Biomedical subjects

Z F Ba

Publications and source records attributed to Z F Ba.

At least 37 records · Page 2Linked to original sources

PubMed1997

Pentoxifylline maintains hepatocellular function and improves cardiac performance during early sepsis.

BACKGROUND AND OBJECTIVE: Although pentoxifylline (PTX) produces various beneficial effects after endotoxemia, it remains unknown whether this agent attenuates the depressed hepatocellular function and improves heart performance during early sepsis. The aim of this study, therefore, was to determine whether PTX maintains hepatocellular function and improves cardiac function during the early hyperdynamic stages of polymicrobial sepsis. DESIGN, MATERIALS, AND METHODS: Rats were subjected to sepsis by cecal ligation and puncture (CLP). At 1 hour after CLP, PTX (50 mg/kg body weight), or an equal volume of saline, was infused intravenously over 30 minutes. At 2 or 5 hours after CLP (i.e., early hyperdynamic stages of sepsis), hepatocellular function was assessed by in vivo indocyanine green clearance. Cardiac output was determined by dye dilution. Left ventricular performance parameters such as maximal rates of left ventricular pressure rise and fall (+/-dP/dtmax), ventricular peak systemic pressure, etc., were determined using a heart performance analyzer. RESULTS: The results indicate that hepatocellular function was significantly depressed at 2 and 5 hours after CLP. Administration of PTX, however, maintained hepatocellular function to sham levels. Although cardiac output increased after CLP with or without PTX treatment, this agent markedly improved cardiac performance as evidenced by significantly higher + dP/dtmax and ventricular peak systemic pressure as well as other heart performance parameters. CONCLUSIONS: Pentoxifylline appears to be a useful adjunct for maintaining hepatocellular function and improving cardiac performance during the early hyperdynamic stages of polymicrobial sepsis.

Animals↗

PubMed1996

Liver endothelial cell dysfunction occurs early following hemorrhagic shock and persists despite crystalloid resuscitation.

Although hepatocellular function is depressed early following hemorrhage, it remains unknown whether liver endothelial cell function is also compromised under such conditions. The aim of this study, however, was to determine if liver endothelial cell function is depressed during hemorrhage and persists following crystalloid resuscitation. To study this, rats underwent a 5-cm laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximal bleedout volume was returned in the form of Ringer's lactate. The animals were then resuscitated with 4 times the volume of maximal bleedout volume with Ringer's lactate. Arterial blood was taken before and during hemorrhage and after resuscitation. Plasma hyaluronic acid (HA) levels were determined using a Pharmacia assay kit. To determine whether the elevated HA is due to a decrease in its removal, HA clearance was assessed at 0 and 24 hr after resuscitation by injecting 30 microgram/100 g body wt HA intravenously. The results indicate that plasma HA levels increased significantly at the time of maximal bleedout, which persisted even 24 hr after the completion of resuscitation. Hyaluronic acid clearance decreased significantly at 0 and 24 hr after resuscitation, suggesting that the decreased HA clearance plays a major role in producing the elevated plasma HA levels. Since circulating HA is cleared exclusively by liver endothelial cells, these results, taken together, indicate that liver endothelial cell dysfunction (i.e., the increased plasma HA levels and decreased HA clearance) occurs early during hemorrhage (i.e., approximately 44 min after the onset of the insult) and persists despite resuscitation. Thus, the depressed liver endothelial cell function may directly or indirectly contribute to hepatocellular dysfunction observed under such conditions.

Animals↗

PubMed1996

Pentoxifylline maintains vascular endothelial cell function during hyperdynamic and hypodynamic sepsis.

BACKGROUND: Although pentoxifylline produces various beneficial effects after endotoxemia or sepsis occurs, it is not known whether this agent attenuates the depressed endothelial cell function during sepsis. Therefore the aim of this study was to determine whether pentoxifylline maintains vascular endothelial cell function (i.e., improves the release of endothelium-derived nitric oxide) during hyperdynamic and hypodynamic stages of polymicrobial sepsis. METHODS: Rats were subjected to sepsis by cecal ligation and puncture (CLP), after which 3 ml/100 gm body wt normal saline solution was injected subcutaneously in these and rats in a sham-operated group. At 1 hour after the onset of sepsis, pentoxifylline (50 mg/kg body wt) or an equal volume of normal saline solution was infused intravenously during a 30 minute period. At 10 and 20 hours after CLP was performed (10-hour CLP, hyperdynamic sepsis; 20-hour CLP, hypodynamic sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) mol/L) was used to achieve near maximal tension. Dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were carried out. The changes in percentage relaxation in the aortic rings by these agonists were then determined. RESULTS: Endothelium-dependent (acetylcholine-induced) vascular relaxation decreased significantly at 10 and 20 hours after CLP. Administration of pentoxifylline, however, maintained acetylcholine-induced vascular relaxation at both time points. In contrast, no significant reduction in nitroglycerine-induced vascular relaxation was seen in rats with sepsis irrespective of pentoxifylline treatment. CONCLUSIONS: Because pentoxifylline prevented endothelial cell dysfunction at 10 and 20 hours after CLP occurred, this agent appears to be a useful agent for maintaining vascular endothelial function during the hyperdynamic and hypodynamic stages of polymicrobial sepsis.

Acetylcholine↗

PubMed1996

Inhibition of the biologic activity of tumor necrosis factor maintains vascular endothelial cell function during hyperdynamic sepsis.

BACKGROUND AND OBJECTIVE: Although vascular endothelial cell function (i.e., the release of endothelium-derived nitric oxide) decreases and plasma tumor necrosis factor (TNF) increases during sepsis, it is not known whether the elevated TNF is responsible for the depression of endothelial cell function under such conditions. The aim of this study, therefore, was to determine if inhibition of TNF biologic activity by polyethylene glycol dimerized conjugate of the recombinant human form of the p55 soluble TNF receptor (PEG-(rsTNF-R1)2) maintains endothelial function during sepsis. DESIGN, MATERIALS AND METHODS: Rats were subjected to sepsis by cecal ligation and puncture (CLP). Immediately before the onset of sepsis, 600 microgram/rat PEG-(rsTNF-R1)2 or an equal volume of saline was infused intravenously. At 10 hours after CLP (i.e., hyperdynamic sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers. Dose responses for an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, nitroglycerine (NTG), were determined. Endothelial cell structure was examined by transmission electron microscopy. RESULTS: Endothelium-dependent vascular relaxation was depressed at 10 hours after the onset of sepsis. Administration of PEG-(rsTNF-R1)2 before CLP, however, maintained ACh-induced relaxation. In contrast, no significant difference in NTG-induced relaxation was seen, irrespective of administration of PEG-(rsTNF-R1)2 Furthermore, the deterioration in endothelial structure during sepsis was prevented by PEG-(rsTNF-R1)2 pretreatment. CONCLUSION: Since administration of PEG-(rsTNF-R1)2 maintains vascular endothelial cell structure and function, it can be concluded that TNF plays a pivotal role in producing endothelial dysfunction during sepsis. Thus, pharmacologic agents that inhibit TNF biologic activity and/or its production may be useful for protecting endothelial cells during sepsis.

Acetylcholine↗

PubMed1996

Administration of a matrix metalloproteinase inhibitor after hemorrhage improves cardiovascular and hepatocellular function.

Although matrix metalloproteinase inhibitors prevent the increase in soluble tumor necrosis factor-alpha during endotoxemia, it remains unknown whether a novel matrix metalloproteinase inhibitor, GM6001, improves cardiovascular and hepatocellular function after trauma and hemorrhage. To determine this, rats underwent laparotomy (i.e., trauma-induced), and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal shed volume was returned in the form of Ringer's lactate. The animals were then resuscitated with 3 times the volume of maximal bleedout with Ringer's lactate over 45 min, followed by 2 times Ringer's lactate over 60 min. GM6001, at a dose of 100 mg/kg or an equal volume of normal saline, was administered subcutaneously 15 min before the completion of resuscitation. At 2 and 4 h after resuscitation, cardiac output was measured by indocyanine green (ICG) dilution. Hepatocellular function (i.e., maximum velocity and the efficiency of ICG clearance) was determined by in vivo ICG clearance. Microvascular blood flow in various organs was assessed by laser Doppler flowmetry. The results indicate that cardiac output, hepatocellular function, and tissue microvascular blood flow decreased significantly at 2 and 4 h after resuscitation. GM6001 treatment, however, significantly improved the depressed cardiovascular and hepatocellular function. Since GM6001 improves cardiovascular and hepatocellular function, this agent may be a useful adjunct to fluid resuscitation after trauma and hemorrhagic shock.

Animals↗

PubMed1996

Effects of nonanticoagulant heparin on cardiovascular and hepatocellular function after hemorrhagic shock.

Although heparinization of animals before hemorrhage improves cell and organ function, the potent anticoagulant activity of conventional heparin sodium precludes its potential clinical use. To determine whether a novel nonanticoagulant heparin, GM1892, would have any beneficial effects on cardiovascular and hapatocellular functions and would decrease susceptibility to sepsis after hemorrhage, laparotomy was performed on rats (i.e., trauma induced), after which they were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal bleedout volume was returned in the form of Ringer lactate solution (RL). The rats were then resuscitated with three times the volume of shed blood with RL over 45 min, followed by infusion of two times RL plus GM1892 (7 mg/kg body wt; approximately 2% the anticoagulant activity of regular heparin) of saline over 60 min. At 2 and 4 h after the completion of resuscitation, cardiac output, hepatocellular function, and microvascular blood flow were determined. The results indicated that cardiac output, hepatocellular function, and microvascular blood flow in the liver, spleen, and small intestine decreased significantly after hemorrhage and resuscitation. Administration of GM1892, however, restored these parameters. The morphological abnormality observed after hemorrhage in the liver, kidney, and small gut was also attenuated with GM1892 treatment. Moreover, GM1892 normalized the elevated plasma prostaglandin E2 levels. Sepsis was induced in additional rats by cecal ligation and puncture (CLP) 20 h after hemorrhage, and the necrotic cecum was excised 10 h thereafter. GM1892 treatment significantly decreased mortality after CLP and cecal excision. Thus GM1892 appears to be a useful adjunct to fluid resuscitation, since it restores the depressed cardiovascular responses and decreases susceptibility to sepsis after trauma and hemorrhage.

Animals↗

PubMed1995

Pentoxifylline attenuates the depressed endothelial cell function and vascular muscle contractility following trauma and hemorrhagic shock.

Although pentoxifylline (PTX) produces various beneficial effects following adverse circulatory conditions, it is not known whether this agent attenuates the depressed vascular endothelial cell function [i.e., the reduced release of endothelium-derived nitric oxide (EDNO)] and smooth muscle contractility after trauma and hemorrhage. To study this, rats underwent a midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximal shed volume was returned in the form of lactated Ringer's solution. The animals were then resuscitated with 4 times the volume of maximal bleedout with lactated Ringer's solution, following which PTX (50 mg/kg body weight), or an equivalent volume of normal saline, was infused intravenously over 95 minutes. At 1.5 hours after resuscitation, the aorta was isolated and studied in vitro. Norepinephrine-induced vascular contraction and dose responses for acetylcholine (ACh), an endothelium-dependent vasodilator, were then determined. The results indicate that the decreased ACh-induced relaxation in hemorrhaged animals was restored with PTX treatment. Moreover, the increased ACh IC50 values (ACh concentration that causes half-maximum relaxation) after hemorrhage were reduced by PTX. In contrast, there was no significant difference in the relaxation induced by an endothelium-independent vasodilator, nitroglycerine, in the tested groups. Thus, PTX restores a hemorrhage-induced decrease in endothelium-derived nitricoxide production. In addition, the depressed smooth muscle contractile function was also attenuated by PTX treatment. Because PTX restored the depressed endothelial cell function and smooth muscle contractility, this agent appears to be a useful adjunct to fluid resuscitation for the management of trauma and hemorrhage.

Animals↗

PubMed1995

Sustained elevation in circulating catecholamine levels during polymicrobial sepsis.

Although studies have indicated that the levels of catecholamines increase during sepsis, it remains unknown whether the elevated levels of epinephrine, norepinephrine, and dopamine observed in early sepsis are sustained during late, hypodynamic stages of sepsis. In this study, rats were subjected to sepsis by cecal ligation and puncture (CLP, i.e., polymicrobial sepsis). Immediately after CLP or sham operation, animals received 3 mL/100 g body weight normal saline subcutaneously. At .5, 2, 10 (i.e., early sepsis), or 20 h (late sepsis) after CLP, blood samples were drawn and the plasma was separated. Plasma levels of epinephrine, norepinephrine, and dopamine were determined using a [3H]-radioenzymatic assay. The results indicate that plasma levels of epinephrine, norepinephrine, and dopamine increased significantly as early as .5 h after CLP. The increase in catecholamine levels persisted throughout the study periods. Thus, circulating levels of catecholamines were elevated in both early and late stages of polymicrobial sepsis. These results suggest that the increased catecholamine levels at .5-10 h after CLP may contribute to the hypermetabolic conditions that occur during early, hyperdynamic sepsis. However, there is a lack of an association between the elevated plasma catecholamine levels and hypometabolic/hypodynamic state in late sepsis.

Animals↗

PubMed1995

Tumor necrosis factor-alpha administration increases Kupffer cell cyclic adenosine monophosphate levels.

Although studies have indicated that both Kupffer cell cyclic adenosine monophosphate (cAMP) and circulating TNF levels increase following trauma-hemorrhage and resuscitation, it remains unknown whether the elevated TNF levels are responsible for the increased Kupffer cell cAMP levels. To determine this, recombinant murine TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (.25 mg/kg body wt) over 30 min in normal rats. At 1 h after TNF-alpha or vehicle infusion, Kupffer cells and hepatocytes were isolated and cAMP levels were determined by radioimmunoassay. The levels of cAMP in the spleen and kidney were also measured. In addition, the maximal binding capacity and affinity of beta-adrenergic receptors were determined in Kupffer cells and hepatocytes by using [125I]iodopindolol. To determine whether there is any correlation between Kupffer cell cAMP and prostaglandin E2 (PGE2) or epinephrine, plasma levels of catecholamines and PGE2 were measured. The results indicated that TNF-alpha infusion significantly increased Kupffer cell cAMP levels while hepatocyte cAMP levels were not altered. Moreover, cAMP levels also increased in the macrophage/lymphocyte-rich spleen but were not altered in the kidney. Kupffer cell beta-receptor binding characteristics were not significantly affected by TNF-alpha infusion. In contrast, TNF-alpha administration markedly increased plasma levels of PGE2 and epinephrine. Thus, the elevated Kupffer cell cAMP levels induced by TNF-alpha are not due to upregulation of beta-adrenergic receptors, but may be associated with the elevated levels of circulating PGE2 and/or epinephrine.

Animals↗

PubMed1995

Downregulation of hepatic beta-adrenergic receptors after trauma and hemorrhagic shock.

Although it is well known that sympathoadrenal activity increases under various adverse circulatory conditions, it is not known whether there are any alterations in hepatic plasma membrane beta-adrenergic receptors after trauma-hemorrhage and crystalloid resuscitation. To study this, rats underwent a 5-cm midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximal bleedout (MB) volume was returned in the form of Ringer lactate. The animals were then resuscitated with four times the volume of MB in the form of Ringer lactate over 60 min. Hepatic plasma membranes were isolated using discontinuous Percoll gradient centrifugation. The maximal binding capacity and dissociation constant (i.e., 1/affinity) of [125I]iodopindolol binding to beta-adrenergic receptors were determined using a membrane filtration assay and Scatchard analysis. The results indicate that there was a significant decrease in the maximal binding capacity at the time of MB, which persisted despite crystalloid resuscitation after hemorrhage. However, there were no significant changes in the dissociation constant at any time point during this study. The downregulation of beta-adrenergic receptor binding capacity may be responsible for metabolic abnormalities observed after hemorrhagic shock.

5'-Nucleotidase↗

PubMed1995

ATP-MgCl2 restores depressed endothelial cell function after hemorrhagic shock and resuscitation.

Although ATP-MgCl2 produces beneficial effects following various adverse circulatory conditions, it remains unknown whether this agent restores the depressed endothelial cell function [i.e., the reduced release of endothelium-derived nitric oxide (EDNO) and endothelium-derived contracting factors (EDCF)] in a model of trauma-hemorrhage and resuscitation. To determine this, rats underwent laparotomy (i.e., trauma induced), were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of shed blood volume was returned in the form of Ringer lactate (RL). The animals were then resuscitated with four times the volume of maximal bleedout with RL, following which ATP-MgCl2 (50 mumol/kg body wt) or saline was administered. At 1.5 h postresuscitation, the aorta and superior mesenteric artery (SMA) were isolated, and dose-responses for acetylcholine (ACh, an endothelium-dependent vasodilator, via EDNO) and nitroglycerin (an endothelium-independent vasodilator) were determined. In addition, hypoxia-induced contraction, a process mediated by EDCF, was assessed. The results indicate that the decreased endothelium-dependent relaxation after hemorrhage (sham 94 +/- 3 and 97 +/- 3% vs. hemorrhage 64 +/- 5 and 57 +/- 11% at 10-5 M ACh in aorta and SMA, respectively, P < 0.05) was restored with ATP-MgCl2 treatment. In contrast, there was no significant difference in nitroglycerin-induced relaxation. Moreover, the decreased hypoxia-induced aortic contraction after hemorrhage (sham 221 +/- 26 mg/ring vs. hemorrhage 124 +/- 22 mg/ring, P < 0.05) was attenuated by administration of ATP-MgCl2.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1995

Endothelium-dependent relaxation is depressed at the macro- and microcirculatory levels during sepsis.

The objective of this study was to determine whether endothelium-derived nitric oxide (NO) production is reduced at the macrocirculatory and microcirculatory levels during sepsis. To examine this, rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h after CLP (i.e., midpoint of hyperdynamic sepsis) or sham operation, the aorta and superior mesenteric artery were isolated. Responses to an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, nitroglycerin (NTG), were determined. In additional studies, the small intestine was isolated 5 or 20 h (hypodynamic sepsis) after CLP. Responses to ACh and NTG were determined in the isolated intestine. The results indicate that endothelium-dependent relaxation in both the aorta and superior mesenteric artery was depressed at 5 h after CLP. In contrast, there was no significant difference in the relaxation induced by NTG. Moreover, ACh-induced vascular relaxation in the isolated small intestine decreased at 5 and 20 h post-CLP without any significant alterations in NTG-induced relaxation. Since studies have shown that ACh-induced relaxation in the aorta is reduced at 20 h after CLP, it could be concluded that endothelium-derived NO release is depressed during hyperdynamic and hypodynamic stages of sepsis, not only in large arteries, but also at the microcirculatory level.

Acetylcholine↗

PubMed1995

Hepatocellular dysfunction occurs earlier than the onset of hyperdynamic circulation during sepsis.

Studies indicate that hepatocellular dysfunction occurs at 2 h after cecal ligation and puncture (CLP, i.e., sepsis model) despite the increased cardiac output (CO) and hepatic perfusion. It, however, remains unknown whether hepatocellular function is depressed earlier than the onset of hyperdynamic circulation in sepsis. To determine this, rats were subjected to sepsis by CLP. At .5, 1, 1.5, or 2 h after CLP, CO was measured by dye dilution. Hepatocellular function (i.e., maximum velocity of indocyanine green clearance and the efficiency of the active transport) was determined using an in vivo indocyanine green clearance technique. Microvascular blood flow was measured by laser Doppler flowmetry. To determine whether there is any association between hemodynamics and prostaglandins (PGs), plasma levels of PGE2 and PGI2 were measured by radioimmunoassay. The results indicate that hepatocellular function decreased significantly as early as 1.5 h after CLP. Cardiac output and microvascular blood flow in the liver and small intestine, however, increased and vascular resistance decreased at 2 h after CLP. Thus, hepatocellular dysfunction occurs earlier than the occurrence of hyperdynamic circulation during sepsis. Although circulating PGE2 levels were not altered, plasma PGI2 increased significantly at 2 h after CLP. The elevated circulating PGI2 levels, therefore, may be partially responsible for the decreased vascular resistance and increased tissue perfusion at 2 h after CLP. Our findings also suggest that cellular dysfunction, observed in the very early stage of sepsis, is not due to any hyperdynamic circulation/hypermetabolism-related events, but may be associated with the release of proinflammatory cytokines.

6-Ketoprostaglandin F1 alpha↗

PubMed1994

Nitric oxide. To block or enhance its production during sepsis?

BACKGROUND: Although it has been suggested that over-production of nitric oxide (NO) is responsible for death during endotoxic shock or sepsis, recent studies indicate that NO inhibition under such conditions is detrimental. The reason for these seemingly controversial findings may be because most studies were not standardized, ie, they were conducted at different stages of sepsis. OBJECTIVE: To determine whether differential alterations in endothelium-derived NO occur at different stages of sepsis. DESIGN, INTERVENTION, AND MAIN OUTCOME MEASURES: Rats were subjected to sepsis by cecal ligation and puncture (CLP) or sham operation, followed by injection of 3 mL/100 g of body weight saline solution. At 2, 3.5, 10, or 20 hours after CLP, the thoracic aorta was isolated and responses to an endothelium-dependent vasodilator, acetylcholine (via NO), and an endothelium-independent vasodilator, nitroglycerine (directly providing NO) were determined. RESULTS: Endothelium-dependent relaxation increased at 2 hours (ie, very early after the onset of sepsis), returned to sham levels at 3.5 hours, but decreased at 10 and 20 hours after CLP (ie, later stage of hyperdynamic sepsis and hypodynamic sepsis, respectively). Moreover, the acetylcholine concentration, required to produce half-maximum relaxation, decreased at 2 hours but increased at 20 hours after CLP. No significant difference in nitroglycerine-induced relaxation was seen, however, in the tested groups. The increased vascular relaxation at 2 hours after CLP was not due to the upregulation of prostacyclin since cyclooxygenase inhibition did not reverse this phenomenon. CONCLUSIONS: This study points out the complexity of the alterations in NO production with the progression of sepsis. The triphasic response of endothelium-derived NO should be taken into account when attempting to manipulate NO levels during sepsis.

Acetylcholine↗

PubMed1994

Chemically modified heparin improves hepatocellular function, cardiac output, and microcirculation after trauma-hemorrhage and resuscitation.

BACKGROUND: Although heparinization before hemorrhagic shock improves tissue perfusion and organ function, the anticoagulant properties of conventional heparin preclude its clinical use. The purpose of this study was to determine whether chemically modified heparin (CMH), which does not have any significant anticoagulant activity, produces any beneficial effects on hepatocellular and cardiovascular function and microcirculation after trauma-hemorrhage and resuscitation. METHODS: After induction of tissue trauma (that is, laparotomy), rats were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximum bleedout volume was returned in the form of Ringer's lactate (RL). The animals were then resuscitated with three times the volume of shed blood with RL over 45 minutes, followed by two times RL and CMH (7 mg/kg body wt; approximately 10% of the anticoagulant activity of conventional heparin), conventional heparin (7 mg/kg), or normal saline solution over 60 minutes. Hepatocellular function, cardiac output, and microvascular blood flow were determined thereafter. RESULTS: The results indicate that hepatocellular function, cardiac output, and microvascular blood flow in the liver, kidney, spleen, and small intestine decreased markedly after trauma-hemorrhage and resuscitation. Infusion of CMH or conventional heparin during resuscitation, however, restored or significantly improved the mentioned parameters. CONCLUSIONS: Because CMH does not have any significant anticoagulant properties and because it restores or significantly improves hepatocellular function, cardiac output, and tissue perfusion, this agent appears to be a useful adjunct in the treatment of trauma and hemorrhagic shock, even in the absence of blood resuscitation.

Animals↗

PubMed1994

Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation.

Although interleukin-6 (IL-6) plays an important role in the pathophysiology of trauma-hemorrhage and resuscitation, the cellular origin of this inflammatory cytokine remains unknown. This study was undertaken to determine whether Kupffer cells (KC) are a major source of IL-6 release following trauma-hemorrhage and resuscitation. KC numbers were significantly (p < .05) reduced in vivo with gadolinium chloride (GdCl3; 10 mg/kg IV). KC-reduced (KC(-)) and KC-normal (saline-treated; KC(+)) rats underwent laparotomy (i.e., trauma-induced), followed by either sham operation or hemorrhage. Hemorrhaged rats were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the shed blood volume was returned as Ringer's lactate, and then resuscitated with Ringer's lactate (four times shed blood volume over 1 h). Results indicate that KC reduction per se had no effect on any measured parameter at any time. At 0.5 and 2.0 h postresuscitation, mean arterial pressure, heart rate, cardiac output, stroke volume, and hematocrit were reduced to a similar extent in both the KC(+) and KC(-) hemorrhage groups. KC reduction did, however, significantly reduce plasma IL-6 concentration (means +/- S.E.; U/ml) at both 0.5 h (KC(+) = 709 +/- 391 vs. KC(-) = 159 +/- 5) and at 2.0 h (KC(+) = 527 +/- 394 vs. KC(-) = 83 +/- 20) postresuscitation. In conclusion, this study demonstrates that KC are a major source of in vivo IL-6 release following trauma-hemorrhage and resuscitation.

Animals↗

PubMed1994

Differential alterations in cyclic nucleotide levels in Kupffer cells and hepatocytes following trauma-hemorrhage and resuscitation.

Although cyclic nucleotides play an important role in regulating the control of metabolism, it is not known whether there are any differential alterations in cyclic nucleotides in Kupffer cells and hepatocytes after trauma-hemorrhage and resuscitation. To study this, rats underwent laparotomy (i.e., trauma-induced) and were rapidly bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximum bleedout volume was returned in the form of Ringer's lactate. The animals were then resuscitated with Ringer's lactate, equivalent to four times the volume of shed blood. At the time of maximum bleedout or at 1.5 h postresuscitation, a portion of the liver was removed, and the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were determined by radioimmunoassay. Moreover, Kupffer cells and hepatocytes were isolated in additional groups of animals and cAMP and cGMP levels were measured. The results indicate that hepatic cAMP decreased, whereas hepatic cGMP increased significantly at the time of maximum bleedout. Although resuscitation normalized hepatic cyclic nucleotide levels, the levels of cAMP and cGMP in Kupffer cells increased significantly at 1.5 h after resuscitation. In contrast, cAMP and cGMP levels in hepatocytes were not significantly different from shams under such conditions. Thus, differential alterations in cyclic nucleotide levels in different liver cell populations occur following trauma-hemorrhage and resuscitation.

Animals↗

PubMed1994

ATP-MgCl2 administration normalizes macrophage cAMP and beta-adrenergic receptors after hemorrhage and resuscitation.

Although ATP-MgCl2 attenuates the release of inflammatory cytokines and restores the defective macrophage (M phi) antigen presentation function after hemorrhage and resuscitation, it is not known whether administration of this agent after hemorrhage affects M phi adenosine 3',5'-cyclic monophosphate (cAMP) levels and beta-adrenergic receptors. To determine this, rats underwent a midline laparotomy (i.e., induction of trauma) and were then bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximum bleedout volume was returned in the form of Ringer lactate (RL). Animals were resuscitated with four times the volume of shed blood with RL, during and after which ATP-MgCl2 (50 mumol/kg) or saline was administered over 95 min. At 1.5 h postresuscitation (i.e., 10 min after completion of ATP-MgCl2 infusion), peritoneal M phi and Kupffer cells were isolated, and cAMP levels were measured by radioimmunoassay. beta-Receptor binding characteristics were also determined in isolated Kupffer cells. The results indicate that cAMP levels increased significantly in both peritoneal M phi and Kupffer cells after hemorrhage and resuscitation. Maximum binding capacity (Bmax) of beta-receptors increased in Kupffer cells, suggesting that the elevated cAMP may be due to the increased beta-receptor Bmax under such conditions. ATP-MgCl2 treatment, however, markedly decreased beta-receptor Bmax in Kupffer cells and cAMP in both peritoneal M phi and Kupffer cells, and the values were similar to shams. Thus normalization of M phi cAMP levels and beta-receptor binding capacity by ATP-MgCl2 may contribute to the immunoenhancing effects of this agent observed after trauma-hemorrhage and fluid resuscitation.

Adenosine Triphosphate↗