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Biomedical subjects

G E Hill

Publications and source records attributed to G E Hill.

At least 19 recordsLinked to original sources
PubMed2000

Differential effects of endoparasitism on the expression of carotenoid- and melanin-based ornamental coloration.

The striking diversity of sexual dimorphisms in nature begs the question: Why are there so many signal types? One possibility is that ornamental traits convey different sets of information about the quality of the sender to the receiver. The colourful, pigmented feathers of male birds seem to meet the predictions of this hypothesis. Evidence suggests that carotenoid pigmentation reflects the nutritional condition of males during moult, whereas in many instances melanin pigmentation is a reliable indicator of social status. However, as of yet there have been no experimental tests to determine how these two ornament types respond to the same form of environmental stress. In this study, we tested the effect of endoparasitic infection by intestinal coccidians (Isospora sp.) on the expression of both carotenoid- and melanin-based ornamental coloration in captive male American goldfinches (Carduelis tristis). We found that the carotenoid-based plumage and bill coloration of parasitized males was less saturated than that developed by unparasitized males, but that the brightness and size of melanin-based black caps did not differ between the groups. These findings provide the most robust empirical support to date for the notion that carotenoid and melanin ornaments reveal different information to conspecifics.

Animals↗
PubMed1999

Ketamine inhibits agonist-induced cAMP accumulation increase in human airway smooth muscle cells.

PURPOSE: Cyclic 3',5' adenosine monophosphate (cAMP) is a second messenger of the beta adrenergic receptor (betaAR). Ketamine causes an increase in the intracellular accumulation of cAMP in several non-human tissue preparations. A "species effect" may explain the differing results of ketamine on betaAR mediated responses, thus reports of a ketamine-induced increase in cAMP in other species may not be applicable to humans. METHODS: The effect of ketamine (10(-3), 10(-4), or 10(-5) M) pretreatment (60 and 120 min) on isoproterenol [ISO, a beta adrenergic receptor (AR) agonist] or forskolin [FSK, an activator of adenylylcyclase (AC)]-induced intracellular accumulation of cAMP in a human airway smooth muscle (tracheal) cell line (HASM) was evaluated. In an in vitro HASM culture, cells with or without pretreatment were labeled with [3H]adenine to produce [3H]ATP, and following stimulation with ISO or FSK to convert the [3H]ATP to [3H]cAMP, the intracellular accumulation of [3H]cAMP was measured by sequential chromatography over Dowex and alumina columns. RESULTS: Pretreatment of the HASM cells with ketamine (10(-3) and 10(-4) M) caused a reduction (P < 0.05, when compared to untreated cells) in ISO-induced cAMP accumulation, but did not effect cAMP accumulation following FSK stimulation. This effect of ketamine was greater at 120 min of pretreatment than at 60 min (10(-3) M ketamine only)(P < 0.05). No effect was found at either time period following pretreatment of the HASM cells with ketamine 10(-5) M. CONCLUSIONS: These results demonstrate that pretreatment of the HASM cells with ketamine reduces ISO-induced cAMP accumulation. Since only ISO-induced cAMP was effected by ketamine, these data suggest that ketamine inhibits production of cAMP proximal to AC in the cAMP production pathway. These results also demonstrate that a mechanism other than that involving the betaAR and intracellular cAMP accumulation is responsible for the ketamine induced bronchodilation in humans.

Adenylyl Cyclases↗
PubMed1999

Pump prime only aprotinin inhibits cardiopulmonary bypass-induced neutrophil CD11b up-regulation.

BACKGROUND: The expression of neutrophil integrin CD11b is up-regulated after cardiopulmonary bypass (CPB) and is the neutrophil adhesive molecule of most importance in neutrophil- endothelial adherence. This neutrophil-endothelial adherence is responsible for post-CPB neutrophil-induced reperfusion injury. Low-dose aprotinin protocols inhibit the CPB-induced neutrophil CD11b up-regulation. This investigation was undertaken to evaluate the effects of pump prime only aprotinin (280 mg) on the CPB-induced up-regulation of this neutrophil integrin. METHODS: Twenty-two patients scheduled for elective myocardial revascularization were randomized into two groups: (1) control (n = 12), or (2) pump prime only aprotinin (280 mg) (n = 10). Neutrophils were isolated at baseline, 50 minutes of CPB, and 30 minutes after CPB and neutrophil CD11b expression was measured. RESULTS: The control group demonstrated a significant (p < 0.05) increase in neutrophil CD11b immunofluorescent staining at 50 minutes of CPB and at 30 minutes after CPB when compared to same group baseline and to the pump prime only aprotinin group at similar time intervals. CONCLUSIONS: These results indicate that pump prime only aprotinin modulates the CPB-induced up-regulation of neutrophil CD11b integrin, an important indicator of the systemic inflammatory response to CPB. In addition to blunting of the CPB-induced up-regulation of this neutrophil integrin expression, this pump prime only dose of aprotinin is also reported to be effective at reducing post-CPB bleeding and transfusion requirements. This salutary effect of pump prime only aprotinin suggests that such low-dose regimens can be both therapeutically effective and cost effective.

Aged↗
PubMed1998

Plasma lipid concentrations correlate inversely with CPB-induced interleukin-6 release.

PURPOSE: Cardiopulmonary bypass (CPB) is characterized by translocation of intestinal endotoxin and subsequent endogenous production of the pro-inflammatory cytokine interleukin-6 (IL-6). Plasma lipid fractions, especially high density lipoproteins, bind and neutralize endotoxin and, therefore, inhibit endotoxin-induced macrophage cytokine production, including IL-6. Increased IL-6 plasma levels have been implicated in adverse consequences associated with CPB. Previous studies demonstrated large interpatient variability in IL-6 plasma levels after CPB. The purpose of this study was to evaluate the relationship between plasma lipid concentrations and the concentrations of IL-6 following CPB in humans. METHODS: In a prospective study, a group of 15 patients selected to exclude variables known to influence post-CPB plasma levels of IL-6 (preoperative left ventricular ejection fraction > 45%, similar durations of aortic cross clamping and total CPB time, similar temperature control during CPB, and avoidance of platelet transfusion and shed mediastinal blood re-infusion), IL-6 was measured at baseline, one and 24 hr post-CPB. RESULTS: Interleukin-6 plasma concentrations (mean +/- SD) increased at one (142 +/- 89 pg.ml-1, P < 0.05) and 24 (129 +/- 82 pg.ml-1, P < 0.05) hr post-CPB compared with baseline (1.5 +/- 1 pg.ml-1) concentrations. An inverse correlation was found between IL-6 plasma concentrations at one hour post-CPB and plasma cholesterol concentrations (r = -0.592, P = 0.02), high density lipoprotein (r = -0.595, P = 0.02), and low density lipoprotein (r = -0.656, P = 0.01). CONCLUSIONS: These results suggest that plasma lipids attenuate the production of IL-6 during CPB and may partly explain the variability of interpatient levels of IL-6 reported post-CPB by others.

Aged↗
PubMed1998

Aprotinin enhances the endogenous release of interleukin-10 after cardiac operations.

BACKGROUND: Cardiopulmonary bypass (CPB) is characterized by the systemic release of proinflammatory cytokines, such as tumor necrosis factor-alpha and the interleukins 1 and 6, as well as endogenous antiinflammatory cytokines, including interleukin-10 (IL-10). Glucocorticoids reduce tumor necrosis factor-alpha plasma concentrations while enhancing IL-10 plasma concentrations after CPB. Aprotinin, a serine protease inhibitor used primarily to reduce blood loss after CPB, reduces CPB-induced proinflammatory cytokine tumor necrosis factor-alpha release similarly to glucocorticoids. This study evaluates the effect of full-dose aprotinin on the plasma concentrations of IL-10 after CPB. METHODS: Twenty adults were randomized into a control (group C, n = 10) and a full-dose aprotinin-treated group (group A, n = 10). Plasma levels of IL-10 were measured by enzyme-linked immunosorbent assay technique at baseline (before anesthetic induction), and at 1 and 24 hours after CPB termination. RESULTS: A significant (p < 0.05) increase of IL-10 occurred in both groups at 1 and 24 hours after termination of CPB when compared with the same group at baseline. In group A, the increase in IL-10 was significantly greater than in group C (p < 0.05) at 24 hours after CPB. CONCLUSIONS: These results demonstrate an endogenous antiinflammatory response generated after CPB, characterized by IL-10 release, that is enhanced by aprotinin therapy. This study demonstrates a unique antiinflammatory activity of aprotinin that may be of clinical significance.

Aprotinin↗
PubMed1998

Association of malondialdehyde-acetaldehyde (MAA) adducted proteins with atherosclerotic-induced vascular inflammatory injury.

Atherosclerosis is a vascular injury characterized by elevated tissue levels of tumor necrosis factor-alpha (TNF-alpha), increased expression of endothelial cell adhesion molecules, and vascular wall inflammatory cell infiltration. Foam cells are associated with atherosclerotic plaque material, and low density lipoprotein (LDL) is a lipid component of foam cells. Malondialdehyde (MDA) is an oxidative product of unsaturated fatty acids and is also present in atherosclerotic lesions. MDA-modified (adducted) proteins, including MDA-modified LDL, are present in atherosclerotic human vascular tissue. Acetaldehyde (AA) is the major metabolic product of ethanol oxidation. Both MDA and AA are highly reactive aldehydes and will combine with proteins to produce an antigenically distinct protein adduct, termed the MAA adduct. This study demonstrates that proteins modified in the presence of high concentrations of MDA can produce MAA-modified proteins in vitro. In addition, MAA adducted proteins are capable of inducing rat heart endothelial cell cultures (rHEC) to produce and release TNF-alpha, and cause rHEC upregulation of endothelial adhesion molecule expression, including ICAM-1. These adhesion molecules are required for circulating inflammatory cells to adhere to endothelium which allows inflammatory cell tissue infiltration. Additionally, MAA modified proteins were defected in human atherosclerotic aortic vascular tissue but not in normal aortic tissue. Since atherosclerosis is associated with an inflammatory vascular injury characterized by elevated tissue TNF-alpha concentrations and inflammatory cell infiltration, these data suggest that MAA-adducted proteins may be formed in atherosclerotic plaque material and may be involved in the inflammatory reaction that occurs in atherosclerosis. These data further suggest that previous studies demonstrating MDA modified protein in atherosclerotic plaque may in fact have MAA modified proteins associated with them.

Acetaldehyde↗
PubMed1998

Cardiovascular stability during carotid endarterectomy: endotracheal intubation versus laryngeal mask airway.

STUDY OBJECTIVE: To compare cardiovascular stability during carotid endarterectomy in groups managed either with laryngeal mask airway (LMA) or endotracheal intubation. DESIGN: Randomized, retrospective, blinded study. SETTING: Teaching hospital. PATIENTS: 61 ASA physical status II, III, and IV unpremedicated adult males scheduled for carotid endarterectomy. INTERVENTIONS: Following standardized anesthetic technique, including intravenous (i.v.) induction with thiopental sodium 3 to 4 mg/kg, fentanyl 2 to 3 microg/kg), and isoflurane, standard intraoperative cardiovascular monitoring plus direct arterial blood pressure measurements were instituted. Patients were randomly assigned to an endotracheal intubation or LMA group. MEASUREMENTS AND MAIN RESULTS: Distinct intraoperative episodes of +/- 25% increase or decrease of mean arterial blood pressure (MABP) and heart rate (HR) when compared with preinduction baseline values, and the number of such episodes requiring interventional therapy were recorded from a blinded anesthesia record retrospectively. Mean end-tidal isoflurane determination and total case duration enabled calculation of minimum alveolar concentration (MAC) hours of isoflurane administered. The LMA group had a significantly (p < 0.05) lower incidence of increased MABP and HR episodes and such episodes requiring drug therapy than did the endotracheal intubation group. No difference was found in the length of surgery, mean end-tidal isoflurane concentration, or the total number of MAC hours of isoflurane administered. CONCLUSIONS: During carotid endarterectomy, a reduced incidence of hypertensive and tachycardic episodes, as well as such episodes requiring interventional drug therapy, was found in the group whose airway is managed by LMA when compared with endotracheal intubation.

Aged↗
PubMed1998

Aprotinin reduces nitric oxide production in vitro and in vivo in a dose-dependent manner.

1. Cardiopulmonary bypass is associated with an increase in nitric oxide concentrations, and plasma levels of tumour necrosis factor and interleukin-1. Aprotinin, a serine protease inhibitor, commonly used during cardiopulmonary bypass to reduce blood loss, has been demonstrated to exhibit significant anti-inflammatory effects during and after cardiopulmonary bypass. 2. Airway nitric oxide was measured during cardiopulmonary bypass in 10 controls (Group 1), 10 subjects receiving half-dose aprotinin (Group 2) and 10 patients receiving full-dose aprotinin (Group 3). In vitro, a murine bronchial epithelial cell line (LA-4) was cultured with cytomix (a combination of tumour necrosis factor, interleukin-1, and (gamma-interferon) with and without aprotinin in increasing concentrations. Nitrite concentrations, the stable and measureable end-product of nitric oxide oxidative metabolism, were measured in the culture supernatant by chemiluminescence. 3. Airway nitric oxide concentrations were increased after 50 min cardiopulmonary bypass compared with that measured at 5 min in controls (53 +/- 5 versus 29 +/- 3 ppb, P < 0.05) but not in the aprotinin-treated groups (25 +/- 4 versus 14 +/- 5, Group 2; 21 +/- 6 versus 15 +/- 3 ppb, Group 3). 4. In a dose-dependent manner, nitrite levels (means +/- S.E.M.) were significantly reduced by aprotinin at 500 and 1000 units/ml when compared with cells cultured in the presence of cytomix alone (P < 0.05). 5. These data demonstrate that aprotinin, in a dose-responsive manner, reduces nitric oxide production in vivo and reduces cytokine-induced nitrite production by murine bronchial epithelial cells in vitro. Since increased airway nitric oxide is found in inflammatory lung diseases, like asthma, and anti-inflammatory therapy reduces the concentration of airway nitric oxide, these data support the concept that aprotinin is anti-inflammatory during cardiopulmonary bypass.

Aged↗
PubMed1998

Does the duration of cardiopulmonary bypass or aortic cross-clamp, in the absence of blood and/or blood product administration, influence the IL-6 response to cardiac surgery?

UNLABELLED: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response characterized by release of proinflammatory cytokines, including interleukin 6 (IL-6). Recent reports suggest that plasma IL-6 is increased after CPB. Previous studies evaluating the influence of duration of CPB and/or aortic cross-clamp time on the release of IL-6 are conflicting. Infusion of blood and blood products during these studies may have influenced plasma concentrations of proinflammatory cytokines by inducing host cell (monocyte) activation and IL-6 release. The purpose of our investigation was to determine, in an environment free from blood and/or blood product administration, the influence of duration of CPB and/or aortic cross-clamp on the magnitude of the IL-6 response in patients undergoing cardiac surgery. We prospectively evaluated plasma IL-6 levels preinduction (T0) and at sternal closure in 16 patients undergoing CPB (coronary artery bypass grafting, n = 9; valvular cardiac surgery, n = 7) to determine whether there is a correlation between the absolute increase in IL-6 and the duration of CPB or aortic cross-clamp time. None of the patients received blood and/or blood products during the study to control for the introduction of additional activated cells and soluble mediators, including IL-6. The results demonstrate that the magnitude of the IL-6 response to CPB is positively correlated with the duration of CPB but not with duration of aortic cross-clamp. It seems that induction of IL-6 release is part of a normal response to CPB and does not depend on activation of host cells during prolonged aortic cross-clamp. The activation or presence of inflammatory cytokines associated with administration of blood and/or blood products could have influenced previously published investigations relating the influence of duration of CPB and/or aortic cross-clamp time to the magnitude of the IL-6 response. IMPLICATIONS: This study found a positive correlation between the magnitude of the interleukin 6 response to cardiopulmonary bypass and duration of cardiopulmonary bypass (but not duration of aortic cross-clamp) when measurements were made in the absence of blood/blood product transfusion. Future studies evaluating strategies to reduce cytokine responses to cardiopulmonary bypass should therefore control for cardiopulmonary bypass duration.

Adult↗
PubMed1998

Ketamine inhibits the proinflammatory cytokine-induced reduction of cardiac intracellular cAMP accumulation.

UNLABELLED: The proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), are increased in heart failure and sepsis, clinical conditions for which the IV anesthetic ketamine is useful. The proinflammatory cytokines cause beta-adrenergic receptor (betaAR) hypofunction secondary to reduced function of the enzyme adenylylcyclase (AC). In this study, we evaluated the effect of ketamine alone, TNF-alpha and IFN-gamma, and ketamine plus TNF-alpha and IFN-gamma, on isoproterenol (ISO, a betaAR agonist) and forskolin (FSK, an activator of AC)-induced intracellular accumulation of cAMP. An in vitro culture of a rat heart cell line (H9c2) was labeled with [3H]adenine to produce [3H]ATP, and we measured the intracellular accumulation of [3H]cAMP after stimulation with ISO or FSK to convert the [3H]ATP to [3H]cAMP. Pretreatment with either cytokine alone did not significantly affect ISO or FSK-induced intracellular cAMP accumulation, whereas the combination of TNF-alpha and IFN-gamma caused a significant (P < 0.05 compared with untreated cells) reduction. Pretreatment with ketamine caused a significant (P < 0.05 compared with untreated cells) increase in ISO or FSK-induced cAMP accumulation. Pretreatment of the H9c2 cells with ketamine, plus the combination of TNF-alpha and IFN-gamma, inhibited the reduction of ISO or FSK-induced intracellular cAMP accumulation caused by the proinflammatory cytokines alone. These results demonstrate that the combination of the proinflammatory cytokines TNF-alpha and IFN-gamma reduce poststimulation (ISO or FSK) intracellular cAMP accumulation. This action of the proinflammatory cytokines is consistent with the observation of betaAR hyporesponsiveness to betaAR agonist therapy in sepsis and heart failure. Ketamine augments the poststimulation cAMP accumulation in H9c2 cells while inhibiting the cytokine-induced reduction of cAMP accumulation. This may partly explain the improvement in cardiac function after ketamine use in clinical conditions known to have increased systemic levels of proinflammatory cytokines, such as sepsis and heart failure. IMPLICATIONS: Tumor necrosis factor-alpha and interferon-gamma reduced poststimulation intracellular cAMP levels, whereas ketamine inhibits this action of the proinflammatory cytokines. Because cAMP is the second messenger for the beta-adrenergic receptor, this may be a mechanism for improved blood pressure and cardiac output in sepsis and heart failure after ketamine use.

Adrenergic beta-Agonists↗
PubMed1998

Cardiopulmonary bypass-induced inflammation: is it important?

The systemic endotoxemia that occurs with the institution of cardiopulmonary bypass (CPB) is a potent stimulus for the release of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. Raised IL-6 levels have been reported to correlate with post-CPB left ventricular wall-motion abnormalities and myocardial ischemic episodes. Neutrophil-endothelial adhesion is strongly implicated in the inflammation and reperfusion injury that may follow a period of CPB, and organ injury is thought to be, in part, neutrophil mediated. The CD11b neutrophil integrin primarily responsible for endothelial binding is rapidly, permanently, and preferentially expressed on exposure to cytokines. The endothelial ligand intercellular adhesion molecule-1 is also upregulated by cytokine exposure. Nitric oxide (NO) synthesized by the vascular endothelium can inhibit neutrophil-endothelial adhesion by downregulating CD11b/CD18 receptor expression and inhibit platelet activation. The cytokines TNF-alpha, IL-1, and endotoxin can cause the induction of NO synthase and the release of large amounts of NO that may cause tissue injury. Various treatment strategies to reduce CPB-induced inflammation provide evidence to support the causal relationship between CPB-activated cytokine release, neutrophil activation, and stimulation of increased NO synthesis. The significant reductions in TNF-alpha and IL-6 levels with hemofiltration during CPB in children are associated with improved hemodynamics and early postoperative oxygenation. Acadesine can inhibit the upregulation of leukocyte CD11b adhesion receptors, and treatment in patients before and during surgery can reduce early cardiac death, myocardial infarction, and combined adverse cardiovascular outcomes. Recent data suggest that administration of the serine protease inhibitor aprotinin to patients undergoing myocardial revascularization with CPB can reduce TNF-alpha blood levels and blunt neutrophil CD11b upregulation. Preliminary data suggest that aprotinin can inhibit cytokine-induced nitric oxide synthase expression and subsequent NO production by murine bronchial epithelial cells. These effects may explain some of the reported antiinflammatory effects of the serine protease inhibitors.

Aminoimidazole Carboxamide↗
PubMed1997

Differing effects of aprotinin and epsilon-aminocaproic acid on cytokine-induced inducible nitric oxide synthase expression.

BACKGROUND: Cell expression of inducible nitric oxide synthase (iNOS) is increased by cytokines, resulting in high endogenous levels of nitric oxide. Expression of iNOS has been implicated in organ injury, including myocardial reperfusion injury. Serine protease inhibitors reduce cytokine-induced iNOS expression. The protease inhibitors aprotinin and epsilon-aminocaproic acid (EACA), used to reduce blood loss after cardiac operations, were evaluated in vitro on cytokine-induced iNOS expression and nitric oxide production. METHODS: A murine bronchial epithelial cell line was stimulated with a mixture of cytokines (tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma) with or without aprotinin or EACA. The resultant iNOS expression was measured by northern blot analysis, and nitric oxide production was assessed by cell supernatant nitrite levels. RESULTS: Nitrite concentrations in the supernatant were significantly increased after cytokine stimulation; they were not affected by any concentration of EACA but were significantly (p < 0.05) reduced by aprotinin. Aprotinin significantly (p < 0.05) reduced cytokine-induced iNOS expression, whereas EACA had no effect. CONCLUSIONS: Aprotinin, but not EACA, reduces cytokine-induced nitric oxide production by inhibition of iNOS expression. Because increased endogenous nitric oxide levels secondary to iNOS activation have been implicated in organ injury, aprotinin may have clinical benefit compared with EACA when used for cardiac operations.

Aminocaproic Acid↗
PubMed1997

Aprotinin is associated with a decrease in nitric oxide production during cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with an increase in airway nitric oxide (NO), plasma levels of tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta. Cytokine induction of the inducible form of nitric oxide synthase (iNOS) has been implicated in organ injury. In addition, serine protease inhibitors reduce cytokine-induced iNOS expression. Aprotinin, a serine protease inhibitor, has been demonstrated to exhibit significant antiinflammatory effects. We hypothesized that aprotinin administration during CPB would significantly reduce endogenous airway NO production. METHODS: Airway NO was measured during CPB in 10 patients receiving aprotinin and in 10 control subjects. In vitro, aprotinin was added to cultures of a murine lung epithelial cell line and was stimulated with cytomix, a combination of TNF, interleukin-1, and interferon-gamma. RESULTS: Airway NO concentration was increased after 50 minutes of CPB duration compared with that measured at 5 minutes in control subjects (53 +/- 5 versus 19 +/- 3 parts per billion, p < 0.05) but not in the aprotinin group (21 +/- 6 versus 15 +/- 3 parts per billion). Aprotinin reduced nitrite concentrations in the cell culture supernatant fluids after 24 hours (cytomix, 21.5 +/- 2.1 mumol/L; cytomix plus aprotinin, 2.7 +/- 0.6 mumol/L, p < 0.05). Immunohistochemistry showed a reduction in cytokine-induced iNOS expression and Northern blot analysis showed a decrease in iNOS mRNA. CONCLUSIONS: These data demonstrate that aprotinin reduces NO production in vivo and reduces cytokine-induced iNOS expression in vitro.

Animals↗
PubMed1997

The role of the vascular endothelium in inflammatory syndromes, atherogenesis, and the propagation of disease.

The vascular endothelium is intimately involved in a wide variety of normal physiological processes, including coagulation/anticoagulation, the maintenance of vascular tone, and pathological processes, including reperfusion injury, inflammatory syndromes, and tumor cell metastasis. This review discusses the importance of increased adhesive molecule expression on the endothelial surface in promoting circulating inflammatory cell-endothelial adherence in inflammatory conditions, as well as the role of the vascular endothelium in reperfusion injury, altered microvascular permeability states, and atherogenesis.

Arteriosclerosis↗
PubMed1997

The influence of cardiopulmonary bypass on cytokines and cell-cell communication.

Cardiopulmonary bypass (CPB) is characterized by systemic endotoxemia immediately after its onset as well as the systemic release of proinflammatory cytokines, including tumor necrosis factor-alpha and the interleukins 1 and 6. Recent studies document that increased morbidity and mortality rates correlate with elevated systemic concentrations of these proinflammatory cytokines during adult and neonatal sepsis, following thoracoabdominal aortic aneurysm repair, as well as following CPB. These proinflammatory cytokines induce increased neutrophil and endothelial surface adhesive molecule expression, thereby promoting enhanced neutrophil-endothelial adherence. Increased neutrophil-endothelial adherence and subsequent neutrophil organ binding are thought to be a "final common pathway" of organ injury during clinical inflammatory conditions. Proinflammatory cytokines also increase cellular expression of inducible nitric oxide synthase, thus increasing cellular production of nitric oxide, a known inflammatory mediator. This review discusses recent evidence of the adverse effects of proinflammatory cytokine release during CPB and therapeutic modalities that can reduce the systemic concentrations of these mediators of inflammation.

Adult↗
PubMed1997

Methylprednisolone and full-dose aprotinin reduce reperfusion injury after cardiopulmonary bypass.

OBJECTIVE: To compare the effects of low- and full-dose aprotinin to methylprednisolone (MPS) in reducing cardiopulmonary bypass (CPB)-induced interleukin-6 (IL-6) release. DESIGN: Prospective, randomized, blinded study. SETTING: Cytokine Laboratory, pharmacology department, in a university teaching hospital. PARTICIPANTS: Forty adult male human patients scheduled for myocardial revascularization were divided into four groups (n = 10): (1) control; (2) MPS, 1 g IV before CPB; (3) aprotinin-low-dose protocol; and (4) aprotinin-full-dose protocol. MEASUREMENTS AND MAIN RESULTS: Plasma levels of IL-6 were measured at baseline and 1 and 24 hours after CPB by enzyme-linked immunosorbent assay technique. Group 1 demonstrated a significant (p < 0.05) increase in IL-6 at 1 and 24 hours post-CPB. Groups 2 and 4 demonstrated significant (p < 0.05) reduction of IL-6 at 1 (group 2 only) and 24 (groups 2 and 4) hours post-CPB when compared with group 1 at the same time periods. CONCLUSIONS: These results demonstrate that MPS, 1 g before CPB, and full-dose aprotinin, but not half-dose aprotinin, achieve significant reduction in IL-6 release after CPB. These results further suggest that MPS and full-dose aprotinin may reduce reperfusion injury after CPB.

Aged↗
PubMed1997

Aprotinin but not tranexamic acid inhibits cytokine-induced inducible nitric oxide synthase expression.

Cell expression of inducible nitric oxide synthase (iNOS) is increased by cytokines, which results in high endogenous concentrations of nitric oxide (NO) and has been implicated in organ injury, including myocardial reperfusion injury. Serine protease inhibitors reduce cytokine-induced iNOS expression. The protease inhibitors aprotinin and tranexamic acid, which are used to reduce blood loss after cardiac surgery, were evaluated in vitro on cytokine-induced iNOS expression and the resulting NO production to demonstrate the relative antiinflammatory effects of each drug. A murine bronchial epithelial cell line (LA-4) was stimulated with cytomix (tumor necrosis factor alpha, interleukin 1beta, and gamma-interferon) with or without aprotinin, tranexamic acid, or N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK; a protease inhibitor). The resultant iNOS expression was measured by using Northern blot analysis and cell supernatant nitrite concentrations (in aqueous media, NO is oxidized primarily to nitrite, NO2-) by chemiluminescence. Nitrite concentrations in the supernatant were significantly increased by cytomix, not affected by any concentration of tranexamic acid, but significantly (P < 0.05) reduced by aprotinin and TLCK. Consistent with the nitrite reduction, aprotinin significantly (P < 0.05) reduced cytokine-induced iNOS expression, while tranexamic acid had no effect. Aprotinin but not tranexamic acid reduces endogenous cytokine-induced NO production by inhibiting iNOS expression. Since increased endogenous NO concentrations secondary to iNOS activation have been implicated in organ injury, aprotinin may have clinical benefits when compared with tranexamic acid.

Animals↗