10 citation statements)

References 13 publications

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“…asation (1), one would expect a relevant effect on neutrophil extravasation only if both chemokines are eliminated. These concerns and other issues are discussed in more detail elsewhere (24).…”

Section: Discussionmentioning

confidence: 98%

Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia

Dorman¹,

Gujral²,

Bajt³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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The hypothesis that the neutrophil chemoattractant CXC chemokines KC and macrophage inflammatory protein-2 (MIP-2) are involved in neutrophil transmigration and liver injury was tested in C3Heb/FeJ mice treated with galactosamine (Gal, 700 mg/kg), endotoxin (ET, 100 microg/kg), or Gal + ET (Gal/ET). Hepatic KC and MIP-2 mRNA levels and plasma CXC chemokine concentrations were dramatically increased 1.5 h after Gal/ET or ET alone and gradually declined up to 7 h. Murine recombinant cytokines (TNF-alpha, IL-1 alpha, and IL-1 beta), but not Gal/ET, induced CXC chemokine formation in the ET-resistant C3H/HeJ strain. To assess the functional importance of KC and MIP-2, C3Heb/FeJ mice were treated with Gal/ET and control IgG or a combination of anti-KC and anti-MIP-2 antibodies. Anti-CXC chemokine antibodies did not attenuate hepatocellular apoptosis, sinusoidal neutrophil sequestration and extravasation, or liver injury at 7 h. Furthermore, there was no difference in liver injury between BALB/cJ wild-type and CXC receptor-2 gene knockout (CXCR2-/-) mice treated with Gal/ET. The higher neutrophil count in livers of CXCR2-/- than in wild-type mice after Gal/ET was caused by the elevated number of neutrophils located in sinusoids of untreated CXCR2-/- animals. The pancaspase inhibitor Z-Val-Ala-Asp-fluoromethylketone eliminated Gal/ET-induced apoptosis and neutrophil extravasation and injury but not CXC chemokine formation. Thus Gal/ET induced massive, cytokine-dependent CXC chemokine formation in the liver. However, neutrophil extravasation and injury occurred in response to apoptotic cell injury at 6-7 h and was independent of CXC chemokine formation.

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Section: Discussionmentioning

confidence: 98%

Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia

Dorman¹,

Gujral²,

Bajt³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Ad injection and stimulates expression of the MIP-2 chemokine, which acts as an efficient neutrophil chemoattractant. In earlier studies it was found that CXC chemokines KC and MIP-2 are the primary mediators of neutrophil activation and sequestration in hepatic vasculature in response to a variety of inflammatory mediators (77,78). Specifically, administration of IL-1␣ induced significantly higher plasma levels and hepatic mRNA for MIP-2 and KC chemokines, compared with TNF-␣ (77).…”

Section: Discussionmentioning

confidence: 99%

Interference with the IL-1-Signaling Pathway Improves the Toxicity Profile of Systemically Applied Adenovirus Vectors

Shayakhmetov

et al. 2005

The Journal of Immunology

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The safety of gene therapy vectors is a major concern when novel viral or nonviral therapeutics are proposed for applications in humans. Adenovirus (Ad) vectors have been extensively used as efficient gene delivery vehicles in vitro over the last two decades. However, upon i.v. application, they elicit robust innate and inflammatory responses that may be fatal for the host. To date, the primary cytokines and chemokines involved in the initiation of these host responses remain illusive. In this study, we demonstrate that IL-1 is a major mediator involved in the initiation of immediate host responses toward i.v. applied Ad vectors. Using mice in which IL-1 signaling was genetically eliminated (IL-1RI-KO), or wild-type animals for which signaling was blocked by anti-IL-1 Abs, we found that i.v. applied Ad vectors elicited dramatically reduced acute inflammatory responses when compared with control animals. Importantly, the efficiency of Ad gene transfer in vivo was not significantly affected by interfering with IL-1 signaling. Using an in situ hybridization technique, we found that hepatocytes and Kupffer cells trigger IL-1 transcription in liver tissue after i.v. Ad vector administration. We also found that expression of the MIP-2 chemokine gene (which is responsible for recruitment of neutrophils to the liver) depends on IL-1 activation. Our data indicate that immediate innate and inflammatory host responses toward i.v. applied Ad vectors can be pharmacologically controlled through interference with IL-1 signaling pathways.

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“…Elevated serum levels of several cytokines, including soluble Fas (sFas) antigen [23], TNF-α, sTNF-αR1, sTNF-αR2, IL-2, IL-2R, IL-6, IL-8, IL-10, and interferon-γ, have been described in patients with ACLF [24,25,26,27,28]. Elevated levels of circulating cytokines in ACLF may be the result of increased production due to endotoxemia [29, 30]. A more recent study showed that presence of bacterial DNA in cirrhosis identifies a subgroup of patients with marked inflammatory response not related to endotoxin.…”

Section: Role Of Cytokines In Liver Complicationsmentioning

confidence: 99%

Role of Cytokines in the Pathophysiology of Acute-on-Chronic Liver Failure

Liu¹

2009

Blood Purif

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Background: This is the first ever decade which has witnessed the emergence of a highly lethal condition termed acute-on-chronic liver failure (ACLF), which today is the leading cause of death compared to acute and chronic liver failure. However, the complex pathophysiology of ACLF remains poorly understood. This article will attempt to summarize recent progress in the understanding of the mechanisms of cytokines in ACLF. Methods: The search terms used on PubMed were cytokines, liver injury, complications of liver disease, and hepatic progenitor cell. Results: Cytokines play a significant role in the pathophysiology of ACLF including hepatocellular death, extrahepatic complications and hepatocyte regeneration. The tissue-damaging mechanisms of cytokines are closely related to their hepatocyte proliferation and regeneration function. Conclusions: It remains a challenge to selectively prevent the detrimental effects of cytokines. To design interventions which selectively target the detrimental effects of cytokines, a detailed understanding of cytokines in the pathophysiology ACLF is critical.

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Critical role of CXC chemokines in endotoxemic liver injury in mice

Cited by 17 publications

References 13 publications

Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia

Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia

Interference with the IL-1-Signaling Pathway Improves the Toxicity Profile of Systemically Applied Adenovirus Vectors

Role of Cytokines in the Pathophysiology of Acute-on-Chronic Liver Failure

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