Aprotinin preserves myocardial biochemical function during cold storage through suppression of tumor necrosis factor

Bull, David A.; Connors, Rafe C.; Albanil, Aida; Reid, B.B.; Neumayer, Leigh; Nelson, Rebecca; Stringham, James C.; Karwande, Shreekanth V.

doi:10.1016/s0022-5223(00)70179-6

Cited by 19 publications

(21 citation statements)

References 11 publications

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“…Thus, while aprotinin favorably affects hemostasis, which is an important determinant of morbidity and mortality in the context of I/R and cardiac surgery, aprotinin likely influences other biological processes which impart deleterious effects. Aprotinin has been shown, particularly at the full Hammersmith dose, to modify cytokine levels, such as TNF 5–6. However, the inter-relationship between aprotinin, LV functional recovery following a period of I/R, and cytokine receptor activation remained unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Aprotinin likely imparts multiple effects on a number of pathways, one of which includes the tumor necrosis factor-alpha (TNF) receptor pathway. Past studies have suggested that aprotinin may affect TNF levels 5–6. TNF is synthesized and in initially bound to the membrane requiring proteolytic cleavage to yield a soluble form which can then bind to the TNF receptor I (TNFRI) and/or TNFRII 7–8.…”

Section: Introductionmentioning

confidence: 99%

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Aprotinin Exacerbates Left Ventricular Dysfunction After Ischemia/Reperfusion in Mice Lacking Tumor Necrosis Factor Receptor I

Sabbagh¹,

Looper²,

Zavadzkas³

et al. 2008

Journal of Cardiovascular Pharmacology

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Aprotinin is a serine protease inhibitor with diverse biological effects, and up until recently was utilized in the context of ischemia/reperfusion (I/R). It has been hypothesized, that a signaling pathway modulated by aprotinin in the context of I/R is the tumor necrosis factor-alpha receptor (TNFR) pathway. An intact mouse model of I/R (30 min-I/60 min-R) was used and LV peak + dP/ dt was measured in wild type mice (WT, C57BL/6; n=10), WT mice with aprotinin (4mL/kg; n=10), transgenic mice devoid of the TNFRI (TNFRInull; n=10), and TNFRInull with aprotinin (n=10). Following I/R, LV peak + dP/dt decreased in both WT groups, but remained similar to baseline values in the TNFRInull group. In contrast, aprotinin caused a marked reduction in LV peak + dP/dt in the TNFRInull group following I/R. Soluble plasma TNF levels increased in the WT and TNFRInull mice with I/R, and was reduced with aprotinin. Soluble TNFRI and TNFRII levels, indicative of TNF activation increased in the WT mice following I/R and remained elevated with aprotinin. Soluble TNFRII levels were increased in the TNFRInull mice following I/R and remained elevated with aprotinin. The new and unique findings of this study were two fold. First, aprotinin failed to improve LV function after I/R despite a reduction in circulating TNF levels. Second, genetic ablation of the TNFRI uncovered a negative inotropic effect of aprotinin. These findings demonstrate that complex biological pathways and interactions are affected with broad spectrum serine protease inhibition, which are relevant to myocardial function in the context of I/R.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aprotinin Exacerbates Left Ventricular Dysfunction After Ischemia/Reperfusion in Mice Lacking Tumor Necrosis Factor Receptor I

Sabbagh¹,

Looper²,

Zavadzkas³

et al. 2008

Journal of Cardiovascular Pharmacology

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“…This suggested that actions of aprotinin include the prevention of upregulation of neutrophil CD11b integrin necessary for neutrophil adherence and degranulation, suppression of the plasma increases of the proinflammatory cytokines IL-6 and IL-8 and enhancement of the release of the anti-inflammatory cytokine IL-10 [47, 48]. Moreover, aprotinin has been shown in vitro to inhibit TNF secretion from activated macrophages by 51% and to reduce elastase release from neutrophils [49, 50]. …”

Section: Discussionmentioning

confidence: 99%

Effects of Vitamin E, Pentoxifylline and Aprotinin on Light-Induced Retinal Injury

Yılmaz

Aydemir²,

Özercan³

et al. 2007

Ophthalmologica

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Purpose: A considerable amount of clinical and experimental evidence exists suggesting the involvement of reactive oxygen species (ROS) in the etiology of light-induced retinal injury. The aim of this study was to investigate the protective role of vitamin E, pentoxifylline (PTX) and aprotinin against light-induced retinal injury in guinea pigs. Methods: Thirty adult male guinea pigs were divided into 5 groups of 6 animals each. The first group was used as control. The guinea pigs were kept in cyclic light for 2 weeks before the experiments. The animals were maintained in 12-hour light-dark cycles, before and after exposure to intense white fluorescent light, for as long as 12 h and then returned to cyclic light. Groups 3–5 received intraperitoneal injections of vitamin E, PTX and aprotinin, respectively. One eye of each animal was selected for histopathological evaluation and the other for biochemical assay. Retinal malondialdehyde (MDA) levels and the thickness of the outer nuclear layers were measured. Results: The compounds had the following relationships: vitamin E more than PTX more than aprotinin in preventing light-induced retinal damage. All 3 gave significant protection against the formation of MDA. Retinas of all 3 treatment groups had been protected from light-induced injury. Conclusion: The intraperitoneal vitamin E, PTX and aprotinin supplementations may strengthen the antioxidant defense system because of decreased ROS, and these agents may play a role in treating light-induced retinal injury.

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“…Endogenous BPTI not only inhibits trypsin, but acts as an inhibitor for chymotrypsin, plasmin and kallikreine (Barbar et al, 2001;Hagihara et al, 2002). BPTI was applied as a potential treatment for acute pancreatitis and coagulation disorders, and hemorrhage in surgery (Bull et al, 2000;Molenaar et al, 2001). BPTI also demonstrated an inhibiting role of protease inhibitors in inflammation.…”

Section: Introductionmentioning

confidence: 99%

Recombinant bovine pancreatic trypsin inhibitor protects the liver from carbon tetrachloride-induced chronic injury in rats

Dong¹,

Lv²,

Wang

et al. 2013

Pharmaceutical Biology

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(2013) Recombinant bovine pancreatic trypsin inhibitor protects the liver from carbon tetrachloride-induced chronic injury in rats, Pharmaceutical Biology, 51:10, 1298-1303, DOI: 10.3109/13880209.2013 Context: Bovine pancreatic trypsin inhibitor (BPTI) has been reported to relieve liver ischemiareperfusion-induced injury in rats. Objective: This study was designed to determine whether the recombinant BPTI (rBPTI) can prevent the chronic liver injury induced by CCl 4 in rats. Materials and methods: Fifty male Wistar rats were divided into five groups. Rats were treated with 40% CCl 4 at a dose of 2 ml/kg body weight twice a week subcutaneously for 12 weeks. In the 8th week, they were administered intraperitoneally with rBPTI (80 MU/kg), BPTI (80 MU/kg) or hepatocyte growth-promoting factor (pHGF; 100 mg/kg) daily for the next 4 weeks. Results: rBPTI significantly prevented the disruption of liver function of alanine aminotransferase (ALT; 172.7 AE 18.16 versus 141.2 AE 15.28, p ¼ 0.003), aspartate aminotransferase (AST; 225.10 AE 36.54 versus 170.06 AE 27.14, p ¼ 0.007) and hydroxyproline (Hyp; 1.14 AE 0.27 versus 0.62 AE 0.17, p ¼ 0.001). rBPTI significantly decreased the level of thiobarbituric acid reactive substances (TBARS; 1.15 AE 0.16 versus 0.87 AE 0.15, p ¼ 0.003) and increased the activities of superoxide dismutase (SOD; 6.07 AE 0.95 versus 7.75 AE 1.12, p ¼ 0.007). rBPTI reduced the production of cytokines of IL-1b and TGF-b. The hepatocyte necrosis, fibrosis, fatty degeneration and inflammatory cell infiltration were ameliorated by rBPTI administration. Conclusion: This study demonstrated that rBPTI exerted a hepatoprotective effect on chronic liver fibrosis induced by CCl 4 , which suggests that rBPTI may have the potential application for chronic liver injury induced by drugs metabolism and toxic substances.

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Aprotinin preserves myocardial biochemical function during cold storage through suppression of tumor necrosis factor

Abstract: Aprotinin preserves myocardial biochemical function during cold storage. This preservation of biochemical function is mediated through suppression of the release, uptake, and activity of tumor necrosis factor alpha.

Cited by 19 publications

References 11 publications

Aprotinin Exacerbates Left Ventricular Dysfunction After Ischemia/Reperfusion in Mice Lacking Tumor Necrosis Factor Receptor I

Aprotinin Exacerbates Left Ventricular Dysfunction After Ischemia/Reperfusion in Mice Lacking Tumor Necrosis Factor Receptor I

Effects of Vitamin E, Pentoxifylline and Aprotinin on Light-Induced Retinal Injury

Recombinant bovine pancreatic trypsin inhibitor protects the liver from carbon tetrachloride-induced chronic injury in rats

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