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T R Billiar

Publications and source records attributed to T R Billiar.

At least 181 records · Page 10Linked to original sources
PubMed1995

Pyruvate inhibits clofibrate-induced hepatic peroxisomal proliferation and free radical production in rats.

In an effort to identify the effects of the 3-carbon compound pyruvate on free radical production, we measured hepatic total peroxisomal beta-oxidation and catalase activity and the production of lipofuscin-like products in male Sprague-Dawley rats consuming an adequate diet supplemented with pyruvate, vitamin E, or the peroxisome proliferator and free radical enhancer clofibrate for 22 days (n = 5 in each group). Clofibrate feeding induced hepatomegaly, a fivefold increase in total peroxisomal beta-oxidation activity, and a threefold increase in hepatic lipofuscin-like products (P < .05). Pyruvate but not vitamin E inhibited the increase in liver size by 70% (P < .05). Both pyruvate and vitamin E completely inhibited clofibrate-induced increases in lipofuscin-like products (P < .05). Pyruvate but not clofibrate or vitamin E increased plasma concentrations of the nitric oxide metabolites nitrite and nitrate (P < .05). We conclude that with clofibrate-induced peroxisomal proliferation and free radical production, pyruvate will inhibit peroxisomal proliferation and free radical production, inhibit free radical-induced lipid peroxidation, and enhance metabolism of nitric oxide.

Animals↗
PubMed1995

Hemorrhagic shock.

A great deal has been learned about the pathophysiologic condition of hemorrhagic shock. The response of the hormonal and inflammatory mediator systems in patients in hemorrhagic shock appears to represent a distinct set of responses different from those of other forms of shock. The classic neuroendocrine response to hemorrhage attempts to maintain perfusion to the heart and brain, often at the expense of other organ systems. This intense vasoconstriction occurs via central mechanisms. The response of the peripheral microcirculation is driven by local tissue hypoperfusion that results in vasodilation in the ischemic tissue bed. Activation of the systemic inflammatory response by hemorrhage and tissue injury is an important component of the pathophysiologic condition of hemorrhagic shock. Activators of this systemic inflammatory response include ischemia/reperfusion injury and neutrophil activation. Capillary "no-flow" with prolonged ischemia and "no-reflow" with reperfusion may initiate neutrophil activation in patients in hemorrhagic shock. The mechanisms that lead to decompensated and irreversible hemorrhagic shock include (1) "arteriolar hyposensitivity" as manifested by progressive arteriolar vasodilation and decreased responsiveness of the microcirculation to alpha-agonists, and (2) cellular injury and activation of both proinflammatory and counterinflammatory mechanisms. These changes represent a failure of the microcirculation. Redistribution of cardiac output and persistent gut ischemia after adequate resuscitation may also contribute to the development of irreversible hemorrhagic shock. Treatment of hemorrhagic shock includes rapid operative resuscitation to limit activation of the mediator systems and abort the microcirculatory changes that result from hemorrhagic shock. Volume resuscitation and control of hemorrhage, should occur simultaneously. The end point in volume resuscitation of hemorrhagic shock must be maintenance of organ system and cellular function. Whether we use adequate urine output, correction of lactic acidemia, optimization of oxygen delivery, or oxygen consumption as our specific goal, the general objective is to provide adequate crystalloid solution and packed red blood cells to achieve and maintain normal organ and cellular perfusion and function.

Adrenal Glands↗
PubMed1995

Regulation and function of inducible nitric oxide synthase during sepsis and acute inflammation.

During sepsis and inflammation profound changes in physiological function are induced by a variety of mediators, including endotoxin, various cytokines, and NO. Many of these mediators, in addition to their other functions, induce the synthesis of NO through the induction of iNOS within a variety of cell types. The regulation of iNOS expression is quite complex. Of interest is the fact that the functions of NO during sepsis range from modulating perfusion to mediating cytotoxicity. In addition, it is unique that many tissues not characterized as being involved in immune function express iNOS in a manner similar to that of tissues involved in immune function. The role of NO during episodes of acute inflammation appears to be a protective one; however, there are examples of chronic localized inflammation in both animal and human models which suggest that chronic iNOS expression may be detrimental. Further investigations into the regulation and function of NO in both the acute and chronic settings are necessary in order to fully understand this small yet unique molecule.

Animals↗
PubMed1995

Nitric oxide. Novel biology with clinical relevance.

OBJECTIVE: The author provides the reader with a view of the regulation and function of nitric oxide (NO), based on the three distinct enzyme isoforms that synthesize NO. SUMMARY BACKGROUND DATA: Nitric oxide is a short-lived molecule exhibiting functions as diverse as neurotransmission and microbial killing. Recent advances in the characterization of the enzymes responsible for NO synthesis and in the understanding of how NO interacts with targets have led to new insights into the many facets of this diverse molecule. METHODS: Nitric oxide is produced by one of three enzyme isoforms of NO synthesis. These enzymes vary considerably in their distribution, regulation, and function. Accordingly, the NO synthesis or lack of NO production will have consequences unique to that isoform. Therefore, this review summarizes the regulation and function of NO generated by each of the three isoforms. RESULTS: Nitric oxide exhibits many unique characteristics that allow this molecule to perform so many functions. The amount, duration, and location of the NO synthesis will depend on the isoform of NO synthase expressed. For each isoform, there probably are disease processes in which deficiency states exist. For induced NO synthesis, states of overexpression exist. CONCLUSIONS: Understanding the regulation and function of the enzymes that produce NO and the unique characteristics of each enzyme isoform is likely to lead to therapeutic approaches to prevent or treat a number of diseases.

Amino Acid Oxidoreductases↗
PubMed1995

Evolution of management of major hepatic trauma: identification of patterns of injury.

Nonoperative management of hemodynamically stable patients following blunt hepatic trauma identified by computed tomography (CT) has been reported in up to 20% of patients presenting with hepatic injury, predominantly low grade. We reviewed 128 consecutive adult patients sustaining blunt hepatic trauma with the hypothesis that severe hepatic injuries (grades III to V) could be safely managed nonoperatively and to determine anatomic pattern and severity of hepatic injuries. Sixty-two of the 128 patients (47%) went directly for laparotomy, based on physical findings or positive peritoneal lavage. Sixty-six patients were hemodynamically stable and underwent abdominal CT scanning; 70% (46 of 66) were successfully managed nonoperatively. Fifty-one percent of grade III and IV injuries were treated nonoperatively. However, the majority of patients with grade V injuries were unstable, and 92% required laparotomy. Twenty-six of 46 patients treated nonoperatively (56%) had injury to the posterior segment of the right lobe of the liver or a "split liver." In retrospect, only 33% of patients with hepatic injury required laparotomy for therapy of the liver injury. Hemodynamic stability and anatomic pattern of injury on presentation were important factors in successful nonoperative management of hepatic injury.

Adolescent↗
PubMed1995

Inhibition of nitric oxide synthase during hemorrhagic shock increases hepatic injury.

The function of nitric oxide (NO) in hemorrhagic shock is controversial. Increased NO synthesis has been temporally correlated with severe shock and has been associated with vascular hyporeactivity to vasoconstrictor agents in isolated vascular rings. Its role in local tissue perfusion, however, is unknown. We studied the role of NO in shock-induced hepatic injury in a rodent model of decompensated hemorrhagic shock by inhibiting its synthesis with Nw-nitro-L-arginine methyl ester (L-NAME). L-NAME infusion (5 micrograms/kg/min) increased the shock-induced hepatic injury and this effect was reversible with L-arginine. L-NAME had only transient effects on systemic mean arterial blood pressure, which quickly returned to pre-L-NAME levels. We conclude that NO synthesis serves a protective function in preventing shock-induced hepatic injury and we postulate that this effect may be due to modulation of the local hepatic circulation.

Analysis of Variance↗
PubMed1995

Role of lipopolysaccharide (LPS), interleukin-1, interleukin-6, tumor necrosis factor, and dexamethasone in regulation of LPS-binding protein expression in normal hepatocytes and hepatocytes from LPS-treated rats.

Lipopolysaccharide (LPS)-binding protein (LBP) has been reported to be an acute-phase protein. LBP binds to LPS with a high affinity; LPS-LBP complexes then interact with the receptor CD14, resulting in increased expression of LPS-inducible genes. Hepatocytes represent a major source of LBP, but little is known about the regulation of rodent hepatocyte LBP synthesis. In these studies, undertaken to characterize hepatocyte LBP expression, we show that greater-than-20-fold increases in LBP mRNA levels in hepatocytes occurred following injection of LPS or turpentine in rats. In primary cultures of rat hepatocytes, the addition of interleukin-6 (IL-6) and LPS led to 4.5- and 3.2-fold stimulation in LBP mRNA levels, respectively. The induction of LBP by IL-6 or LPS was attenuated by dexamethasone. In contrast to IL-6 and LPS, in the presence of 10(-6) M dexamethasone, IL-1 and tumor necrosis factor (TNF) led to maximal LBP mRNA induction levels, 4.7- and 3.8-fold, respectively, suggesting that IL-6 and LPS stimulate LBP expression by mechanisms different from those of IL-1 and TNF. Similar induction levels of LBP mRNA were seen in rat H35 hepatoma cells for all four stimuli, and dexamethasone inhibited these responses. Dexamethasone alone increased the spontaneous induction in primary hepatocytes at early time points but suppressed induction at later time points. Furthermore, hepatocytes from rats treated with LPS in vivo exhibited a > 10-fold increase in mRNA expression in response to LPS and enhanced responses to TNF and IL-1. As with the normal hepatocytes, dexamethasone inhibited the LPS-dependent induction in the LPS-treated rat hepatocytes. These data suggest that LBP synthesis by hepatocytes is under the control of LPS, IL-1, TNF, IL-6, and glucocorticoids and that the LPS treatment primes hepatocytes for subsequent responses to LPS, TNF, and IL-1 for LBP synthesis.

Acute-Phase Proteins↗
PubMed1995

Nitric oxide causes hyporeactivity to phenylephrine in isolated perfused livers from endotoxin-treated rats.

Systemic vascular hyporeactivity to vasoconstrictors has been described in rats following endotoxin administration. Inducible nitric oxide synthase (iNOS) expression is known to occur in the liver in endotoxemia, but consequences of iNOS induction on hepatic hemodynamics are unknown. The reactivity of the hepatic circulation to phenylephrine was tested in perfused livers from normal rats and rats previously injected with endotoxin (20 mg/kg ip). In control rats (n = 5), phenylephrine-induced portal pressure increases were similar in livers perfused with Krebs-Henseleit-bicarbonate (KHB) buffer, KHB plus the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA, 1 mM), or KHB plus the substrate for NO synthesis, L-arginine (1 mM). In contrast, livers from endotoxin-treated rats (n = 5) exhibited a marked reduction in the vasoconstrictive response to phenylephrine (14.6 vs. 55.1% in livers from control rats, P < 0.05). Perfusion with L-NMMA restored the phenylephrine response, and the L-NMMA effect was reversible with L-arginine. Perfusate NO2-/NO3- and guanosine 3',5'-cyclic monophosphate (cGMP) levels were increased in endotoxin-treated rats and significantly reduced by L-NMMA perfusion. In control livers, the NO donor S-nitroso-N-acetyl-DL-penicillamine blocked the portal pressure increase after phenylephrine administration. These results suggest that rat hepatic circulation takes part in the systemic vascular hyporeactivity to vasoconstrictors observed in endotoxemia and that NO is involved in this hyporeactivity to phenylephrine.

Animals↗
PubMed1995

Sources of arginine for induced nitric oxide synthesis in the isolated perfused liver.

Hepatocytes can be stimulated to express high levels of inducible nitric oxide synthase (iNOS), which utilizes arginine for nitric oxide (NO) synthesis. Hepatocytes also synthesize and catabolize arginine, an intermediate in the urea cycle, raising the possibility that the urea pathway may provide substrate for hepatic NO synthesis. To identify the sources of arginine for iNOS, we measured the release of NO-2 + NO-3 and urea in isolated rat livers perfused in a recirculation model with a Krebs-Henseleit-bicarbonate buffer containing either no added amino acid, arginine, or precursors for urea synthesis. To induce iNOS expression, rats were injected with killed Corynebacterium parvum (C. parvum) or with endotoxin. In livers from C. parvum- and endotoxin-treated rats, we found that 1) an intracellular source of arginine exists that provides substrate to iNOS; 2) additional exogenous arginine increase NO synthesis, demonstrating that endogenous arginine is insufficient for maximal NO synthesis; and 3) an increase in the rate of endogenous arginine synthesis within the urea cycle is inefficient in increasing NO synthesis, demonstrating the independence of the two pathways in the liver.

Animals↗
PubMed1995

Induction of lipopolysaccharide-binding protein gene expression in cultured rat pulmonary artery smooth muscle cells by interleukin 1 beta.

Lipopolysaccharide (LPS)-binding protein (LBP) binds with high affinity to LPS, and the LBP-LPS complex enhances cellular inflammatory responses to LPS. Although it is present in normal serum, LBP is also induced as part of the acute phase response. Synthesis of LBP is though to be limited to the liver, but we have recently reported significant extrahepatic (including pulmonary) LBP mRNA expression in in vivo rat models of sepsis and inflammation. In the present study, we tested the hypothesis that a cellular source of pulmonary LBP in the rat may be vascular smooth muscle, by exposing cultured rat pulmonary artery smooth muscle cells (RPASMC) to cytokines and LPS. Treatment of RPASMC for 4 and 24 h with a combination of tumor necrosis factor alpha, interleukin 1 beta (IL-1 beta), interferon gamma, and LPS resulted in significant LBP mRNA expression. Of this mixture, IL-1 beta alone was sufficient to induce LBP mRNA expression in both a time- and dose-dependent manner. The effects of IL-beta on LBP mRNA expression were significantly antagonized by IL-1 receptor antagonist protein. Furthermore, supernatants from RPASMC treated with IL-1 beta enhanced the binding of [125I]ASD-LPS by the macrophage cell line RAW 264.7, indicative of LBP bioactivity. We conclude that pulmonary artery smooth muscle cells stimulated with IL-1 beta produce a transcript for LBP or a homologous product in vitro. Local production of LBP could play an important role in the pulmonary response to inflammation and sepsis.

Acute-Phase Proteins↗
PubMed1995

Regulation and functions of nitric oxide in the liver in sepsis and inflammation.

The liver plays important roles in metabolic and immune responses during sepsis. It is the major site of acute-phase protein synthesis and is responsible for the clearance of circulating pathogens. In addition to mediators such as cytokines and eicosanoids, numerous studies have emphasized the role of nitric oxide (NO.) in influencing hepatic function during sepsis. The induction and the distribution of inducible nitric oxide synthase in the liver, the regulation of the enzyme, and the functions of NO. in the liver are the subject of this review.

Amino Acid Oxidoreductases↗
PubMed1995

The role of nitric oxide in Kupffer cell-hepatocyte interactions.

A certain level of normal or near-normal hepatic function is essential for survival. Over the last few years, the importance of the regulation of hepatic function by the interaction of specific cell populations in the liver has become increasingly evident. Kupffer cells, the fixed hepatic macrophages, have the ability to profoundly affect hepatocyte function, while hepatocytes, in turn, possess the capacity to modify Kupffer cell function. Nitric oxide, produced from the amino acid L-arginine, is a short-lived radical that is a potent mediator of cellular function and cell-cell interaction, and is synthesized by both Kupffer cells and hepatocytes. The purpose of this review is to examine the numerous areas in which nitric oxide may mediate the interactions between Kupffer cells and hepatocytes, and therefore regulate both normal and abnormal hepatic physiology and function.

Amino Acid Oxidoreductases↗
PubMed1995

Further characterization and comparison of inducible nitric oxide synthase in mouse, rat, and human hepatocytes.

Marked differences in induced nitric oxide (NO) synthesis occur between species. We have previously shown that both human and rat hepatocytes express an inducible NO synthase in response to cytokines and lipopolysaccharide. In this study, we compare the expression and regulation of cytokine-induced NO synthase in hepatocytes isolated from three species, human, rat, and mouse. On stimulation with tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interferon gamma (IFN gamma), and lipopolysaccharide (LPS), it was found that hepatocytes from all three species produce high levels of NO with levels of production exhibiting the following hierarchy: rat hepatocytes > mouse hepatocytes > human hepatocytes. Whereas rat and mouse hepatocytes express inducible NO synthase messenger RNA (mRNA) in response to TNF alpha, IL-1 beta, or IFN gamma as a single stimulus, human hepatocytes respond to LPS alone. Inhibition of NO generation through transforming growth factor (TGF-beta 1) was seen in mouse (77% +/- 5.9) and rat hepatocytes (17% +/- 2.6) whereas only about 10% was seen in human hepatocytes. Epidermal growth factor (EGF) was shown to inhibit NO synthesis in human and mouse hepatocytes but not rat. A marked NO-dependent inhibition of total protein synthesis was seen in rat and human hepatocytes, whereas mouse hepatocytes showed almost no inhibition in protein synthesis when stimulated. NO-dependent cyclic guanosine monophosphate (cGMP) release was found in all three species.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1994

The effects of administration of nitric oxide inhibitors during small bowel preservation and reperfusion.

The effects of nitric oxide (NO) during small bowel preservation and reperfusion were studied in a rat model of heterotopic, syngeneic LEW-->LEW transplantation. A 6-hr preservation interval was chosen, which leads consistently to moderate graft injury permitting graft and recipient survival. To evaluate the function of NO during preservation and reperfusion, two inhibitors (NitroG-L-arginine methyl ester [L-NAME] and NG-monomethyl-L-arginine [NMA]) were administered and compared with a transplanted group receiving no treatment. The extent of preservation and reperfusion injury were delineated by histologic study and by the measurement of mucosal glutaminase on tissue specimens obtained 20 min after revascularization and 24 hr and 4 weeks postoperatively. Serum and mucosal NO(2-)+NO3- levels were determined at the same time points. Graft function and survival was inferior in all cases where NO production was inhibited. When recipients were treated with NO inhibitors, graft function and survival was more impaired when L-NAME was administered compared with NMA administration. Donor and graft pretreatment with NO inhibitors impaired graft function but not survival, and was less detrimental than recipient treatment. Mucosal NO(2-)+NO3- levels significantly increased in untreated transplanted animals 20 min after reperfusion. This increase was abolished in groups treated with NO inhibitors. Serum NO(2-)+NO3- levels increased significantly after 24 hr, and this increase was even more pronounced when NO inhibitors were administered. Furthermore, liver function deteriorated after inhibition of NO, indicating a more severe inflammatory response of the recipient after NO inhibition. These data indicate that mucosal NO production within the graft during preservation, and especially during reperfusion, has beneficial effects, but increased serum NO(2-)+NO3- levels coincided with inferior graft condition due to preservation and reperfusion injury.

Animals↗
PubMed1994

Inhibition of nitric oxide synthesis enhances the expression of inducible nitric oxide synthase mRNA and protein in a model of chronic liver inflammation.

In septic shock the inhibition of inducible nitric oxide synthase (iNOS) could be of therapeutic value. However, side effects have to be investigated. Therefore we studied the effects of chronic NOS inhibition on the level of iNOS expression in a model of chronic liver inflammation induced by Corynebacterium parvum (C. parvum) which causes sustained iNOS expression in the liver. NOS inhibitors decreased the rise in plasma levels and urinary excretion of nitrite/nitrate by about 50%; however, iNOS mRNA and protein were increased to 200% and 150%, respectively. Thus chronic inhibition of NOS can result in an increase in iNOS mRNA level and protein under conditions when iNOS is expressed. This could result in an overproduction of NO upon removal of the NOS-inhibitor.

Amino Acid Oxidoreductases↗
PubMed1994

Molecular cloning, characterization, and tissue distribution of rat lipopolysaccharide binding protein. Evidence for extrahepatic expression.

LPS binding protein (LBP) is a glycoprotein present in normal serum that becomes markedly elevated during acute phase responses. LBP has been reported to greatly potentiate host responses to endotoxin or LPS. Therefore, LBP may play a critical role in the body's response to injury and infection. Little is known about the factors regulating production of LBP. To investigate the regulation of LBP expression, we have cloned the full-length cDNA for rat LBP. The deduced amino acid sequence of rat LBP was highly homologous with that reported for rabbit and human LBP. The sequence of rat LBP further refines the conserved regions found within the family of proteins that bind LPS; this family is comprised of bactericidal permeability-increasing protein and LBP from multiple species. Use of the rat LBP cDNA clone for Northern blot analysis reveals that LBP mRNA levels are markedly up-regulated in liver during acute phase responses. However, in contrast to previous reports, we also find evidence of extrahepatic expression of LBP under these induced conditions. The presence of LBP mRNA in activated tissues other than liver suggests that LBP may play a larger role in local tissue responses to LPS than previously appreciated.

Acute-Phase Proteins↗