PubMed Health⌕ Search

Biomedical subjects

Satoshi Gando

Publications and source records attributed to Satoshi Gando.

At least 19 recordsLinked to original sources

A prospective comparative study of three sets of criteria for disseminated intravascular coagulation: ISTH criteria vs Japanese criteria.

Clinical and laboratory criteria and a scoring system for disseminated intravascular coagulation (DIC) were recently published by the International Society on Thrombosis and Haemostasis (ISTH). In Japan, the DIC Diagnostic Standards published in 1988 have been widely used for more than 10 years. In a general intensive care unit, we prospectively compared the diagnostic properties of the overt DIC, nonovert DIC, and Japanese DIC criteria sets, and investigated the influences of each set on patient morbidity and mortality. Seventy-four patients with platelet counts below 150 x 10(9)/L were included in this study. Blood samples were collected daily from day 0 to day 4 after inclusion in the study. The Japanese DIC included the overt DIC and both of these were included in the nonovert DIC. The Japanese DIC criteria diagnosed DIC earlier than the nonovert DIC criteria did (P = .020). The DIC patients diagnosed by the Japanese criteria and those diagnosed by the overt DIC criteria showed a higher incidence of multiple organ failure than those without DIC (P = .013 and P = .022, respectively). The Japanese and the nonovert DIC criteria tended to predict patient prognoses effectively. In conclusion, the Japanese and the nonovert DIC criteria are of value in predicting outcome. However, the nonovert DIC criteria take more time to diagnose DIC than the Japanese criteria do. A more precise clinical study is needed to determined appropriate specific criteria and cutoff points in the nonovert DIC criteria set.

Aged↗

Differential expression, time course and distribution of four PARs in rats with endotoxin-induced acute lung injury.

The hypothesis that the expression of protease-activated receptors (PARs) protein is regulated at the level of transcription and that PAR isoforms, PAR-1, PAR-2, PAR-3, and PAR-4, in lung tissue show different patterns of expression in lipopolysaccharide (LPS)-induced acute lung injury (ALI) was tested. Male Wistar rats were rendered endotoxemic by intra-peritoneal injection of LPS (15 mg/kg body weight). We examined the expression of protein and mRNA and the immunohistochemical localization of PAR isoforms in lung tissues 1, 3, 6, and 10 h after LPS administration. Induction of ALI by LPS was confirmed based on histopathological changes. LPS administration induced significant increases in the expression of PAR isoforms (protein) at the level of transcription in ALI. While the time course of PAR-1 and -2 expressions were different, those of PAR-3 and -4 were almost similar. An immunohistochemical analysis showed localization of PAR isoforms in the vascular endothelium, alveolar epithelium, and alveolar macrophages. However, the cellular distribution patterns of PAR isoforms were different. We conclude that LPS induces increase in protein expression of PAR isoforms at the level of transcription in rats with ALI. The differential expression patterns (over a time course) and distribution of PAR isoforms suggests a distinct role for each isoform in the pathogenesis of LPS-induced ALI.

Animals↗

An alternative pathway for fibrinolysis is activated in patients who have undergone cardiopulmonary bypass surgery and major abdominal surgery.

INTRODUCTION: We conducted this prospective study in order to investigate the hypotheses that an alternative pathway for fibrinolysis is activated in patients who have undergone cardiopulmonary bypass (CPB) surgery and major abdominal surgery and that the levels of fibrin degradation products digested by polymorphonuclear neutrophil elastase (elastase-XDP) and the D-dimer increase in the patients' plasma. MATERIALS AND METHODS: We studied a total of 77 patients who were scheduled to undergo either CPB surgery (36 patients) or major abdominal surgery (41 patients) and then measured the elastase-XDP and D-dimer levels at several time points both during and after the surgeries. The CPB surgery was divided into surgery for aortic dissection (AD) and cardiac surgery. The major abdominal surgery consists of hepatic resection and esophagectomy. RESULTS: The elastase-XDP and D-dimer levels significantly increased in the patients who underwent both CPB surgery and major abdominal surgery. The elastase-XDP levels in AD surgery showed highest values at the end of the CPB, while the levels in the other surgeries reached their peak on the day after the surgery. Statistical difference was seen in the levels of elastase-XDP among the three subgroups undergoing a hepatic resection. While we found significant correlations between the levels of elastase-XDP and D-dimer in patients undergoing CPB surgery and a subsegmentectomy of a cirrhotic liver, the correlation coefficients were markedly low in comparison to those of the other surgeries. CONCLUSIONS: Our findings demonstrated that the elastase-mediated pathway of fibrinolysis is activated to varying degrees depending on the surgery performed. Variations in the correlation coefficients between the levels of elastase-XDP and D-dimer may suggest that elastase-mediated fibrinolysis play a different role from the physiological fibrinolysis mediated by plasmin.

Cardiopulmonary Bypass↗

Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat.

To elucidate roles of microvascular factors in the pathogenesis of renal complications during endotoxemia, that is characterized by renal vasoconstriction and systemic hypotension/generalized non-renal vasodilation, we profile the expression pattern and time-course of three key vaso-regulators, namely endothelin (ET)-1, nitric oxide (NO), and angiotensin II (Ang II). We hypothesize that disruption of the overall balance between vasodilatation and vasoconstriction in the kidney, during the early phase of sepsis, contribute to its (kidney) predisposition to acute renal failure. Adult male Wistar rats were rendered endotoxemic at different time points (1, 3, 6 and 10 h) by a single i.p. injection of lipopolysaccharide (LPS) (15 mg/kg) dissolved in saline. Control group was injected vehicle only (saline). Both systolic and diastolic blood pressures significantly decreased at different time points after LPS administration. Surprisingly, renal histopathological evaluation showed no remarkable changes in LPS-induced endotoxemia. However, overall, levels of the vaso-regulators and, where applicable, their respective receptors were upregulated: (1) plasma ET-1 increased 25-fold and peaked, as renal ET-1 mRNA, at 3 h; renal ET-1 protein and its receptors, ET type A (ET(A)) receptor (vasoconstrictive) and ET type B (ET(B)) receptor (vasodilatatory) increased in a time-dependent fashion, (2) Ang II increased by 53% compared to control, peaking at 6 h. However, while levels of Ang II type 1 (AT1) receptor increased over time after LPS injection, those of Ang II type 2 (AT2) receptor were downregulated, (3) data of NO system (NO-NOS), the key vasodilator, were the most intriguing. Whereas levels of renal NO increased time-dependently following LPS administration, with a 2240-fold increase in renal iNOS expression, levels of eNOS, were almost unchanged. In conclusion, the present study overall reveals intriguing and complex dynamics between levels of vasoconstrictors and vasodilators during the early phase of LPS-induced endotoxemia. These shifts in molecular expressions are likely triggered by compensatory mechanisms aimed at counteracting the undesirable and dominant effects of one group of vaso-regulatory moiety over the other.

Angiotensin II↗

First day dynamic changes in antithrombin III activity after supplementation have a predictive value in critically ill patients.

To evaluate the changes in the antithrombin III (antithrombin) values after initial supplementation to predict outcome in critically ill patients, we conducted a retrospective study. All consecutive patients admitted to the intensive care unit (ICU) and treated with antithrombin were enrolled in the study. Initial doses of 1,500 IU or 30 IU/kg antithrombin concentrates were administered over an hour. The clinical backgrounds of the patients were collected from computer-based records. Serial data of antithrombin were collected from the first day of administration (Day 0) to days 1-4. The patients were subdivided into two groups based on whether they demonstrated an increased antithrombin activity of more than 60% on the first day after the initial supplementation (responders) or not (nonresponders). Four hundred thirty-five patients were enrolled in the present study. Two hundred eighty-eight patients could achieve an antithrombin activity of more than 60%. The outcome was significantly different between the two groups. A logistic regression analysis revealed the day 1 antithrombin level and an initial increase of less than 60% after supplementation to be independently associated with ICU mortality. We also found a significant increase in the platelet counts and fibrinogen levels, and a decrease in the disseminated intravascular coagulation (DIC) scores for the responders. In conclusion, our findings demonstrated the first-day dynamic change in antithrombin activity, and not the basal level, to be able to predict critically ill patient death. This dynamic change was associated with an improvement in the platelet counts, fibrinogen levels, and the DIC score.

Adult↗

Tissue factor in trauma and organ dysfunction.

Tissue factor (TF) performs an essential role in the blood clotting system by activating the extrinsic coagulation pathway following vascular injury. In addition to this physiological hemostatic role for wound repair, TF also plays pivotal roles in organ dysfunction in trauma patients by triggering pathological disseminated thrombosis and inflammation. Constitutively expressed TF in subendothelial cells is released into the circulation following trauma and can be detected as slightly elevated TF levels in the plasma. Liberation of constitutive TF into the blood and inducible tissue factor expression on monocytes and the other cells may synergistically increase plasma TF levels to higher values at the early stage of posttrauma, especially in patients with disseminated intravascular coagulation (DIC) in association with sustained systemic inflammatory response syndrome. Marked TF generation not adequately balanced by physiological coagulation inhibitors such as tissue factor pathway inhibitor in posttrauma DIC patients has been observed. Based on these pieces of evidence, it has now been accepted that combined activation of TF-dependent coagulation inadequately regulated by anticoagulant mechanisms and inflammation may synergistically play important roles in the pathogenesis of posttrauma multiple organ dysfunction syndrome.

Blood Coagulation↗

A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria.

OBJECTIVES: To validate scoring algorithm criteria established by the Japanese Association for Acute Medicine (JAAM) for disseminated intravascular coagulation (DIC) and to evaluate its diagnostic property by comparing the two leading scoring systems for DIC, from the Japanese Ministry of Health and Welfare (JMHW) and International Society on Thrombosis and Haemostasis (ISTH). DESIGN: Prospective, multicenter study during a 3-month period. SETTING: General critical care center in a tertiary care hospital. PATIENTS: Two hundred seventy-three patients with platelet counts<150x109/L were enrolled. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The JAAM, JMHW, and ISTH DIC scoring algorithms were prospectively applied within 12 hrs of patients meeting the inclusion criteria (day 0) to days 1-3, by global coagulation tests. The numbers of systemic inflammatory response syndrome (SIRS) criteria and Sequential Organ Failure Assessment (SOFA) scores were determined simultaneously. Mortality associated with any cause was also assessed 28 days after the enrollment. All global coagulation tests and SIRS criteria adopted in the JAAM criteria and their cutoff points were validated with use of SOFA scores and mortality rate. DIC diagnostic rate of the JAAM DIC scoring system was significantly higher than that of the other two criteria (p<.001). The JAAM DIC algorithm was the most sensitive for early diagnosis of DIC (p<.001). PATIENTS who fulfilled the JAAM DIC criteria included almost all those whose DIC was diagnosed by the JMHW and ISTH scoring systems. The JAAM DIC scores showed significant correlation with SOFA scores ([rho]=0.499; p<.001). SOFA score and mortality rate worsened in accordance with an increase in the JAAM DIC score. Fibrinogen criteria had little effect in predicting outcome for the DIC patients, and a total score of 4 points in the JAAM scoring system without fibrinogen was closely related to poor prognosis. According to the results, we revised the JAAM criteria by excluding fibrinogen and confirmed that the DIC diagnostic properties of original criteria remained unchanged in the revised JAAM criteria. CONCLUSIONS: The JAAM scoring system has an acceptable property for the diagnosis of DIC. The scoring system identified most of the patients diagnosed by the JMHW and ISTH criteria. Revised JAAM DIC criteria preserved all properties of the original criteria for DIC diagnosis. The revised scoring system can be useful for selecting DIC patients for early treatment in a critical care setting.

Algorithms↗

Evaluation of haemostatic molecular markers for diagnosis of disseminated intravascular coagulation in patients with infections.

Early treatment of disseminated intravascular coagulation (DIC) is recommended but global coagulation tests used in authorized DIC criteria are not sensitive for diagnosis of early-phase DIC. We examined the plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC) and D-dimer in patients with suspected DIC to determine the cutoff values for diagnosis of DIC. Plasma levels of D-dimer, TAT and PPIC were significantly elevated in patients with DIC and correlated with DIC score. The cutoff values were determined using the receiver operative curve analysis. The cutoff value represented the point at which the sensitivity curve crossed the specificity curve. The cutoff values of D-dimer, TAT and PPIC for DIC were 12.0 mug/ml, 11.0 ng/ml and 1.8 mug/ml, respectively. These values were moderately to highly sensitive for the diagnosis of DIC but not for poor outcome. The combination of D-dimer, TAT and PPIC showed high sensitivity and low specificity when one or more tests were positive, but showed low sensitivity and high specificity when all three tests were positive. We conclude that hemostatic molecular markers might be useful for the diagnosis of DIC and should be confirmed by several trials.

Aged↗

Alterations of gene expressions of preproET-1 and ET receptors in brains of endotoxemic Sprague-Dawley rats.

During severe sepsis, several immunological defense mechanisms initiate a cascade of inflammatory events leading to multiorgan failure, including septic encephalopathy and ultimately death. Endothelin-1 (ET-1) has recently been investigated in different cerebral pathologies. Some reports suggest the involvement of ET-1 in sepsis. However, no study to date has reported the alterations in expression of the genes encoding preproET-1 and ET receptors in the frontal cortex of the septic brain. Male Sprague-Dawley (SD) rats 8 weeks of age were administered either saline or 15 mg/kg lipopolysaccharide (LPS) at different time points (1, 3, 6, and 10 hrs). Rats that did not receive LPS were considered to be controls. The rats were sacrificed with ether, and the brain tissues were harvested. Systolic and diastolic blood pressure decreased 1 hr after LPS administration and then gradually returned to normal, without any change in the heart rate. We confirmed the induction of endotoxemia in the brains of SD rats by measuring the expression of nitric oxide synthase (NOS) mRNA induced in the cerebrum. The expression of inducible NOS (iNOS) mRNA in the brains of SD rat after LPS administration was 30-fold higher than that in the brains of control rats. mRNA expression of preproET-1 in the frontal cortex of SD rats after LPS administration was 2-fold higher than that in control rats. A time-dependent increase in the expression of the gene encoding the ET(A) receptor (vasoconstrictive property) after LPS administration was observed in SD rat brain, whereas expression of the gene encoding the ET(B) receptor (vasodilatatory property) showed an initial upregulation and then gradually decreased as sepsis progressed. In conclusion, we report for the first time that expressions of the genes encoding ET-1 and ET receptors are altered in the endotoxemic brain and that these alterations are time-dependent in SD rats. The alterations in the ET system in brain tissue observed in the present study may contribute to the understanding of the pathophysiological changes in the endotoxemic brain.

Animals↗

Altered expression of endothelin, vascular endothelial growth factor, and its receptor in hepatic tissue in endotoxemic rat.

Sepsis involves a heterogeneous class of syndromes, and septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs. The present study examined the time-dependent alterations of endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) levels in liver tissue in a septic rat model. Healthy male Wistar rats aged 15 weeks received 15 mg/kg lipopolysaccharide (LPS) and were sacrificed at different time points (1, 3, 6, and 10 hrs after treatment). Rats that did not receive LPS were considered to be controls. A 28-fold increase in the ET-1 level was observed in liver tissue 10 hrs after LPS administration. VEGF was also altered in hepatic tissue in a time-dependent manner. A gradual increase of VEGF expression in liver tissue after LPS administration was observed. Expression of Flt-1, the vascular permeability receptor of VEGF, was also increased in liver tissue after LPS administration. ET-1 is a potent vasoconstrictor and, therefore, may play a role in the regulation of hepatic perfusion in a sepsis model. On the other hand, VEGF may be involved in capillary leakage in liver tissue after LPS administration. The present findings suggest that there might be a loss of balance between the ET-1 and VEGF levels in the septic liver at different time points, which could contribute to the pathogenesis of acute liver injury in endotoxemia.

Animals↗

Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis.

The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease- activated receptors (PARs) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-a (TNF-a) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PARs in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.

Acute Disease↗

Evaluation of new Japanese diagnostic criteria for disseminated intravascular coagulation in critically ill patients.

New Japanese diagnostic criteria were prepared for disseminated intravascular coagulation (DIC) in critically ill patients and their usefulness was compared with the criteria of the International Society of Thrombosis and Haemostasis (ISTH) and those of the Japan Ministry of Health and Welfare (JMHW). In a retrospective study of patients with platelet counts of less than 150 x10(3)/mL, 52 cases (33.3%), 66 cases (42.3%), and 101 cases (64.7%) were diagnosed as DIC by the ISTH, JMHW, and new Japanese DIC criteria, respectively. The DIC state as diagnosed by the new Japanese DIC criteria included both DIC states as diagnosed by ISTH or JMHW criteria. Some DIC states diagnosed by the JMHW criteria included those diagnosed by ISHT criteria but this was not universal. The mortality of DIC as diagnosed by the ISTH or JMHW criteria was markedly high, compared to that for DIC diagnosed by the new Japanese criteria. The mortality of patients without DIC by ISTH was also high when they were diagnosed as DIC by the new Japanese criteria. The frequency of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection. The mortality of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection, and the mortality of overt-DIC by ISTH diagnostic criteria was also high in patients without infection.

Critical Illness↗

[Successful percutaneous drainage of epidural abscess with a 4Fr sheath and pig-tail catheter].

A 61-year-old woman was transfered to our emergency center because of epidural abcess with neurological deficits. Magnetic resonance imaging (MRI) revealed high intensity (T 2 WI) abscess in the epidural space from 5 th cervical to 3 rd thoracic spine level. Surgical drainage was interfered with her poor general conditions. Instead of surgical approach, we inserted a 4 Fr pig-tail catheter into the epidural space with a loss of resistance method, then made a continuous drainage of the abscess. Her neurological state improved after the procedure. Diminished epidural abscess was found on the MRI after the drainage. We demonstrated successfully treated epidural abscess by percutaneous drainage with a 4 Fr short sheath and pig-tail catheter.

Catheterization↗

Nuclear factor-kappaB decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis.

The transcription factor nuclear factor-kappaB (NF-kappaB) plays a key role in expression of many inflammatory genes responsible for the pathophysiology of sepsis-induced acute lung injury. We investigated whether the introduction of synthetic double-stranded oligodeoxynucleotides (ODNs) with consensus NF-kappaB sequence as transcription factor decoy can prevent acute lung injury with suppression of pulmonary expression of multiple genes involved in its pathological process in a cecal ligation and puncture septic mouse model. NF-kappaB decoy ODNs were introduced with the aid of the hemagglutinating virus of Japan-envelope vector method. Northern blot analysis indicated that transfection of NF-kappaB decoy ODN, but not of its scrambled form, resulted in a significant inhibition of sepsis-induced gene overexpression of inducible nitric-oxide synthase (iNOS), cyclooxygenase-2, histamine H(1)-receptor, platelet-activating factor receptor, and bradykinin B(1) and B(2) receptors in lung Histological damage in lungs tissues. (wall thickening, inflammatory infiltrate, and hemorrhage), increased pulmonary vascular permeability, and blood gas exchange impairment were clearly documented in mice after cecal ligation and puncture. These changes were strongly eliminated by the introduction of NF-kappaB decoy but not of scrambled ODN. The effects of the iNOS inhibitor FR260330 on these histological and functional derangements compared unfavorably with those of NF-kappaB decoy ODN transfection. Our results suggest that ODN decoy, acting as in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent an effective strategy in the treatment of septic acute lung injury.

Animals↗

Serial changes in neutrophil-endothelial activation markers during the course of sepsis associated with disseminated intravascular coagulation.

INTRODUCTION: For systematic elucidation of serial changes in neutrophil-endothelial activation markers as well as to investigate the correlationship among the inflammation markers, disseminated intravascular coagulation (DIC), and multiple organ dysfunction syndrome (MODS) in patients with sepsis, we made this prospective study. MATERIALS AND METHODS: Forty-five patients with sepsis, severe sepsis, and septic shock were subdivided into two groups, 27 with DIC and 18 without DIC. Eight normal healthy volunteers served as control subjects. Serial levels of soluble L-, P-, and E-selectins, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), thrombomodulin (sTM), and neutrophil elastase were measured within 12 h after the diagnosis of sepsis (day 0) and on days 1-4 after the diagnosis. The numbers of systemic inflammatory response syndrome (SIRS) criteria that patients met and the DIC score were determined simultaneously. RESULTS: Acute Physiology and Chronic Health Evaluation (APACHE) II score was identical between the two groups. In the DIC patients, higher DIC scores, lower platelet counts, and more maximum numbers of SIRS criteria being met were observed compared with the non-DIC patients. The incidence of MODS and the number of the dysfunctioning organs were higher in the patients with DIC than those without DIC, and the DIC patients had poor outcome. Soluble L-selectin (sL-selectin) levels in both groups tended to be lower than those in the control subjects. All other parameters both in the two groups were continuously higher than those in the control subjects during study period. The levels of soluble E-selectin (sE-selectin), sICAM-1, sVCAM-1, neutrophil elastase, and sTM were more elevated in the DIC patients than those in the non-DIC patients. There were no differences in the sP-selectin levels between the two groups; however, more increased sP-selectin levels per platelet were found in the DIC patients compared with the non-DIC patients. Maximum DIC scores in the DIC group positively correlated with the peak levels of neutrophil elastase and sTM and the number of the dysfunctioning organs. CONCLUSIONS: We found close relations among the neutrophil-endothelial cell interactions, DIC, and MODS in patients with sepsis, severe sepsis, and septic shock. The results indirectly confirm the concept that DIC can produce organ dysfunction and that DIC reflects an inflammatory disorder of the microvasculature.

Biomarkers↗

Therapeutic effect of in vivo transfection of transcription factor decoy to NF-kappaB on septic lung in mice.

Nuclear factor-kappaB (NF-kappaB) plays a key role in regulating expression of several genes involved in the pathophysiology of endotoxic shock. We investigated whether in vivo introduction of synthetic double-stranded DNA with high affinity for the NF-kappaB binding site could block expression of genes mediating pulmonary vascular permeation and thereby provide effective therapy for septic lung failure. Endotoxic shock was induced by an intravenous injection of 10 mg/kg Escherichia coli endotoxin in mice. We introduced NF-kappaB decoy oligodeoxynucleotide (ODN) in vivo 1 h after endotoxic shock by using a gene transfer kit. At 10 h, blood samples were collected for measurement of histamine and for blood-gas analysis. Gene and protein expression levels of target molecules were determined by means of Northern and Western blot analyses, respectively. The transpulmonary flux of (125)I-labeled albumin was used as an index of lung vascular permeability. Administration of endotoxin caused marked increases in plasma histamine and gene and protein expressions of histidine decarboxylase, histamine H(1) receptors, and inducible nitric oxide synthase in lung tissues. Elevated lung vascular permeability was also found. Blood-gas analysis showed concurrent decreases in arterial Po(2), Pco(2), and pH. All of these events induced by endotoxin were significantly inhibited by transfection of NF-kappaB decoy ODN but not by its mutated (scrambled) form (used as a control). Our results indicate for the first time the potential usefulness of NF-kappaB decoy ODN for gene therapy of endotoxic shock.

Animals↗

Histamine H1 and H2 receptor gene and protein levels are differentially expressed in the hearts of rodents and humans.

Histamine is highly concentrated in the heart of animals and humans. Excessive release in pathophysiological conditions, such as immediate hypersensitivity and septic shock, causes cardiac dysfunction and arrhythmias. Previous pharmacological studies revealed that H(1) and H(2) receptors mediate these effects. Yet, an accurate estimate of the distribution and molecular characteristics of cardiac histamine receptors is missing. Recently, the genes encoding H(1) and H(2) receptors have been cloned, and the amino acid sequence and protein structure have been elucidated. Accordingly, we analyzed gene and protein expression levels of H(1) and H(2) receptors in atria and ventricles of guinea pig, rabbit, rat, and human hearts. With immunocytochemical techniques, we examined the regional expression of H(1) and H(2) receptor proteins in the sinoatrial and atrioventricular nodes and surrounding myocardium of the guinea pig heart. Northern and Western blot studies revealed that cardiac histamine H(1) and H(2) receptors are variably distributed among different mammalian species and different regions of the heart, whereas H(2) receptors are abundantly expressed in human atrial and ventricular myocardium. These findings agree with those of previous pharmacological studies, clearly demonstrating that the responses of the heart to histamine depend on the expression level of H(1) and H(2) receptors. The highly abundant expression of H(2) receptors in the human heart substantiates histamine arrhythmogenicity in various disease states. The new knowledge of a differential distribution of histamine receptor subtypes in the human heart will foster a better understanding of histamine roles in cardiovascular pathophysiology and may contribute to new therapeutic approaches to histamine-induced cardiac dysfunctions.

Animals↗

Systemic inflammation and disseminated intravascular coagulation in early stage of ALI and ARDS: role of neutrophil and endothelial activation.

To determine the existence of a close link between inflammation and coagulation in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and to examine their prognostic value in the development of ARDS and clinical outcome, we made a prospective cohort study. The study subjects consisted of 57 patients: 19 patients with ARDS and 38 patients with ALI as defined by a Lung Injury Score of > or =2.5 and 1.0 to less than 2.5, respectively. According to the outcome, the patients were subdivided into the survivors and the nonsurvivors. Ten normal healthy volunteers served as control subjects. Plasma levels of soluble L-, P-, and E-selectins, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), thrombomodulin (sTM), and neutrophil elastase were measured within 24 h after the diagnosis of ALI or ARDS. The number of systemic inflammatory response syndrome (SIRS) criteria being met by the patients and the disseminated intravascular coagulation (DIC) scores were determined simultaneously. The number of SIRS criteria and the DIC scores of the patients with ALI or ARDS showed high values, and more than half of the patients were complicated by DIC. The levels of sL-selectin in both groups of the patients were significantly lower than those of the control subjects. All other soluble adhesion molecules, neutrophil elastase, and sTM in the patients with ALI and ARDS were markedly elevated than those in the control subjects. The levels sICAM-1, sVCAM-1, and sTM in the ARDS patients significantly increased compared with the ALI patients. The number of SIRS criteria and the DIC scores in the nonsurvivors showed higher values than those in the survivors. In addition, we found significant differences in the levels of soluble adhesion molecules, neutrophil elastase, and sTM between the survivors and the nonsurvivors. In conclusion, we found a concurrent activation of both inflammation and coagulation in the patients with ALI or ARDS. The results also suggest that systemic activation of inflammation and coagulation associated with endothelial injury has prognostic value for the development of ARDS and poor outcome.

Disseminated Intravascular Coagulation↗