Farnesyltransferase inhibitors reduce ras activation and ameliorate acetaminophen-induced liver injury in mice #

Saha, Banishree; Nandi, Dipankar

doi:10.1002/hep.23180

Cited by 19 publications

(19 citation statements)

References 35 publications

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“…Farnesylation regulates several protein functions, including membrane localization, activity, and protein interactions. Accumulating studies have reported that inhibition of farnesyltransferase inhibits proinflammatory activities, such as inhibition of NF-〉 and Ras activation (23,28). Here, we show that inhibition of farnesyltransferase protects against M1 protein-provoked lung edema and tissue injury.…”

Section: Discussionsupporting

confidence: 53%

Streptococcal M1 Protein Triggers Farnesyltransferase-Dependent Formation of CXC Chemokines in Alveolar Macrophages and Neutrophil Infiltration of the Lungs

et al. 2012

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The M1 serotype of Streptococcus pyogenes plays an important role in streptococcal toxic shock syndrome. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to inhibit streptococcal M1 protein-induced acute lung damage, although downstream mechanisms remain elusive. Protein isoprenylation, such as farnesylation and geranylgeranylation, has been suggested to regulate anti-inflammatory effects exerted by statins. Here, we examined the effect of a farnesyltransferase inhibitor (FTI-277) on M1 protein-triggered lung inflammation. Male C57BL/6 mice were treated with FTI-277 prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema, and CXC chemokine formation. Flow cytometry was used to determine Mac-1 expression on neutrophils. The gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative reverse transcription (RT)-PCR. We found that the administration of FTI-277 markedly decreased M1 protein-induced accumulation of neutrophils, edema formation, and tissue damage in the lung. Notably, inhibition of farnesyltransferase abolished M1 protein-evoked production of CXC chemokines in the lung and gene expression of CXC chemokines in alveolar macrophages. Moreover, FTI-277 completely inhibited chemokine-induced neutrophil migration in vitro. However, farnesyltransferase inhibition had no effect on M1 protein-induced expression of Mac-1 on neutrophils. Our findings suggest that farnesyltransferase is a potent regulator of CXC chemokine formation in alveolar macrophages and that inhibition of farnesyltransferase not only reduces neutrophil recruitment but also attenuates acute lung injury provoked by streptococcal M1 protein. We conclude that farnesyltransferase activity is a potential target in order to attenuate acute lung damage in streptococcal infections. Streptococcal toxic shock syndrome (STSS) is a fatal condition associated with acute lung injury (2, 5, 24). Due to the limited understanding of the underlying pathophysiology, management of patients with STSS poses a major challenge to clinicians and is largely limited to antibiotics and supportive therapy. It is known that the M1 serotype of Streptococcus pyogenes is most frequently associated with fatal STSS (14, 25). M1 protein is a potent stimulator of neutrophils (40), and STSS-associated lung injury is characterized by massive infiltration of neutrophils (32, 39). Neutrophils are generally considered to be the first line of defense against microbial invasion. Nonetheless, overwhelming neutrophil infiltration appears to constitute a rate-limiting step in the pathophysiology of M1 protein-induced lung damage. For example, systemic depletion of neutrophils abolishes acute lung injury in mice challenged with M1 protein (32, 40). Chemokines are known to be key regulators of leukocyte trafficking at sites of inflammation. CXC chemokines, such as CXCL1 and CXCL2, orchestrate tissue recruitment of neutrophils. C...

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Section: Discussionsupporting

confidence: 53%

Streptococcal M1 Protein Triggers Farnesyltransferase-Dependent Formation of CXC Chemokines in Alveolar Macrophages and Neutrophil Infiltration of the Lungs

et al. 2012

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“…The CTGF-initiated PI3-K and Akt activation was blocked by the PI3-K inhibitor wortmannin. The CTGF-stimulated Ras, ERK1/2, PI3-K and Akt activation were all abolished by manumycin A, a Ras activation inhibitor (farnesyltransferase inhibitor) [38]. Similarly, pretreatment of the cells with LXA 4 partially but significantly downregulated CTGF-initiated activation of Ras, ERK1/2, PI3-K and Akt.…”

Section: Resultsmentioning

confidence: 99%

Lipoxin A4 Inhibits Transition of Epithelial to Mesenchymal Cells in Proximal Tubules

Zhang

Tao

et al. 2010

Am J Nephrol

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Background: Previous studies showed that connective tissue growth factor (CTGF)-induced proliferation of lung fibroblasts and production of chemokines in mesangial cells could be inhibited by lipoxin A₄ (LXA₄). It is speculated that LXA₄ could modulate the CTGF-induced epithelial to mesenchymal transition. Methods: The expressions of α-smooth muscle actin (α-SMA), E-cadherin, integrin-linked kinase (ILK), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K), Akt and Smad signaling were assessed by Western blot and/or real-time RT-PCR, and activation of Ras or ILK by activity assay, expressions of α-SMA and zonula occludens-1 by immunofluorescence assay in proximal tubular epithelial cells (HK-2). Results: Pretreatment of HK-2 cells with LXA₄ inhibited the morphological fibroblast-like changes and α-SMA expression induced by CTGF but not by transforming growth factor-β₁ (TGF-β₁). The expressions of E-cadherin and zonula occludens-1 reduced by CTGF but not by TGF-β₁ were increased by LXA₄. LXA₄ inhibited the expression and activity of ILK and activation of Ras, ERK1/2, PI3-K and Akt in HK-2 cells stimulated by CTGF. LXA₄ did not affect TGF-β₁-induced expression of ILK, Smad-2/3 phosphorylation and Smad-2’s binding to Smad-4 and subsequent nuclear translocation. Conclusion: LXA₄ inhibits the tubular epithelial to mesenchymal transition, initiated by CTGF but not by TGF-β₁, via downregulation of ILK, Ras/MEK/ERK1/2 and PI3-K/Akt-dependent signal pathway stimulated by CTGF.

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“…These findings are in agreement with previous reports showing in isolated hepatocytes and in vivo that a massive chemical-induced oxidant stress leads to JNK activation (Czaja et al, 2003; Conde de la Rosa et al, 2006; Hong et al, 2009). However, the oxidant stress most likely does not activate JNK directly, but targets upstream events such promoting either the dissociation of thioredoxin and apoptosis signal-regulating kinase 1 (ASK1) (Nakagawa et al, 2008) or the Ras pathway (Saha and Nandi, 2009). Alternatively, JNK can be released from a complex with glutathione-S-transferase Pi (GST-Pi) by binding of NAPQI to GST (Elsby et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity

Saito

Lemasters

Jaeschke

2010

Toxicology and Applied Pharmacology

242

244

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Acetaminophen (APAP) overdose, which causes liver injury in animals and humans, activates c-jun N-terminal kinase (JNK). Although it was shown that the JNK inhibitor SP600125 effectively reduced APAP hepatotoxicity, the mechanisms of protection remain unclear. C57Bl/6 mice were treated with 10 mg/kg SP600125 or vehicle (8% dimethylsulfoxide) 1h before 600 mg/kg APAP administration. APAP time-dependently induced JNK activation (detected by JNK phosphorylation). SP600125, but not the vehicle, reduced JNK activation, attenuated mitochondrial Bax translocation and prevented the mitochondrial release of apoptosis-inducing factor at 4–12 h. Nuclear DNA fragmentation, nitrotyrosine staining, tissue GSSG levels and liver injury (plasma ALT release and necrosis) were partially attenuated by the vehicle (−65%) and completely eliminated by SP600125 (−98%) at 6 and 12h. Furthermore, SP600125 attenuated the increase of inducible nitric oxide synthase (iNOS) mRNA and protein. However, APAP did not enhance plasma nitrite+nitrate levels (NO formation); SP600125 had no effect on this parameter. The iNOS inhibitor L-NIL did not reduce NO formation or injury after APAP but prevented NO formation caused by endotoxin. Since SP600125 completely eliminated the increase in hepatic GSSG levels, an indicator of mitochondrial oxidant stress, it is concluded that the inhibition of peroxynitrite was mainly caused by reduced superoxide formation. Our data suggest that the JNK inhibitor SP600125 protects against APAP-induced liver injury in part by attenuation of mitochondrial Bax translocation but mainly by preventing mitochondrial oxidant stress and peroxynitrite formation and thereby preventing the mitochondrial permeability transition pore opening, a key event in APAP-induced cell necrosis.

show abstract

Farnesyltransferase inhibitors reduce ras activation and ameliorate acetaminophen-induced liver injury in mice #

Cited by 19 publications

References 35 publications

Streptococcal M1 Protein Triggers Farnesyltransferase-Dependent Formation of CXC Chemokines in Alveolar Macrophages and Neutrophil Infiltration of the Lungs

Streptococcal M1 Protein Triggers Farnesyltransferase-Dependent Formation of CXC Chemokines in Alveolar Macrophages and Neutrophil Infiltration of the Lungs

Lipoxin A4 Inhibits Transition of Epithelial to Mesenchymal Cells in Proximal Tubules

c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity

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