Limiting Injury During Saphenous Vein Graft Preparation For Coronary Arterial Bypass Prevents Metabolic Decompensation.

Standard harvest and preparation of human saphenous vein (HSV) for autologous coronary and peripheral arterial bypass procedures is associated with injury and increased oxidative stress that negatively affect graft performance. In this study we investigated the global metabolomic profiles of HSV before (unprepared; UP) and after standard vein graft preparation (AP). AP-HSV showed impaired vasomotor function that was associated with increased oxidative stress, phospholipid hydrolysis and energy depletion that are characteristic of mechanical and chemical injury. A porcine model (PSV) was utilized to validate these metabolomic changes in HSV and to determine the efficacy of an improved preparation technique (OP) using pressure-regulated distension, a non-toxic vein marker, and graft storage in buffered PlasmaLyte solution in limiting metabolic decompensation due to graft preparation. Deficits in vasomotor function and metabolic signature observed in AP-PSV could be largely mitigated with the OP procedure. These findings suggest that simple strategies aimed at reducing injury during graft harvest and preparation represents a straightforward and viable strategy to preserve conduit function and possibly improve graft patency.

Outcomes of thoracic endovascular aortic repair using aortic arch chimney stents in high-risk patients.

BACKGROUND: Aortic arch disease is a challenging clinical problem, especially in high-risk patients, in whom open repair can have morbidity and mortality rates of 30% to 40% and 2% to 20%, respectively. Aortic arch chimney (AAC) stents used during thoracic endovascular aortic repair (TEVAR) are a less invasive treatment strategy than open repair, but the current literature is inconclusive about the role of this technology. The focus of this analysis is on our experience with TEVAR and AAC stents. METHODS: All TEVAR procedures performed from 2002 to 2015 were reviewed to identify those with AAC stents. Primary end points were technical success and 30-day and 1-year mortality. Secondary end points included complications, reintervention, and endoleak. Technical success was defined as a patient's surviving the index operation with deployment of the AAC stent at the intended treatment zone with no evidence of type I or type III endoleak on initial postoperative imaging. The Kaplan-Meier method was used to estimate survival. RESULTS: Twenty-seven patients (age, 69 ± 12 years; male, 70%) were identified, and all were described as being at prohibitive risk for open repair by the treating team. Relevant comorbidity rates were as follows: coronary artery disease/myocardial infarction, 59%; oxygen-dependent emphysema, 30%; preoperative creatinine concentration >1.8 mg/dL, 19%; and congestive heart failure, 15%. Presentations included elective (67%; n = 18), symptomatic (26%; n = 7), and ruptured (7%; n = 2). Eleven patients (41%) had prior endovascular or open arch/descending thoracic repair. Indications were degenerative aneurysm (49%), chronic residual type A dissection with aneurysm (15%), type Ia endoleak after TEVAR (11%), postsurgical pseudoaneurysm (11%), penetrating ulcer (7%), and acute type B dissection (7%). Thirty-two brachiocephalic vessels were treated: innominate (n = 7), left common carotid artery (LCCA; n = 24), and left subclavian artery (n = 1). Five patients (19%) had simultaneous innominate-LCCA chimneys. Brachiocephalic chimney stents were planned in 75% (n = 24), with the remainder placed for either LCCA or innominate artery encroachment (n = 8). Overall technical success was 89% (one intraoperative death, two persistent type Ia endoleaks in follow-up). The 30-day mortality was 4% (n = 1; intraoperative death of a patient with a ruptured arch aneurysm), and median length of stay was 6 (interquartile range, 4-9) days. Seven (26%) patients experienced a major complication (stroke, three [all with unplanned brachiocephalic chimney]; respiratory failure, three; and death, one). Nine (33%) patients underwent aorta-related reintervention, and no chimney occlusion events occurred during follow-up (median follow-up, 9 [interquartile range, 1-23] months). The 1-year and 3-year survival is estimated to be 88% ± 6% and 69% ± 9%, respectively. CONCLUSIONS: TEVAR with AAC can be performed with high technical success and acceptable morbidity and mortality in high-risk patients. Unplanned AAC placement during TEVAR results in an elevated stroke risk, which may be related to the branch vessel coverage necessitating AAC placement. Acceptable midterm survival can be anticipated, but aorta-related reintervention is not uncommon, and diligent follow-up is needed.

Femorofemoral Shunt During Surgery for Acute DeBakey Type 1 Dissection to Treat Peripheral Extremity Malperfusion.

Peripheral extremity ischemia in patients presenting with a DeBakey type 1 aortic dissection is an independent predictor for mortality. We present a patient with a DeBakey type 1 aortic dissection and peripheral extremity malperfusion that underwent simultaneous aortic repair and percutaneous femorofemoral shunt with arterial sidearm. Our approach allows for immediate peripheral extremity reperfusion and subsequent objective determination of the necessity of femorofemoral bypass via perfusion pressures.

Use of Brilliant Blue FCF during vein graft preparation inhibits intimal hyperplasia.

BACKGROUND: Intimal hyperplasia remains the primary cause of vein graft failure for the 1 million yearly bypass procedures performed using human saphenous vein (HSV) grafts. This response to injury is caused in part by the harvest and preparation of the conduit. The use of Brilliant Blue FCF (FCF) restores injury-induced loss of function in vascular tissues possibly via inhibition of purinergic receptor signaling. This study investigated whether pretreatment of the vein graft with FCF prevents intimal hyperplasia. METHODS: Cultured rat aortic smooth muscle cells (A7r5) were used to determine the effect of FCF on platelet-derived growth factor-mediated migration and proliferation, cellular processes that contribute to intimal hyperplasia. The effectiveness of FCF treatment during the time of explantation on preventing intimal hyperplasia was evaluated in a rabbit jugular-carotid interposition model and in an organ culture model using HSV. RESULTS: FCF inhibited platelet-derived growth factor-induced migration and proliferation of A7r5 cells. Treatment with FCF at the time of vein graft explantation inhibited the subsequent development of intimal thickening in the rabbit model. Pretreatment with FCF also prevented intimal thickening of HSV in organ culture. CONCLUSIONS: Incorporation of FCF as a component of vein graft preparation at the time of explantation represents a potential therapeutic approach to mitigate intimal hyperplasia, reduce vein graft failure, and improve outcome of the autologous transplantation of HSV.

MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia.

Autologous vein grafts are commonly used for coronary and peripheral artery bypass but have a high incidence of intimal hyperplasia (IH) and failure. We present a nanopolyplex (NP) approach that efficiently delivers a mitogen-activated protein kinase (MAPK)-activated protein (MAPKAP) kinase 2 inhibitory peptide (MK2i) to graft tissue to improve long-term patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smooth muscle cells revealed that formulation into MK2i-NPs increased cell internalization, endosomal escape, and intracellular half-life of MK2i. This efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of inflammatory cytokine production and migration in vascular cells. In intact human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as confirmed by reduced phosphorylation of the posttranscriptional gene regulator heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP (adenosine 3',5'-monophosphate) element-binding protein, and the chaperone heat shock protein 27. The molecular effects of MK2i-NPs caused functional inhibition of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant model, a 30-min intraoperative graft treatment with MK2i-NPs significantly reduced in vivo IH 28 days posttransplant compared with untreated or free MK2i-treated grafts. The decrease in IH in MK2i-NP-treated grafts in the rabbit model also corresponded with decreased cellular proliferation and maintenance of the vascular wall smooth muscle cells in a more contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure.

Neonatal carotid repair at ECMO decannulation: patency rates and early neurologic outcomes.

PURPOSE: Neonates placed on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) undergo either carotid repair or ligation at decannulation. Study aims were to evaluate carotid patency rates after repair and to compare early neurologic outcomes between repaired and ligated patients. METHODS: A retrospective study of all neonates without congenital heart disease (CHD) who had VA-ECMO between 1989 and 2012 was completed using our institutional ECMO Registry. Carotid patency after repair, neuroimaging studies, and auditory brainstem response (ABR) testing at time of discharge were examined. RESULTS: 140 neonates were placed on VA-ECMO during the study period. Among survivors, 84% of carotids repaired and imaged remained patent at last study. No significant differences were observed between infants in the repaired and ligated groups regarding diagnosis, ECMO duration, or length of stay. A large proportion (43%) developed a severe brain lesion after VA-ECMO, but few failed their ABR testing. Differences in early neurologic outcomes between the two groups of survivors were not significant. CONCLUSIONS: At this single institution, carotid patency is excellent following repair at ECMO decannulation. No increased incidence of severe brain lesions or greater neurosensory impairment in the repair group was observed. Further studies are needed to investigate the effects of ligation on longer-term neurocognitive outcomes.

Brilliant blue FCF as an alternative dye for saphenous vein graft marking: effect on conduit function.

IMPORTANCE: Surgical skin markers are used off-label to mark human saphenous veins (HSVs) to maintain orientation before implantation as aortocoronary or peripheral arterial bypass grafts. These surgical skin markers impair functional responses of the HSV tissue. OBJECTIVES: To investigate the effect of brilliant blue dye 1 (brilliant blue FCF [for food coloring]; hereinafter, FCF) as a nontoxic alternative marking dye and to determine whether FCF has pharmacological properties. DESIGN, SETTING, AND PARTICIPANTS: Segments of HSVs were collected in university hospitals from patients undergoing coronary artery bypass grafting procedures immediately after harvest (unmanipulated) or after typical intraoperative surgical graft preparation (after manipulation). Rat inferior venae cavae were used to determine the pharmacological properties and cellular targets of FCF. Endothelial and smooth muscle functional responses were determined in a muscle bath, and intimal thickening in HSVs was determined after 14 days in organ culture. MAIN OUTCOMES AND MEASURES: Contractile responses were measured in force and converted to stress. Smooth muscle function was expressed as maximal responses to potassium chloride depolarization contractions. Endothelial function was defined as the percentage of relaxation of maximal agonist-induced contraction. Neointimal thickness was measured by histomorphometric analysis. RESULTS: Human saphenous veins stored in the presence of FCF had no loss of endothelial or smooth muscle function. Unmanipulated HSVs preserved in the presence of FCF demonstrated a significant increase in endothelial-dependent relaxation (mean [SEM], 25.2% [6.4%] vs 30.2% [6.7%]; P = .02). Application of FCF to functionally nonviable tissue significantly enhanced the smooth muscle responses (mean [SEM], 0.018 [0.004] × 105 N/m² vs 0.057 [0.016] × 105 N/m²; P = .05). Treatment with FCF reduced intimal thickness in organ culture (mean [SEM], -17.5% [2.1%] for unmanipulated HSVs vs -27.9% [3.7%] for HSVs after manipulation; P < .001). In rat inferior venae cavae, FCF inhibited the contraction induced by the P2X7 receptor agonist 2'(3')-O-(4-benzoyl)benzoyl-adenosine-5'-triphosphate (mean [SEM], 14.8% [2.2%] vs 6.5% [1.8%]; P = .02) to an extent similar to the P2X7 receptor antagonist oxidized adenosine triphosphate (mean [SEM], 5.0% [0.9%]; P < .02 vs control) or the pannexin hemichannel inhibitor probenecid (mean [SEM], 7.3% [1.6%] and 4.7% [0.9%] for 0.5mM and 2mM, respectively; P < .05). CONCLUSIONS AND RELEVANCE: Treatment with FCF did not impair endothelial or smooth muscle function in HSVs. Brilliant blue FCF enhanced endothelial-dependent relaxation, restored smooth muscle function, and prevented intimal hyperplasia in HSVs in organ culture. These pharmacological properties of FCF may be due to P2X7 receptor or pannexin channel inhibition. Brilliant blue FCF is an alternative, nontoxic marking dye that may improve HSV conduit function and decrease intimal hyperplasia.

Surgical vein graft preparation promotes cellular dysfunction, oxidative stress, and intimal hyperplasia in human saphenous vein.

INTRODUCTION: Human saphenous vein (HSV) is the most widely used bypass conduit for peripheral and coronary vascular reconstructions. However, outcomes are limited by a high rate of intimal hyperplasia (IH). HSV undergoes a series of ex vivo surgical manipulations prior to implantation, including hydrostatic distension, marking, and warm ischemia in solution. We investigated the impact of surgical preparation on HSV cellular function and development of IH in organ culture. We hypothesized that oxidative stress is a mediator of HSV dysfunction. METHODS: HSV was collected from patients undergoing vascular bypass before and after surgical preparation. Smooth muscle and endothelial function were measured using a muscle bath. Endothelial preservation was assessed with immunohistochemical staining. An organ culture model was used to investigate the influence of surgical preparation injury on the development of IH. Superoxide levels were measured using a high-performance liquid chromatography-based assay. The influence of oxidative stress on HSV physiologic responses was investigated by exposing HSV to hydrogen peroxide (H2O2). RESULTS: Surgical vein graft preparation resulted in smooth muscle and endothelial dysfunction, endothelial denudation, diminished endothelial nitric oxide synthase staining, development of increased IH, and increased levels of reactive oxygen species. Experimental induction of oxidative stress in unmanipulated HSV by treatment with H2O2 promoted endothelial dysfunction. Duration of storage time in solution did not contribute to smooth muscle or endothelial dysfunction. CONCLUSIONS: Surgical vein graft preparation causes dysfunction of the smooth muscle and endothelium, endothelial denudation, reduced endothelial nitric oxide synthase expression, and promotes IH in organ culture. Moreover, increased levels of reactive oxygen species are produced and may promote further vein graft dysfunction. These results argue for less injurious means of preparing HSV prior to autologous transplantation into the arterial circulation.

Role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia: therapeutic potential for prevention of vein graft failure?

The saphenous vein remains the most widely used conduit for peripheral and coronary revascularization despite a high rate of vein graft failure. The most common cause of vein graft failure is intimal hyperplasia. No agents have been proven to be successful for the prevention of intimal hyperplasia in human subjects. The renin-angiotensin system is essential in the regulation of vascular tone and blood pressure in physiologic conditions. However, this system mediates cardiovascular remodeling in pathophysiologic states. Angiotensin II is becoming increasingly recognized as a potential mediator of intimal hyperplasia. Drugs modulating the renin-angiotensin system include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These drugs are powerful inhibitors of atherosclerosis and cardiovascular remodeling, and they are first-line agents for management of several medical conditions based on class I evidence that they delay progression of cardiovascular disease and improve survival. Several experimental models have demonstrated that these agents are capable of inhibiting intimal hyperplasia. However, there are no data supporting their role in prevention of intimal hyperplasia in patients with vein grafts. This review summarizes the physiology of the renin-angiotensin system, the role of angiotensin II in the pathogenesis of cardiovascular remodeling, the medical indications for these agents, and the experimental data supporting an important role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia.

Emergency airway management in critically injured patients: a survey of U.S. aero-medical transport programs.

OBJECTIVE: Pre-hospital airway management represents the intervention most likely to impact outcomes in critically injured patients. As such, airway management issues dominate quality improvement (QI) reviews of aero-medical programs. The purpose of this study was to evaluate current practice patterns of airway management in trauma among U.S. aero-medical service (AMS) programs. METHODS: The Association of Air Medical Services (AAMS) Resource Guide from 2005 to 2006 was utilized to identify the e-mail addresses of all directors of U.S. aero-medical transport programs. Program directors from 182 U.S. aero-medical programs were asked to participate in an anonymous, web-based survey of emergency airway management protocols and practices. Non-responders to the initial request were contacted a second time by e-mail. RESULTS: 89 programs responded. 98.9% have rapid sequence intubation (RSI) protocols. 90% use succinylcholine, 70% use long-acting neuromuscular blockers (NMB) within their RSI protocol. 77% have protocols for mandatory in-flight sedation but only 13% have similar protocols for maintenance paralytics. 60% administer long-acting NMB immediately after RSI, 13% after confirmation of neurological activity. Given clinical scenarios, however, 97% administer long-acting NMB to patients with scene and in-flight Glasgow Coma Scale (GCS) of 3, even for brief transport times. CONCLUSIONS: The majority of AMS programs have well defined RSI and in-flight sedation protocols, while protocols for in-flight NMB are uncommon. Despite this, nearly all programs administer long-acting NMB following RSI, irrespective of GCS or flight time. Given the impact of in-flight NMB on initial assessment, early intervention, and injury severity scoring, a critical appraisal of current AMS airway management practices appears warranted.

Early prediction of massive transfusion in trauma: simple as ABC (assessment of blood consumption)?

BACKGROUND: Massive transfusion (MT) occurs in about 3% of civilian and 8% of military trauma patients. Although many centers have implemented MT protocols, most do not have a standardized initiation policy. The purpose of this study was to validate previously described MT scoring systems and compare these to a simplified nonlaboratory dependent scoring system (Assessment of Blood Consumption [ABC] score). METHODS: Retrospective cohort of all level I adult trauma patients transported directly from the scene (July 2005 to June 2006). Trauma-Associated Severe Hemorrhage (TASH) and McLaughlin scores calculated according to published methods. ABC score was assigned based on four nonweighted parameters: penetrating mechanism, positive focused assessment sonography for trauma, arrival systolic blood pressure of 90 mm Hg or less, and arrival heart rate > or = 120 bpm. Area under the receiver operating characteristic curve (AUROC) used to compare scoring systems. RESULTS: Five hundred ninety-six patients were available for analysis; and the overall MT rate of 12.4%. Patients receiving MT had higher TASH (median, 6 vs. 13; p < 0.001), McLaughlin (median, 2.4 vs. 3.4; p < 0.001) and ABC (median, 1 vs. 2; p < 0.001) scores. TASH (AUROC = 0.842), McLaughlin (AUROC = 0.846), and ABC (AUROC = 0.842) scores were all good predictors of MT, and the difference between the scores was not statistically significant. ABC score of 2 or greater was 75% sensitive and 86% specific for predicting MT (correctly classified 85%). CONCLUSIONS: The ABC score, which uses nonlaboratory, nonweighted parameters, is a simple and accurate in identifying patients who will require MT as compared with those previously published scores.

Use of scene vital signs improves TRISS predicted survival in intubated trauma patients.

INTRODUCTION: The Trauma Related Injury Severity Score (TRISS) has been previously validated to predict outcomes in nonintubated, nonparalyzed trauma patients. The purpose of this study was to assess the impact of scene vital signs on predicting survival in intubated trauma patients. METHODS: Our Trauma Registry of the American College of Surgeons was reviewed for all trauma patients admitted between 10/01/04 and 09/30/06, arriving by aeromedical transport. TRISS was evaluated for each patient based on their (1) scene vital signs and (2) arrival vital signs. Additionally, the "TRISS-like" score was calculated for each patient. Expected mortality for each score was measured against observed mortality. RESULTS: Four thousand four hundred ninety-nine Trauma Registry of the American College of Surgeons patients were admitted during the study period; 695 (15%) were transported by air; 163 patients (23%) arrived intubated; 480 arrived nonintubated. Observed survival in the intubated group was 76%. Observed survival in the nonintubated group was 100%. TRISS using scene vital signs more closely predicted mortality among intubated patients than the other scoring systems (69% versus 39% using TRISS-arrival versus 80% using TRISS-like). Scene vital signs with TRISS also resulted in fewer "unexpected" outcomes (survivors and deaths). CONCLUSIONS: Traditionally, patients arriving at trauma centers intubated are either excluded from the trauma registry or have their physiological score "modified" to account for pharmacologically altered respiratory rate and Glasgow Coma Scale. In intubated patients, TRISS using scene vital signs more reliably predicts survival and does so with far fewer "unexpected" outcomes than with other available scoring systems.

TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer.

PURPOSE: Activation of the epidermal growth factor receptor (EGFR) requires cell surface cleavage of EGFR ligands, uptake of soluble ligand by the receptor, and initiation of EGFR tyrosine kinase activity. We define these collective events as the EGFR axis. Transforming growth factor-alpha (TGF-alpha) and amphiregulin are two EGFR ligands that are delivered preferentially to the basolateral surface of polarized epithelial cells where the EGFR resides. TACE/ADAM-17 (tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloprotease) has been implicated in ectodomain cleavage of TGF-alpha and amphiregulin. EXPERIMENTAL DESIGN: Using a human polarizing colorectal cancer (CRC) cell line, HCA-7, and a tissue array of normal colonic mucosa and primary and metastatic CRC, we determined the intracellular localization of TACE and the effects of EGFR axis inhibition in CRC. RESULTS: Herein, we show that TACE is localized to the basolateral plasma membrane of polarized HCA-7 cells. TACE is overexpressed in primary and metastatic CRC tumors compared with normal colonic mucosa; the intensity of its immunoreactivity is inversely correlated with that of TGF-alpha and amphiregulin. Pharmacologic blockade of HCA-7 cells with an EGFR monoclonal antibody, a selective EGFR tyrosine kinase inhibitor, and a selective TACE inhibitor results in concentration-dependent decreases in cell proliferation and active, phosphorylated mitogen-activated protein kinase. Combining suboptimal concentrations of these agents results in cooperative growth inhibition, increased apoptosis, and reduced mitogen-activated protein kinase pathway activation. Furthermore, an EGFR tyrosine kinase-resistant clone of HCA-7 cells is growth-inhibited by combined monoclonal antibody and TACE inhibition. CONCLUSION: These results implicate TACE as a promising target of EGFR axis inhibition in CRC.

Microarray gene analysis of the liver in a rat model of chronic, voluntary alcohol intake.

The mechanisms underlying alcoholic liver disease are not fully understood. It has been established that alcohol interferes with transcriptional and translational regulatory steps of cell function. To understand such an effect, assessment of alcohol-induced changes in the simultaneous expression of a large number of genes may prove very useful. The purpose of the current study was to test a large number of genes ( approximately 8700) for possible changes in expression induced by alcohol alone or in addition to treatment with lipopolysaccharide (LPS), a putative mediator of alcohol effects on the liver. Male rats were fed an alcohol-containing liquid diet (Lieber-DeCarli) for 14-15 weeks, injected with Escherichia coli LPS (0.8 mg x kg(-1)), and killed 24 h later. Blood samples were taken for determination of plasma liver enzyme activity, and liver samples were obtained for histologic evaluation and total RNA extraction. Total RNA was analyzed for gene expression (Rat Toxicology U34 Array; Affymetrix, Santa Clara, CA). Of 8740 genes on the microchip, 2259 were expressed in the liver. Seven hundred ninety-eight genes underwent significant changes induced by either alcohol or LPS, but listed in this article are only those that significantly increased or decreased expression twofold or more. The genes were assigned to functional groups and reviewed. Gene changes were discussed from two viewpoints: relevance to established hypotheses of alcohol and LPS mechanisms of action and revealing of novel mechanisms of alcohol-induced liver injury. Application of DNA microarray technology to the study of alcohol-induced liver injury generated novel theoretical and experimental approaches to alcohol-induced liver injury.

Alcohol, but not lipopolysaccharide-induced liver apoptosis involves changes in intracellular compartmentalization of apoptotic regulators.

BACKGROUND: While alcohol-induced augmentation of liver apoptosis has been demonstrated in humans and laboratory animals, the underlying mechanisms are not fully elucidated. This study addresses the question whether alcohol and bacterial lipopolysaccharide (LPS), a putative mediator of alcohol effects on the liver, induce augmentation of liver apoptosis by intrinsic or extrinsic signaling pathways. This information may prove important for future design of therapies for alcoholic liver disease. METHODS: Male rats were fed either an alcohol-containing liquid diet or an isocaloric, control diet for 15-16 weeks. At the end of feeding period, the rats were treated with LPS (0.8 mg.kg-1 body weight) or sterile saline and killed 3 and 24 hr later. The liver and blood were sampled for histology and biochemical assays. Hepatocytes were isolated by collagenase perfusion and fractionated to yield mitochondria and cytoplasm. The propensity of mitochondria to undergo permeability transition in the presence of a Ca2+ overload was determined along with distribution of various apoptotic regulators (AIF, Smac2, Bax, cytochrome c, Bcl-XL, Bfl-1, and caspase-2) between mitochondria and cytoplasmic fractions. RESULTS: Increased liver apoptosis in alcohol-treated rats was associated with translocation of several apoptotic regulators between mitochondria and cytoplasm in a manner suggesting that alcohol induces augmentation of apoptosis by recruiting intrinsic apoptotic signals. LPS treatment of rats counteracted alcohol-induced changes in intracellular compartmentalization of apoptotic regulators despite an increased rate of apoptosis. LPS may, therefore, recruit extrinsic apoptotic signals, such as proinflammatory cytokines. CONCLUSIONS: Hepatocytes are to be able to mount an apoptotic response to both intrinsic and extrinsic signals. Alcohol increases liver apoptosis predominantly through an intrinsic signaling pathway while LPS recruits extrinsic signaling pathways.