Inhibition of tyrosine-kinase–mediated cellular signaling by tyrphostins AG 126 and AG556 modulates murine experimental acute pancreatitis

Balachandra, Srinivasan; Genovese, Tiziana; Mazzon, Emanuela; Paola, Rosanna Di; Thiemerman, Christoph; Siriwardena, Ajith K.; Cuzzocrea, Salvatore

doi:10.1016/j.surg.2005.05.021

Cited by 22 publications

(15 citation statements)

References 28 publications

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“…Neutrophil infiltration into inflamed tissue plays a crucial role in the destruction of foreign antigens and in the breakdown and remodeling of injured tissue. The adhesion molecules ICAM‐1 and P‐selectin play an important role in the recruitment of neutrophils into the pancreas during acute pancreatitis after ischemia and reperfusion 44 . In this study, as previously published, 43,44 we demonstrate that experimental acute pancreatitis leads to an increased expression of ICAM‐1 and P‐selectin, which also results in a significant neutrophil infiltration.…”

Section: Discussionsupporting

confidence: 85%

“…The adhesion molecules ICAM‐1 and P‐selectin play an important role in the recruitment of neutrophils into the pancreas during acute pancreatitis after ischemia and reperfusion 44 . In this study, as previously published, 43,44 we demonstrate that experimental acute pancreatitis leads to an increased expression of ICAM‐1 and P‐selectin, which also results in a significant neutrophil infiltration. Thus, the enhanced expression of ICAM‐1 and P‐selectin, as well as the increased neutrophil infiltration observed in the absence of endogenous PPAR‐α ligand, suggests that endogenous PPAR‐α ligand reduced neutrophil infiltration, modulating the expression and the up‐regulation of adhesion molecules.…”

Section: Discussionsupporting

confidence: 85%

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Role of peroxisome proliferator‐activated receptor‐α in acute pancreatitis induced by cerulein

et al. 2006

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Summary The peroxisome proliferator‐activated receptor‐α (PPAR‐α) is a member of the nuclear receptor superfamily of ligand‐dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous PPAR‐α ligand on the development of acute pancreatitis caused by cerulein in mice. Intraperitoneal injection of cerulein into PPAR‐α wild‐type (WT) mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and by elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as an increase in myeloperoxidase activity) was associated with enhanced expression of the adhesion molecules intercellular adhesion molecule‐1 (ICAM‐1) and P‐selectin. Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for transforming growth factor‐β (TGF‐β) and vascular endothelial growth factor (VEGF) in the pancreas of cerulein‐treated PPAR‐α wild‐type (WT) mice in comparison to sham‐treated mice. Acute pancreatitis in PPAR‐αWT mice was also associated with a significant mortality (20% survival at 5 days after cerulein administration). In contrast, the degree of pancreatic inflammation and tissue injury (histological score), up‐regulation/formation of ICAM‐1 and P‐selectin, infiltration of neutrophils, and the expression of TGF‐β and VEGF was markedly enhanced in pancreatic tissue obtained from cerulein‐treated PPAR‐α knockout (KO) mice. Thus, endogenous PPAR‐α ligands reduce the degree of pancreas injury caused by acute pancreatitis induced by cerulein administration.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 85%

Role of peroxisome proliferator‐activated receptor‐α in acute pancreatitis induced by cerulein

et al. 2006

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“…Recent data show that many tyrosine kinase inhibitors, tyrphostins have a beneficial effect in various acute and chronic inflammatory conditions. When compared the action of AG-126 and AG-556 in autoimmune myocarditis only the latter was effective [39] but both have a positive impact in murine experimental acute peritonitis [40] and in experimental cord trauma [41]. Comparison between different tyrphostins cannot differentiate precisely their mode of action, since they affect a number of mediators with different meaning in each model.…”

Section: Discussionmentioning

confidence: 99%

Tyrphostin AG-490 inhibited the acute phase of zymosan-induced inflammation

Dimitrova¹,

Ivanovska²

2008

International Immunopharmacology

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“…The signalling pathway involves the p55 death domain, the activation of phosphatidylcholine-specific phohpholipase C [70], the rapid production of 1,2-diacilglycerol (DAG) and the translocation of PKC-and PKC-, which in turn regulate the downstream events independently. A cascade involving I B kinases subsequently occurs, thereby leading to hyperphosphorylation, polyubiquination and proteolytic degradation of I B proteins [71]. Hence, NF-B dimers translocate from the cytosol to the cell nucleus, where they bind to their consensus sequence on the promoter-enhancer region of inflammatory genes.…”

Section: Regulation Of Tnf-productionmentioning

confidence: 99%

TNF-Alpha as a Therapeutic Target in Inflammatory Diseases, Ischemia- Reperfusion Injury and Trauma

Esposito

Cuzzocrea

2009

CMC

247

185

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Tumor necrosis factor-alpha (TNF-alpha) is a central regulator of inflammation, and TNF-alpha antagonists may be effective in treating inflammatory disorders in which TNF-alpha plays an important pathogenetic role. Recombinant or modified proteins are an emerging class of therapeutic agents. To date, several recombinant or modified proteins which acts as TNF antagonists have been disclosed. In particular, antibodies that bind to and neutralise TNF have been sought as a means to inhibit TNF activity. Inhibition of TNF has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis, psoriatic arthritis, and ankylosing spondylitis, inflammatory bowel disease. Additionally, the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research. The currently available therapies include a soluble p75 TNF receptor:Fc construct, etanercept, a chimeric monoclonal antibody, infliximab, and a fully human monoclonal antibody, adalimumab. Certolizumab pegol is a novel TNF inhibitor which is an antigen-binding domain of a humanized TNF antibody coupled to polyethylene glycol (PEG) to increase half-life, and thus is Fc-domain-free. In this review, we discuss briefly the present understanding of TNF-alpha-mediated biology and the current therapies in clinical use, and focus on some of the new therapeutic approaches with small-molecule inhibitors. Moreover, we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs, as TNF-alpha activity inhibitories, especially in therapies of several inflammatory diseases within the nervous system.

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Inhibition of tyrosine-kinase–mediated cellular signaling by tyrphostins AG 126 and AG556 modulates murine experimental acute pancreatitis

Cited by 22 publications

References 28 publications

Role of peroxisome proliferator‐activated receptor‐α in acute pancreatitis induced by cerulein

Role of peroxisome proliferator‐activated receptor‐α in acute pancreatitis induced by cerulein

Tyrphostin AG-490 inhibited the acute phase of zymosan-induced inflammation

TNF-Alpha as a Therapeutic Target in Inflammatory Diseases, Ischemia- Reperfusion Injury and Trauma

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