Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Sevransky, Jonathan; Shaked, Gad; Novogrodsky, Abraham; Levitzki, Alexander; Gazit, Aviv; Hoffman, A. G. D.; Elin, Ronald J.; Quezado, Zenaide M.N.; Freeman, Bradley D.; Eichacker, Peter Q.; Danner, Robert L.; Banks, Steven M.; Bacher, John; Thomas, Marvin L.; Natanson, Charles

doi:10.1172/jci119364

Cited by 48 publications

(22 citation statements)

References 37 publications

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“…Furthermore, treatment of the animals 1 h after induction of meningitis still inhibited the increase in rCBF. This is consistent with significantly improved hemodynamic parameters seen in tyrphostintreated animals with multiorgan failure caused by Escherichia coli (26).…”

Section: Discussionsupporting

confidence: 85%

Tyrosine Kinase Inhibition Reduces Inflammation in the Acute Stage of Experimental Pneumococcal Meningitis

et al. 2004

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Bacterial meningitis is an acute inflammatory disease of the central nervous system with a mortality rate of up to 30%. Excessive stimulation of the host immune system by bacterial surface components contributes to this devastating outcome. In vitro studies have shown that protein tyrosine kinase inhibitors are highly effective in preventing the release of proinflammatory cytokines induced by pneumococcal cell walls in microglia. In a well-established rat model, intracisternal injection of purified pneumococcal cell walls induced meningitis characterized by increases in the regional cerebral blood flow and intracranial pressure, an influx of leukocytes, and high concentrations of tumor necrosis factor alpha (TNF-␣) in the cerebrospinal fluid. Compared with the values at the beginning of the experiment, intraperitoneal injection of tyrphostin AG 126 reduced the increases in regional cerebral blood flow (at 6 h, 127% ؎ 14% versus 222% ؎ 51% of the baseline value; P < 0.05) and intracranial pressure (at 6 h, 0.8 ؎ 2.4 versus 5.4 ؎ 2.0 mm of Hg; P < 0.05), the influx of leukocytes (at 6 h, 1,336 ؎ 737 versus 4,350 ؎ 2,182 leukocytes/l; P < 0.05), and the TNF-␣ concentration (at 6 h, 261 ؎ 188 versus 873 ؎ 135 pg/l; P < 0.05). These results demonstrate that inhibition of AG 126-sensitive tyrosine kinase pathways may provide new approaches for preventing excessive inflammation and reducing the increases in blood flow and intracranial pressure in the acute phase of bacterial meningitis.

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Section: Discussionsupporting

confidence: 85%

Tyrosine Kinase Inhibition Reduces Inflammation in the Acute Stage of Experimental Pneumococcal Meningitis

et al. 2004

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“…Fink et al implanted a fibrin clot containing live E. coli in the peritoneal cavity of dogs, which increased cardiac output and decreased blood pressure and systemic vascular resistance (SVR) (85). This canine sepsis model has been used for drug evaluation (86)(87)(88)(89). Recently a new canine sepsis model induced by intrabronchial Staphylococcus aureus administration has been developed (90).…”

Section: Large Animal Models and Bacterial Infusion/inoculationmentioning

confidence: 99%

Animal models of sepsis and sepsis-induced kidney injury

Doi

Leelahavanichkul²,

Yuen³

et al. 2009

J. Clin. Invest.

491

424

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Sepsis and sepsis-induced acute kidney injury: a life-threatening conditionSepsis is a characteristic set of systemic reactions to overwhelming infection. Sepsis, severe sepsis, and septic shock are defined according to established criteria (Table 1) (1). Discovery of antibiotics has dramatically improved the morbidity and mortality of the infectious diseases for the last decades; indeed, antibiotics and volume resuscitation are the first line of sepsis treatment strategy (2). However, overwhelming inflammatory response accompanied by depression in immunological function causes multiple organ injury and determines clinical outcomes. In addition to inflammation and immunological dysregulation, a number of different mechanisms contribute to sepsis at different phases (Figure 1). For instance, systemic hemodynamics evolves from an early hyperdynamic ("warm shock") state to a late hypodynamic ("cold shock") state.Sepsis is the leading cause of death in critically ill patients, and the incidence of sepsis is increasing (3, 4). The mortality rate of severe sepsis is very high (up to 70%), and the calculated costs exceed $15 billion per year in the United States (3). The rate of severe sepsis during hospitalization almost doubled during the last decade and is considerably greater than previously predicted (5). Sepsis causes multiorgan failure, including acute kidney injury (AKI) (6), and patients with both sepsis and AKI have an especially high mortality rate (7). AKI is diagnosed by a sudden decrease in glomerular filtration rate (GFR), the primary measure of kidney function, which is currently detected clinically as a rise in serum creatinine. A multinational prospective observational study including 29,269 critically ill patients revealed that the occurrence of AKI in the intensive care unit (ICU) was approximately 6%, the most frequent contributing factor to AKI being sepsis (50%) (8). Other reports showed that between 45% and 70% of all AKI is associated with sepsis (9-11). Several different pathophysiological mechanisms have been proposed for sepsis-induced AKI: vasodilation-induced glomerular hypoperfusion, dysregulated circulation within the peritubular capillary network, inflammatory reactions by systemic cytokine storm or local cytokine production (12), and tubular dysfunction induced by oxidative stress (13).Continuing concern over the efficacy and safety of the only FDAapproved therapy for severe sepsis (activated protein C) highlights the critical need to improve our understanding of the pathophysiology of sepsis and sepsis-induced AKI and to develop novel treatment strategies for critically ill patients (14). A multitude of potential drug targets have been identified in animal models of sepsis; however, translation from animals to humans has been exceedingly difficult. Several reviews have pointed out that the failure to translate results from animals to humans has been attributed to disease characteristics of sepsis (complexity and heterogeneity), inappropriate clinical trials (study of ineffective drugs...

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“…In the lung, the positive effects of AG126 and AG556 have been attributed to the suppressed iNOS and COX-2 protein expression and activity. AG126 and AG556 have been studied in canine Escherichia coli sepsis also 19 . While AG556 significantly lowered the serum TNF levels, thus preventing cytokine-induced multiorgan failure and death, AG126 on whole, did not show such therapeutic effect in this model.…”

Section: Tyrphostins In Sepsis Modelsmentioning

confidence: 99%

“…Later, a broad spectrum of biological activities have been added like antioxidant, increase of cellular glutathione level, suppression of poly ADP (adenosine diphosphate)-ribose polymerase (PARP) activation 11 , as well as these compounds potentiate the expression of some redox-sensitive genes associated to mitogen-activated protein kinase (MAPK), AP-1 and Nrf2 factors 12,13 . TYK inhibitors, except being broadly used in cancer clinical trials 14 , have also been evaluated in animal models of type 1 diabetes 15,16 , multiple sclerosis 17 , intestinal inflammation 18 and septic shock 19 . A number of studies have shown that in general tyrphostins express their anti-inflammatory activity by modulation of pro-inflammatory gene expression, such as cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS) and several pivotal cytokines ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Tyrphostins as a promising therapeutic tool in inflammation-related conditions

Dimitrova¹,

Ivanovska²

2013

OA Inflammation

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IntroductionProtein kinases regulate the expression of many genes that are pivotal for inflammation. This review aims to summarise data on a group of small molecules capable to inhibit tyrosine kinases (TYKs), named tyrphostins. They are derivatives of benzylidenemalonitrile that decrease tyrosine phosphorylation, thereby affecting not a single mediator, but cell signalling transduction is affected. No single animal model fully represents the human disease, but these models provide valuable tools to understand particular pathways. In this review, we describe some of the recent investigations on tyrphostins as anti-inflammatory agents in vivo in animal models, and in vitro in cell culture systems. ConclusionIt is anticipated that tyrphostins are suitable for the treatment of inflammation-related diseases. Future research is required to understand the mechanisms of their action to pave way for gaining pharmacological benefits in clinical practice.

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Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Cited by 48 publications

References 37 publications

Tyrosine Kinase Inhibition Reduces Inflammation in the Acute Stage of Experimental Pneumococcal Meningitis

Tyrosine Kinase Inhibition Reduces Inflammation in the Acute Stage of Experimental Pneumococcal Meningitis

Animal models of sepsis and sepsis-induced kidney injury

Tyrphostins as a promising therapeutic tool in inflammation-related conditions

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