Fu-Chao Liu

Inflammation Confers Dual Effects on Nociceptive Processing in Chronic Neuropathic Pain Model

Background:Although inflammation induces pain, immune cells also produce mediators that can effectively counteract it. To further elucidate the role of the immune response, we analyzed the relationship of pain behavior, several inflammatory signals, and opioid peptides using partial sciatic nerve ligation in mice at different levels of immunocompromise. Methods:Sciatic nerves of C57BL/6C, nonobese diabetic (NOD), or nonobese diabetic–severe combined immune deficiency (NOD-SCID) mice were partially ligated. Responses to mechanical and radiant heat stimuli were observed. Inflammation was detected by immunohistochemistry and flow cytometry. Inflammatory cytokines and opioid peptides were analyzed using real-time polymerase chain reaction and enzyme-linked immunosorbent assay or immunostaining. Results:Inflammation in immunocompromised mice was subordinate when compared with that seen in C57BL/6C mice. In addition, immunocompromised mice had less pain hypersensitivity at early stages. Whereas proinflammatory tumor necrosis factor-&agr; (TNF-&agr;), interleukin 1&bgr; (IL-1&bgr;), interleukin 6 (IL-6), and interferon-&ggr; (IFN-&ggr;), as well as antiinflammatory interleukin 1 receptor antagonist (IL-1Ra), interleukin 4 (IL-4), interleukin 10 (IL-10), and interleukin 13 (IL-13) cytokine expression and protein were increased in C57BL/6C mice, they were lower in immunocompromised mice. Although enkephalin, dynorphin, and &bgr;-endorphin messenger RNA expression also increased in C57BL/6C mice, peaking on day 14, this result was not observed in immunocompromised mice. Conclusion:The contribution of inflammation to nerve injury is complex with biphasic modulation. During the early phase, a wide range of proinflammatory cytokines are released, leading to enhanced pain. In contrast, the analgesic effect of opioid peptides and antiinflammatory cytokines was more predominate in the later phases of injury, leading to attenuated pain responses.

Inhibition of the cyclic adenosine monophosphate pathway attenuates neuropathic pain and reduces phosphorylation of cyclic adenosine monophosphate response element-binding in the spinal cord after partial sciatic nerve ligation in rats

BACKGROUND:Recent reports have identified a role for cyclic adenosine monophosphate (cAMP) transduction in nociceptive processing. Spinal activation of the cAMP induced gene transcription through the activation of protein kinase A and cAMP response element-binding protein (CREB). Intrathecal injection of protein kinase A inhibitor reversed the mechanical hyperalgesia, whereas injection of CREB antisense attenuated tactile allodynia caused by partial sciatic nerve ligation (PSNL) in rats. In the present study, we aimed to assess the effects of spinal cAMP transduction on the nociceptive processing in a chronic neuropathic pain model. METHODS:PSNL was performed in male Sprague-Dawley rats 1 wk after intrathecal catheterization. Nociception to mechanical and thermal stimuli was assessed at the hindpaw 2 h, 3, 7, and 14 days after PSNL. The effects of adenylate cyclase inhibitor, SQ22536 (0.7 &mgr;mol, intrathecal) on these nociceptions were evaluated. Changes in the expression and immunoreactivity of CREB and its phosphorylated proteins (CREB-IR and pCREB-IR) in the dorsal horn of the spinal cord were also measured. RESULTS:The expression of CREB-IR and pCREB-IR proteins was shown to increase for 2 wk after PSNL. The increase in pCREB was partially reversed by the blockade of the cAMP pathway in the early 3 days, with a parallel increase in mechanical and thermal withdrawal thresholds. CONCLUSION:These results revealed the possible contribution of an increase in pCREB to the PSNL-induced tactile allodynia and thermal hyperalgesia. Modulation of the cAMP pathway may be clinically relevant if early intervention can be achieved in patients with chronic neuropathic pain.

Cardiac Output Derived From Arterial Pressure Waveform Analysis: Validation of the Third-Generation Software in Patients Undergoing Orthotopic Liver Transplantation

BACKGROUND The upgraded third-generation software (version 3.02) for the FloTrac/Vigileo system has been developed to particularly improve the accuracy of cardiac output (CO) measurements in hyperdynamic conditions. The aim of our study was to compare the CO values obtained using the FloTrac/Vigileo system during orthotopic liver transplantation (OLT) with those obtained in the same circumstances using a Swan-Ganz catheter (bolus thermodilution method). METHODS Twenty consecutive recipients scheduled for OLT were studied. Simultaneous CO values measured by both devices were obtained at 10 predefined time points throughout the surgery. A percentage error of not more than 30% was established as the criterion for device interchangeability. RESULTS A total of 200 paired measurements were obtained. The CO values derived from the FloTrac/Viligeo ranged from 2.8 to 10.9 L/min, with a mean of 5.91±1.81 L/min. The values from bolus thermodilution ranged from 2.2 to 13.2 L/min, with a mean of 6.12±2.07 L/min. The bias was 0.22, and the limits of agreement were -3.13 to 3.56 L/min. The percentage error between the FloTrac/Viligeo and bolus thermodilution measurements was 54.93%. The percentage errors of paired measurements in three surgical phases by subgroup analysis were 43.50% (dissecting phase), 62.9% (anhepatic phase), and 56.05% (reperfusion phase), respectively. CONCLUSION CO measurements obtained using the less invasive arterial waveform FloTrac/Vigileo system upgraded with the third-generation software had poor intraoperative agreement with pulmonary artery thermodilution CO measurements in patients undergoing OLT.

Sirtinol attenuates hepatic injury and pro-inflammatory cytokine production following trauma-hemorrhage in male Sprague-Dawley rats.

Background: Although studies have demonstrated that sirtinol administration following adverse circulatory conditions is known to be protective, the mechanism by which sirtinol produces the salutary effects remains unknown. We hypothesized that sirtinol administration in male rats following trauma‐hemorrhage decreases cytokine production and protects against hepatic injury.

Sirtinol Inhibits Neutrophil Elastase Activity and Attenuates Lipopolysaccharide-Mediated Acute Lung Injury in Mice

Enhanced activity of neutrophil elastase leads to a protease–antiprotease imbalance, and plays an essential pathogenic role in acute lung injury (ALI) and acute respiratory distress syndrome. We assayed the pharmacological effects and mechanisms of the action of sirtinol in human neutrophils, and in neutrophil elastase (HNE)-induced paw edema and lipopolysaccharide (LPS)-mediated ALI in mice. Sirtinol significantly inhibited the activity of HNE from human neutrophils in response to various stimulators. The inhibitory effects on HNE activity were not mediated through protein kinase A, calcium, extracellular-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, Akt, or Src family kinases. Analysis of enzymatic activities showed that sirtinol inhibited HNE activity in a concentration-dependent manner. These results demonstrate that sirtinol does not affect neutrophil function and is an HNE inhibitor. In addition, administration of sirtinol significantly inhibited HNE-induced paw edema, and attenuated the myeloperoxidase activity and reduced pulmonary wet/dry weight ratio in the LPS-induced ALI mouse model. Our study indicates that sirtinol has anti-inflammatory effects through direct inhibition of HNE activity and attenuates HNE-induced and LPS-mediated tissue or organ injury in vivo. Sirtinol is a novel HNE inhibitor and may have the potential for clinical application in the treatment of inflammatory lung diseases.

Organ-Protective Effects of Red Wine Extract, Resveratrol, in Oxidative Stress-Mediated Reperfusion Injury

Resveratrol, a polyphenol extracted from red wine, possesses potential antioxidative and anti-inflammatory effects, including the reduction of free radicals and proinflammatory mediators overproduction, the alteration of the expression of adhesion molecules, and the inhibition of neutrophil function. A growing body of evidence indicates that resveratrol plays an important role in reducing organ damage following ischemia- and hemorrhage-induced reperfusion injury. Such protective phenomenon is reported to be implicated in decreasing the formation and reaction of reactive oxygen species and pro-nflammatory cytokines, as well as the mediation of a variety of intracellular signaling pathways, including the nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, deacetylase sirtuin 1, mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, hemeoxygenase-1, and estrogen receptor-related pathways. Reperfusion injury is a complex pathophysiological process that involves multiple factors and pathways. The resveratrol is an effective reactive oxygen species scavenger that exhibits an antioxidative property. In this review, the organ-protective effects of resveratrol in oxidative stress-related reperfusion injury will be discussed.

Hydroxyethyl starch interferes with human blood ex vivo coagulation, platelet function and sedimentation.

BACKGROUND Hydroxyethyl starch (HES) solutions are widely used for intravascular volume expansion. In Taiwan, the medium molecular weight of HES 200/0.5 and HES 130/0.4 solutions are most commonly used. It has been demonstrated that HES may affect coagulation and platelet function significantly. However, the differential effects of each medium molecular weight HES on platelets remain poorly reported. Therefore, we studied the influence of the two HES solutions on platelet function in vitro by mixing whole blood with different proportions of HES 130 kD, HES 200 kD, and saline to determine the differences. METHODS Human blood samples for platelet function analyzer (PFA), aggregometry and blood/HES mixed test were drawn from the antecubital vein and put into test tubes containing 3.2% trisodium citrate (blood:citrate, 9:1). The specimens were divided into four groups, designated as whole blood, 10%, 20%, and 30% dilution with normal saline (N/S), HES130 or HES200 solution. The platelet function of each sample was measured by both PFA and platelet aggregometry. RESULTS The results showed that the PFA-100 closure times CEPI-CT and CADP-CT were significantly prolonged in the samples diluted with normal saline, HES130 and HES200 than in the controls. The ADP triggered whole blood aggregometry showed that attenuated impedance was observed in samples of 20% diluted with HES130 and HES200 groups. The blood/HES mixed sedimentation test showed significantly increased proportion of the upper liquid layer in the HES200 group than in other groups. CONCLUSION Our data demonstrated that HES200 and HES130 possess noticeably inhibitory effects on platelet function, especially when the HES replaced proportion was more than 20%. HES200 has a greater effect on blood cells and plasma separation than does HES130.

Protective Effect of Tropisetron on Rodent Hepatic Injury after Trauma-Hemorrhagic Shock through P38 MAPK-Dependent Hemeoxygenase-1 Expression

Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1) pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35–40 mmHg for 90 min), followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight), or a single dose of tropisetron (1 mg/kg body weight) with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight) or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight). Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST) and alanine aminotransferases (ALT), hepatic myeloperoxidase (MPO) activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α). These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic injury after trauma-hemorrhage is likely mediated through p38 MAPK-dependent HO-1 expression.

Exogenous granulocyte colony-stimulating factor exacerbate pain-related behaviors after peripheral nerve injury

Previous studies have demonstrated that inflammatory cells produce several mediators that can effectively counteract pain. This study was designed to test the hypothesis that exogenous administration of recombinant mouse granulocyte-colony-stimulating factor (rmG-CSF) to enhance the recruitment of inflammatory cells to painful inflamed sites could attenuate pain in a chronic neuropathic pain model in mice. Our results indicate that treatment with rmG-CSF increased several cytokines and opioid peptides content; however, it did not attenuate but exacerbate neuropathic pain. Our study highlights the potent pro-inflammatory potential of G-CSF and suggests they may be targets for therapeutic intervention in chronic neuropathic pain.

Hemeoxygenase-1 Upregulation Is Critical for Sirtinol-mediated Attenuation of Lung Injury After Trauma-hemorrhage in a Rodent Model

BACKGROUND: Hemeoxygenase-1 induction in response to adverse circulatory conditions is protective. Our recent study has shown that administration of sirtinol attenuates hepatic injury in male Sprague-Dawley rats after trauma-hemorrhage; however, the mechanism by which sirtinol produces the salutary effects remains unknown. We hypothesized that sirtinol administration in male Sprague-Dawley rats after trauma-hemorrhage decreases cytokine production and protects against lung injury through a hemeoxygenase-1 related pathway. METHODS: Male Sprague-Dawley rats (n = 8 per group) underwent trauma-hemorrhage (mean arterial blood pressure 40 mm Hg for 90 min, then resuscitation). A single dose of sirtinol (1 mg/kg of body weight) with or without a hemeoxygenase enzyme inhibitor (chromium-mesoporphyrin) or vehicle was administered IV during resuscitation. Twenty-four hours thereafter, myeloperoxidase activity (a marker of neutrophil sequestration) and tumor necrosis factor &agr;, interleukin-6, and interleukin-10 levels in the lung, protein concentrations in bronchoalveolar lavage fluid and tissue histology were measured. Lung hemeoxygenase-1 protein level was also determined. RESULTS: In the sirtinol-treated rats subjected to trauma-hemorrhage, there were significant improvements in lung myeloperoxidase activity (4.68 ± 0.31 vs 9.36 ± 1.03 U/mg protein, P < 0.05), tumor necrosis factor &agr; levels (710.7 ± 28 vs 1288 ± 40.69 pg/mg protein, P < 0.05), interleukin-6 levels (343.6 ± 18.41 vs 592.7 ± 22.3 pg/mg protein, P < 0.05), and protein concentrations (303.8 ± 24.54 vs 569.6 ± 34.82 &mgr;g/mL, P < 0.05) and lesser damage in histology. There was no statistically significant difference in interleukin-10 levels in the lung between sirtinol-treated trauma-hemorrhaged rats and vehicle-treated trauma-hemorrhaged rats (842.5 ± 54.18 vs 756.2 ± 41.34 pg/mg protein, respectively). Lung hemeoxygenase-1 protein levels were increased in rats receiving sirtinol treatment as compared with vehicle-treated trauma-hemorrhaged rats (5.18 ± 0.25 vs 2.70 ± 0.16, P < 0.05). Administration of the hemeoxygenase inhibitor chromium-mesoporphyrin prevented the sirtinol-induced attenuation of shock-induced lung damage. CONCLUSION: The salutary effects of sirtinol administration on attenuation of lung inflammation after trauma-hemorrhage are mediated via upregulation of hemeoxygenase-1 expression.