Soluble CD163 is a biomarker for accelerated atherosclerosis in systemic lupus erythematosus patients at apparent low risk for cardiovascular disease.

Objective: This study aimed to determine whether sCD163, a soluble macrophage marker up-regulated in numerous inflammatory disorders, is predictive of accelerated atherosclerosis associated with systemic lupus erythematosus (SLE).Methods: Carotid ultrasound was prospectively performed, at baseline and during follow-up, in 63 consecutive SLE patients asymptomatic for cardiovascular disease (CVD) and 18 volunteer health workers. Serum sCD163 level was determined at baseline using enzyme-linked immunosorbent assay. The primary outcome was the presence of a carotid plaque. Factors associated with carotid plaques were identified through multivariate analysis.Results: Despite a low risk for cardiovascular events according to Framingham score in both groups (2.1 ± 3.8% in SLE vs 2.1 ± 2.9% in controls; p = 0.416), ultrasound at baseline showed a carotid plaque in 23 SLE patients (36.5%) and two controls (11.1%) (p = 0.039). Multivariate analysis showed that SLE status increased the risk for carotid plaque by a factor of 9 (p = 0.017). In SLE patients, sCD163 level was high (483.7 ± 260.8 ng/mL vs 282.1 ± 97.5 ng/mL in controls; p < 0.001) and independently associated with carotid plaques, as assessed by stratification based on sCD163 quartile values (p = 0.009), receiver operating characteristics (p = 0.001), and multivariate analysis (p = 0.015). sCD163 at baseline was associated with the onset of carotid plaque during follow-up (3 ± 1.4 years) in SLE patients who had no carotid plaque at the first evaluation (p = 0.041).Conclusion: sCD163 is associated with progressing carotid plaque in SLE and may be a useful biomarker for accelerated atherosclerosis in SLE patients at apparent low risk for CVD.

Pituitary-adrenal function after prolonged glucocorticoid therapy for systemic inflammatory disorders: an observational study.

CONTEXT: Glucocorticoid therapy is being used in a wide variety of systemic disorders. Reference papers, published more than 20 years ago, showed no correlation between adrenal insufficiency risk and dose or duration of glucocorticoid therapy. OBJECTIVE: Our objective was to evaluate the extent to which long-term glucocorticoid therapy damages the pituitary-adrenal axis in patients with systemic inflammatory disorders. DESIGN: We conducted a retrospective observational study from January 2011 to August 2012. SETTING: This was a monocentric study at the Department of Internal Medicine, Bichat Hospital, Paris-Diderot University, Paris, France. PARTICIPANTS: Sixty consecutive patients who were receiving long-term prednisone therapy for systemic inflammatory disorders and in whom discontinuation of glucocorticoid treatment was planned. INTERVENTION: A short Synacthen test was performed. A bolus of 0.25 mg 1-24-ACTH was injected in the morning, 24 hours after the most recent dose of prednisone. Cortisol was measured at baseline and 60 minutes after Synacthen injection. MAIN OUTCOME MEASURES: We assessed frequency and risk estimate of pituitary-adrenal dysfunction. RESULTS: Twenty-nine patients (48.3%) had adrenal insufficiency defined by a plasmatic cortisol <100 nmol/L (n = 13) at baseline (time 0) or <550 nmol/L (n = 16) 60 minutes after Synacthen injection. Cumulative dose (area under the receiver operating characteristic curve = 0.77 [95% confidence interval = 0.62-0.91], P = .007) and exposure (area under the receiver operating characteristic curve 0.80 [95% confidence interval = 0.67-0.93], P = .002) to prednisone were predictive for adrenal insufficiency based on a T0 <100 nmol/L. Prednisone was stopped in 29 of 31 patients (93.5%) showing a normal response to short Synacthen test; none of these patients required hydrocortisone replacement with a mean follow-up of 10 (± 6) months. CONCLUSION: Adrenal insufficiency is frequent in patients treated with long-term glucocorticoids for systemic inflammatory disorders and is related to duration and cumulative dose of steroids.

Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation.

Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by IGF-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by LPS injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNFα together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.

Assessment of salivary amylase as a stress biomarker in pregnant patients.

BACKGROUND: Chronic stress during pregnancy has been associated with worsened maternal and fetal outcomes. Acute stress immediately before spinal anaesthesia for caesarean section may contribute to hypotension. Therefore objective measures of acute stress may help identify women at risk of adverse outcomes. Salivary alpha-amylase is a stress biomarker that has so far been poorly investigated during pregnancy. The reference change value is the difference between two sequential results that must be exceeded for a change to be considered clinically relevant. Our first aim was to determine if salivary alpha-amylase increased in pregnant patients when subjected to the stress of transfer to the operating room. Our second aim was to determine if changes in salivary alpha-amylase were likely to be clinically significant by measuring reference change value in healthy volunteers. METHODS: In 15 pregnant patients undergoing planned caesarean section under spinal anaesthesia, salivary alpha-amylase, systolic blood pressure, heart rate, and immediate anxiety were measured on the morning of surgery on the ward and again in the operating room. The reference change value was calculated from 18 healthy volunteers. RESULTS: A median 220% increase in salivary alpha-amylase activity (P=0.0015) and a 17% increase in systolic blood pressure (P=0.0006) were observed between the ward and operating room. No changes of immediate anxiety or heart rate were observed. Reference change value was ±76% in volunteers and 13 of the 15 pregnant patients had a salivary alpha-amylase increase greater than the reference change value. CONCLUSION: When pregnant women are taken to the operating room, a clinically and statistically significant increase in salivary alpha-amylase was observed. Further studies are required to define its clinical usefulness.

Alveolar fibroblasts in acute lung injury: biological behaviour and clinical relevance.

Although fibroblasts are key cells in the lung repair/fibrosis process, their characteristics are poorly studied in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The aims of our study were to: 1) determine the biological behaviour of alveolar fibroblasts during ALI; and 2) to evaluate the clinical relevance of positive alveolar fibroblast culture from patients with ALI/ARDS. Cells were cultured from bronchoalveolar lavage (BAL) obtained from 68 critically ill, ventilated patients: ALI n = 17; ARDS n = 31; and ventilated controls n = 20. Patients were followed for 28 days and clinical data was recorded. We studied proliferation, migration and collagen-1 synthesis capacities of fibroblasts. Cells expressing fibroblast markers were cultured from BAL obtained in six (35%) ALI patients and six (19%) ARDS patients, but never from ventilated controls. Alveolar fibroblasts exhibited a persistent activated phenotype with enhanced migratory and collagen-1 production capacities, with hyporesponsiveness to prostaglandin E(2) compared to normal lung fibroblasts (p< or =0.04). Positive fibroblast culture was associated with both an increased collagen-1 concentration and monocyte/macrophage percentage in BAL fluid (p< or =0.01), and with a reduced duration of mechanical ventilation (p<0.001). We conclude that activated alveolar fibroblasts can be cultured either in ALI or ARDS and that their presence might reflect the initiation of the organising phase of ALI.

Selenoprotein P, rather than glutathione peroxidase, as a potential marker of septic shock and related syndromes.

BACKGROUND/AIMS: Oxidative stress is involved in sepsis-related endothelium dysfunction. Selenoprotein-P (Sel-P), the main plasma selenoprotein, may have high antioxidant potential, and binds to endothelium. We hypothesize that, in septic shock, and similar syndromes such as systemic inflammatory response syndrome (SIRS), Sel-P binds massively to endothelium, causing a drop in Sel-P plasma concentration. METHODS: Plasma Se, Sel-P and albumin concentrations, and glutathione peroxidase (GPx) activity were measured in patients with septic shock and SIRS with organ failure (S group, n = 7 and n = 3, respectively) admitted to the intensive care unit (ICU) and compared to non-SIRS patients (NS group, n = 11) and healthy volunteers (HV group, n = 7). RESULTS: On ICU admission, plasma Sel-P concentrations were 70% lower in the S group than in the other groups [15 (10-26) vs. 44 (29-71) and 50 (45-53) nmol/l] and were lower in nonsurviving septic-shock patients. GPx activity did not differ between groups. Sel-P was significantly lower before ICU death in the 3 deceased patients of the S group (septic shock) than in the 3 patients of the non-SIRS group. CONCLUSIONS: Early decrease in Sel-P plasma concentrations was specifically observed in septic shock and was similar in SIRS patients whereas GPx activity remained unchanged. Further studies are needed to determine whether Sel-P can be an early marker of septic shock linked to microvascular injury.

Immunohistochemical study of HLA-G expression in lung transplant recipients.

Human leukocyte antigen-G (HLA-G), a nonclassical HLA class I protein, promotes immune tolerance of solid-organ allografts, yet its role in lung transplantation (LTx) is unknown. We examined the expression of HLA-G in lung allografts through immunohistochemistry by a cross-sectional study of 64 LTx recipients, classified into four groups (stable patients, acute rejection [AR], bronchiolitis obliterans syndrome [BOS] and symptomatic viral shedders). A marked expression of HLA-G in bronchial epithelial cells (BEC) was frequently observed in stable recipients (n = 18/35 [51%]), but not in patients with AR (n = 14) or with BOS (n = 8). HLA-G was also expressed by 4 of 7 symptomatic viral shedders. In addition, HLA-G-positive patients from the stable group (n = 35) experienced lower incidence of resistant AR and/or BOS during long-term follow-up, as compared with their HLA-G-negative counterparts. Finally, in vitro data showed that interferon-gamma, a cytokine present in lung allograft microenvironment, upregulated HLA-G mRNA and protein expression in primary cultured human BEC. We conclude that HLA-G expression in the bronchial epithelium of lung allograft is elevated in some LTx recipients in association with their functional stability, suggesting a potential role of HLA-G as a tolerance marker.

Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice.

Serotonin (5-hydroxytryptamine; 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes, 5-HT2A and 5-HT2B, have been shown to play the most important roles in the lung. In the present study, the role of serotonin in lung fibrosis was investigated using the bleomycin mouse model. Serotonin concentrations in lung homogenates increased significantly over the time course of bleomycin-induced fibrosis, with a maximum at day seven. The expression of serotonin receptors 5-HT2A and 5-HT2B increased in the lung after bleomycin treatment, as assessed by PCR, specific binding and immunohistochemistry. Blockage of 5-HT2A receptors by ketanserin and 5-HT2B receptors by SB215505 reduced bleomycin-induced lung fibrosis, as demonstrated by reduced lung collagen content and reduced procollagen 1 and procollagen 3 mRNA expression. Serotonin antagonists promoted an antifibrotic environment by decreasing the lung mRNA levels of transforming growth factor-beta1, connective growth factor and plasminogen activator inhibitor-1 mRNA, but had minimal effects on lung inflammation as assessed by bronchoalveolar lavage cytology analysis. Interestingly, the 5-HT2B receptor was strongly expressed by fibroblasts in the fibroblastic foci in human idiopathic pulmonary fibrosis samples. In conclusion, the present study showed involvement of serotonin in the pathophysiology of bleomycin-induced lung fibrosis in mice and identified it as a potential therapeutic target in lung fibrotic disorders.

Changes in airway inflammation following nasal allergic challenge in patients with seasonal rhinitis.

BACKGROUND: Seasonal allergic rhinitis could predispose to the development of chronic bronchial inflammation as observed in asthma. However, direct links between nasal inflammation, bronchial inflammation and airway responsiveness in patients with seasonal allergic rhinitis and without asthma are not fully understood. The aim of this study was to analyse the changes induced by allergic nasal challenge outside the pollen season in airway responsiveness and bronchial inflammation of patients with seasonal allergic rhinitis. METHODS: Nine patients were evaluated after either grass pollens or placebo nasal challenge in a randomized cross-over double-blinded trial. Nasal parameters were recorded hourly and airway responsiveness was assessed by methacholine challenge. Cytological examinations and cytokine measurements were performed in nasal lavage and induced sputum. Eosinophil activation was investigated by eosinophil-cationic protein expression and secretion. RESULTS: Airway responsiveness was increased after allergic nasal challenge. Total eosinophils and eosinophils expressing eosinophil-cationic protein were increased in induced sputum after allergic nasal challenge. Both eosinophil number and eosinophil-cationic protein concentration in induced sputum were correlated to methacholine responsiveness. CONCLUSIONS: These results suggest that eosinophils participate to the bronchial inflammation in patients with seasonal allergic rhinitis following allergic nasal challenge outside the pollen season and might explain changes in airway responsiveness.

[The use of cardiac troponins (T or I) measurement in cardiology and various clinical settings]. / Dosage des isoformes cardiaques des troponines T ou I: intérêt en cardiologie et en anesthésie-réanimation.

Measurement of cardiac troponin I or T in serum (highly specific for the myocardium) have replaced classical markers, such as creatine kinase MB. Cardiac troponins are preferred markers because of their high specificity and sensitivity. This had led to modifications of the original World Health Organization criteria for acute myocardial infarction. Furthermore, the place of the troponins as superior markers of subsequent cardiac risk in acute coronary syndrome has now become firmly established, for both diagnostic and risk stratification purposes. The use of C-reactive protein and/or other inflammatory biomarkers may add independent information in this context. After non cardiac surgery, the total cardiospecificity of cardiac troponins explains why other biomarkers of necrosis should no longer be used. Recent studies suggest that any elevation of troponin in the postoperative period is indicative of increased risk of long-term cardiac complications. This prognostic value has been previously demonstrated in other clinical settings such as invasive coronary intervention (surgical myocardial revascularization and percutaneous coronary intervention) and after heart valve surgery. Increases of troponin indicate cardiac damage, whatever the mechanism (ischemic or not). Other causes of cardiac injury include: pulmonary embolism, myocarditis, pericarditis, congestive heart failure, septic shock, myocardial contusion. In most cases, elevation of troponins has been shown to be associated with a bad outcome.

Decreased expression of interleukin 13 in human lung emphysema.

BACKGROUND: The overexpression of interferon (IFN)gamma or interleukin (IL)-13 in the adult murine lung induces the development of changes that mirror human lung emphysema. METHODS: IL-13 and IFNgamma expression was determined in lung samples from five groups of PATIENTS: severe emphysema without alpha(1)-antitrypsin deficiency (SE+, n = 10); severe emphysema with alpha(1)-antitrypsin deficiency (SE-, n = 5); mild localised emphysema (ME, n = 8); non-emphysema smokers (NE-S, n = 9), and non-emphysema non-smokers (NE-NS, n = 11). Lung IL-13 and IFNgamma mRNA were analysed by RT-PCR. Lung concentrations of IL-13 protein were assessed by ELISA. RESULTS: The expression of IFNgamma mRNA was similar in patients with or without emphysema. IL-13 mRNA was markedly decreased in the SE+ group compared with the SE- (p = 0.04), ME (p = 0.02), and non-emphysema groups (p = 0.01). IL-13 mRNA correlated with forced expiratory volume in 1 second (r = 0.5, p = 0.04) and arterial oxygen tension (r = 0.45, p = 0.03) in emphysema patients. In contrast to the non-emphysematous lung, IL-13 protein was below the detection limit of the assay in most emphysematous lung homogenates. CONCLUSION: The lung IL-13 content is reduced in patients with severe emphysema without alpha(1)-antitrypsin deficiency.

[Keratinocyte growth factor and Hepatocyte growth factor: their roles in alveolar epithelial repair]. / Keratinocyte growth factor et Hepatocyte growth factor: rôles dans la réparation épithéliale alvéolaire.

INTRODUCTION: The alveolar epithelium is the principal target in the course of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) and to a lesser extent in chronic reactions like pulmonary fibrosis. STATE OF ART: Keratinocyte growth factor (KGF) and Hepatocyte growth factor (HGF) are potent growth factors for type II pneumocytes and seem to play a specific role in the process of alveolar repair. PERSPECTIVES: The studies conducted by our group have demonstrated 1) that KGF and HGF are present in biologically active concentrations in human pulmonary alveoli in ALI and ARDS, 2) that in these patients as well as those with pulmonary fibrosis circulating neutrophils are an important source of HGF. HGF and KGF act within a system involving other factors such as parathyroid hormone related protein (PTHrP). PTHrP acts in an autocrine and paracrine manner to regulate the balance between proliferation and apoptosis of alveolar epithelial cells. CONCLUSIONS: Our results obtained in humans suggest a beneficial role for neutrophils in the alveolar repair after acute or chronic lung injury. The experimental data suggest that use of KGF and HGF might be considered in the future in the treatment of human acute or chronic lung injury.

Utility of cardiac troponin measurement after cardiac surgery.

Postoperative cardiac failure due to myocardial necrosis remains a major complication in cardiac surgical procedures and its diagnosis is still difficult. In fact, cardiac enzymes, electrocardiogram and echographic signs are often misleading. The prognostic valve of troponin I after coronary artery bypass or conventional value surgery has been evaluated in 500 adult patients. Postoperative troponin I concentrations after cardiac surgery represent an independent variable associated with mortality (in-hospital death) and morbidity (low cardiac output and acute renal failure).

Oncostatin M production by blood and alveolar neutrophils during acute lung injury.

Polymorphonuclear neutrophils (PMN) are involved in the pathogenesis of acute lung injury (ALI), secreting numerous mediators such as proteases, reactive oxygen species, and cytokines. Because we had recently observed the ability of normal human PMN to degranulate and synthesize oncostatin M (OSM), an IL-6-family cytokine, we quantified OSM production ex vivo by highly purified blood and alveolar PMN from 24 ventilated patients with ALI, including some patients with severe pneumonia. Most of the patients had no detectable OSM in plasma, and OSM production by cultured blood PMN was similar to that of healthy controls. However, OSM was present in bronchoalveolar lavage (BAL) fluid supernatant, with significantly higher levels during pneumonia. In addition, alveolar OSM levels correlated with the number of PMN obtained by BAL, suggesting that PMN are an important source of OSM within the alveoli. Indeed, purified alveolar PMN from all of the patients, especially those with pneumonia, strongly produced OSM. Interestingly, in the latter patients, alveolar PMN always produced more OSM than autologous blood PMN. These results document the functional duality of PMN in ALI by showing the participation of PMN in the modulation of lung inflammation.

Hyperprocalcitonemia in patients with perioperative myocardial infarction after cardiac surgery.

OBJECTIVE: To describe and compare procalcitonin (PCT) concentrations after cardiac surgery in uncomplicated patients and in patients with perioperative myocardial infarction (PMI). DESIGN: Retrospective comparative study. SETTING: One university hospital. PATIENTS: Fifty-eight adult patients undergoing cardiac surgery. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: In a first step, plasma PCT and C-reactive protein concentrations were measured preoperatively and until 72 hrs postoperatively in ten consecutive patients who underwent uncomplicated cardiac surgery. PCT concentrations increased progressively from the end of cardiopulmonary bypass (0.09 +/- 0.09 ng/mL), peaked at 24 hrs postoperatively (1.14 +/- 1.24 ng/mL), and began to decrease at 48 hrs. C-reactive protein appeared to peak at 48 hrs (from 5.8 +/- 11.7 mg/L preoperatively to 265.1 +/- 103.5 mg/L on the second postoperative day). In a second step, PCT concentrations were measured at day one in 23 patients (PMI group) who presented high postoperative plasma cardiac troponin I concentrations and were compared with PCT concentrations observed in 25 matched uncomplicated patients. All patients were free from infection. PCT in the PMI group was significantly higher than in the control group (27.1 +/- 63.2 vs. 2.0 +/- 2.4 ng/mL, respectively; p =.0053). CONCLUSION: Because high plasma concentrations of PCT were found in patients with PMI after cardiac surgery, it may be suggested that, in the early postoperative period, elevated plasma PCT concentrations should be interpreted with caution regarding infection diagnosis.

Halothane reduces the early lipopolysaccharide-induced lung inflammation in mechanically ventilated rats.

Several studies suggest that anesthetics modulate the immune response. The aim of this study was to investigate the effect of halothane and thiopental on the lung inflammatory response. Rats submitted or not to intratracheal (IT) instillation of lipopolysaccharides (LPS) were anesthetized with either halothane (0. 5, 1, or 1.5%) or thiopental (60 mg. kg(-1)) and mechanically ventilated for 4 h. Control rats were treated or not by LPS without anesthesia. Lung inflammation was assessed by total and differential cell counts in bronchoalveolar lavage fluids (BALF) and by cytokine measurements (tumor necrosis factor-alpha [TNF-alpha], interleukin-6 [IL-6], macrophage inflammatory protein-2 [MIP-2], and monocyte chemoattractant protein-1 [MCP-1]) in BALF and lung homogenates. In the absence of LPS treatment, neither halothane nor thiopental modified the moderate inflammatory response induced by tracheotomy or mechanical ventilation. Cell recruitment and cytokine concentrations were increased in all groups receiving IT LPS. However, in halothane-anesthetized rats (halothane > or = 1%), but not in thiopental-anesthetized rats, the LPS-induced lung inflammation was altered in a dose-dependent manner. Indeed, when using 1% halothane, polymorphonuclear leukocyte (PMN) recruitment was decreased by 55% (p < 0.001) and TNF-alpha, IL-6, and MIP-2 concentrations in BALF and lung homogenates were decreased by more than 60% (p < 0.001) whereas total protein and MCP-1 concentrations remained unchanged. The decrease of MIP-2 (observed at the protein and messenger RNA [mRNA] level) was strongly correlated to the decrease of PMN recruitment (r = 0.73, p < 0.05). This halothane-reduced lung inflammatory response was transient and was reversed 20 h after the end of the anesthesia. Our study shows that halothane > or = 1%, delivered during 4 h by mechanical ventilation, but not mechanical ventilation per se, alters the early LPS-induced lung inflammation in the rat, suggesting a specific effect of halothane on this response.

Keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients.

OBJECTIVES: To determine bronchoalveolar lavage (BAL) fluid concentrations of keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), two potent growth factors for alveolar type II epithelial cells, in patients with acute respiratory distress syndrome (ARDS). DESIGN: Prospective study. SETTING: An adult trauma/surgical intensive care unit in an urban teaching hospital. PATIENTS: A total of 32 ventilated patients with pulmonary infiltrates prospectively identified with ARDS (n = 17) or without ARDS (n = 15), including eight patients with hydrostatic edema (HE), and ten nonventilated patients serving as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: BAL was performed 2.88 days +/- 2.4, 3.5 days +/- 2.4, and 2.3 days +/- 2.2 after the lung insult in ARDS, HE, and other non-ARDS patients respectively (p = .32). KGF was detected in BAL fluid in 13 of the 17 ARDS patients (median, 31.6 pg/mL), in one patient with HE, and in none of other non-ARDS patients. In ARDS patients, detection of KGF in BAL was associated in BAL fluid with the detection of type III procollagen peptide (PIIIP), a biological marker of fibroproliferation. In ARDS patients, detection of KGF in BAL was associated with death (p = .02). HGF was detected in 15 ARDS patients (median, 855 pg/mL), in seven patients with HE (median, 294 pg/mL; p = .05 for the comparison with ARDS group), in six of other non-ARDS patients (median, 849 pg/mL; p = .32 with ARDS group). HGF concentrations were higher in nonsurvivors than in survivors (p = .01). None of the ten BAL of controls contained either KGF or HGF. CONCLUSION: KGF was detected almost exclusively in BAL fluid from ARDS patients and correlated with a poor prognosis in this group. In contrast, HGF was detected in the BAL fluid from a majority of patients with or without ARDS. Elevated HGF concentrations were associated with a poor prognosis in the overall group.

Cardiopulmonary bypass decreases cytokine production in lipopolysaccharide-stimulated whole blood cells: roles of interleukin-10 and the extracorporeal circuit.

OBJECTIVE: To determine whether cardiopulmonary bypass (CPB) alters the ex vivo cytokine production of whole blood cells stimulated by lipopolysaccharide (LPS) and to assess the roles of interleukin (IL)-10 and an extracorporeal circuit (ECC) in the alteration. DESIGN: Prospective, controlled study. SETTING: Biochemistry laboratory and surgical intensive care unit in a university hospital. PATIENTS: Seventeen consecutive adult patients undergoing coronary artery bypass grafting or valve surgery with normothermic CPB and eight healthy volunteers. INTERVENTIONS: Blood samples for cytokine measurement were drawn from patients before and during (at 60, 90, 120, 180 and 360 mins) CPB and were cultured with and without LPS and with and without anti-IL-10 antibodies. Blood was also drawn from healthy subjects and sampled for cytokine analysis before and during circulation in an isolated ECC. MEASUREMENTS AND MAIN RESULTS: The concentrations of ex vivo tumor necrosis factor (TNF)-alpha, IL-6, IL-8, and IL-10, measured by enzyme-linked immunosorbent assay, were reduced in both experimental settings. In patients on CPB, LPS hyporesponsiveness was detected at 60 mins after the onset of CPB and was maximal at 120 mins (78% to 86% decreases from pre-CPB levels) but was transient, except for TNF-alpha. The plasma concentration of IL-10 peaked at 90 mins after the start of CPB, but the role of IL-10 in LPS hyporesponsiveness appears limited because anti-IL-10 antibodies significantly increased ex vivo production of IL-6 but not TNF-alpha or IL-8. In the isolated ECC study, no IL-10 was detected in plasma, yet the ex vivo production of the cytokines (except IL-8) was decreased (by 66% to 95%). CONCLUSION: Our results demonstrate the following: a) CPB induces an early and transient LPS hyporesponsiveness of whole blood as measured by cytokine production; b) IL-10 seems only partly involved in this process, and its role is restricted to an in vivo situation; and c) contact of blood with an ECC is sufficient to induce LPS hyporesponsiveness.

Alteration of mannose transport in fibroblasts from type I carbohydrate deficient glycoprotein syndrome patients.

The aim of the present study was to explore how mannose enters fibroblasts derived from a panel of children suffering from different subtypes of type I carbohydrate deficient glycoprotein syndrome: seven carbohydrate deficient glycoprotein syndrome subtype Ia (phosphomannomutase deficiency), two carbohydrate deficient glycoprotein syndrome subtype Ib (phosphomannose isomerase deficiency) and two carbohydrate deficient glycoprotein syndrome subtype Ix (not identified deficiency). We showed that a specific mannose transport system exists in all the cells tested but has different characteristics with respect to carbohydrate deficient glycoprotein syndrome subtypes. Subtype Ia fibroblasts presented a mannose uptake equivalent or higher (maximum 1.6-fold) than control cells with a D-[2-3H]-mannose incorporation in nascent N-glycoproteins decreased up to 7-fold. Compared to control cells, the mannose uptake was greatly stimulated in subtype Ib (4.0-fold), due to lower Kuptake and higher Vmax values. Subtype Ib cells showed an increased incorporation of D-[2-3H]-mannose into nascent N-glycoproteins. Subtype Ix fibroblasts presented an intermediary status with mannose uptake equivalent to the control but with an increased incorporation of D-[2-3H]-mannose in nascent N-glycoproteins. All together, our results demonstrate quantitative and/or qualitative modifications in mannose transport of all carbohydrate deficient glycoprotein syndrome fibroblasts in comparison to control cells, with a relative homogeneity within a considered subtype of carbohydrate deficient glycoprotein syndrome. These results are consistent with the possible use of mannose as a therapeutic agent in carbohydrate deficient glycoprotein syndrome Ib and Ix.