Epigenetic modifiers as new immunomodulatory therapies in solid tumours.

Background: Immune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest. Material and methods: We reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents. Experimental approaches, clinical applicability and corresponding ongoing clinical trials are described. Results: Several epigenetic modifiers, such as histone deacetylase inhibitors, DNA methyl transferase inhibitors, bromodomain inhibitors, lysine-specific histone demethylase 1 inhibitors and enhancer of zeste homolog 2 inhibitors, display intrinsic immunomodulatory properties. The latter can be achieved through the action of these drugs either on cancer cells (e.g. presentation and generation of neoantigens, induction of immunogenic cell death, modulation of cytokine secretion), on immune cells (e.g. linage, differentiation, activation status and antitumor capability), or on components of the microenvironment (e.g. regulatory T cells and macrophages). Several promising combinations, notably with immune checkpoint blockers or adoptive T-cell therapy, can be envisioned. Dedicated clinically relevant approaches for patient selection and trial design will be required to optimally develop such combinations. Conclusion: In an era where immune therapies are becoming a treatment backbone in many tumour types, epigenetic modifiers could play a crucial role in modulating tumours' immunogenicity and sensitivity to immune agents. Optimal trial design, including window of opportunity trials, will be key in the success of this approach, and clinical evaluation is ongoing.

Targeting chromatin defects in selected solid tumors based on oncogene addiction, synthetic lethality and epigenetic antagonism.

Background: Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors. Material and methods: We reviewed preclinical and clinical studies that described epigenetic oncogenic addictions, synthetic lethal relationships or epigenetic antagonisms in chromatin regulators. Experimental approaches, their clinical relevance and applicability, as well as corresponding on-going studies are described. Results: The most successful approaches that have been clinically validated so far include the targeting of the BRD4-NUT fusion transcript in NUT-midline carcinoma by BET (Bromodomain Extra-Terminal) inhibitors, and the use of EZH2 (Enhancer of Zest Homolog 2) inhibitors in SMARCB1-deficient malignant rhabdoid tumors and SMARCA4-deficient ovarian small cell carcinomas. Clinical validation is still required for other synthetic lethal relationships or epigenetic antagonisms, including those described between EZH2 inhibitors and deficiencies in components of the Polycomb or SWI/SNF chromatin-remodeling complexes (including BAP1, ARID1A and PBRM1 subunits), as well as between the CREBBP and EP300 histone acetylases. Further, interplays between epigenetic modifiers and non-epigenetic cellular processes might be therapeutically exploited, and combinatorial strategies could be envisioned to overcome resistance or to sensitize cells to already approved drugs. Conclusion: Epigenetic-targeting drugs have historically failed proving efficacy in solid malignancies when used broadly, but novel mechanism-based approaches in molecularly selected patient populations have facilitated recent successes in proof-of-concept studies in solid tumors. Appropriate clinical trial design and molecular patient selection will be key for the success of epigenetic modifiers in solid tumours.

Pertinence of the Sysmex XE-5000™ parameters: rule of slide review in a context of 'normal' lymphocyte count (defined from control and mantle cell lymphoma blood specimens).

INTRODUCTION: As most hematology cell analyzers, the different parameters of Sysmex XE-5000™ are little informative in the qualitative analysis of lymphoid cells, and especially when the lymphocyte count is below 4 × 10(9) /L (i.e., 'normal'). The aim of our study was to investigate whether some parameters and/or 'flags' not routinely provided by this analyzer, but reachable by operator could be reliable to define rules of slide review in absence of common qualitative and quantitative alarms particularly in case of 'normal' lymphocyte count. METHODS: Blood samples from 13 mantle cell lymphoma fully annotated cases, and 180 control specimens were studied with Sysmex XE-5000™ analyzer. All cases did not present any anomalies in common quantitative and structural parameters. RESULTS: Using the method of area under the curve and ROC curve analysis, we described a novel threshold of alarm VAL_ABN LYMPH (≥40 instead of 100 defined by Sysmex), as well as a pertinent LyX threshold (≥89). The combination of these thresholds allowed defining a rule of slide review in context of 'normal' lymphocyte count. CONCLUSION: Among the parameters provided by the Sysmex XE-5000™ analyzer, the combination of the alarm VAL_ABN LYMPH and the LyX value, routinely available on a simple blood analysis appears particularly informative to trigger slide review in a context of 'normal' lymphocyte count with a good sensitivity (85%) to detect circulating lymphoma cells and with <1% of false positive results.

Interobserver concordance in the assessment of features used for the diagnosis of cervical atypical squamous cells and squamous intraepithelial lesions (ASC-US, ASC-H, LSIL and HSIL).

OBJECTIVES: Given the well-known poor reproducibility of cervical cytology diagnosis, especially for atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL), this study surveyed reproducibility in the assessment of individual cytomorphological features. METHODS: One hundred and fifty cells or groups of cells, with a variety of morphological appearances, including normal cells, high-grade squamous intraepithelial lesion (HSIL), LSIL, ASC-US and ASC cannot exclude HSIL (ASC-H), were precisely marked on 150 different liquid-based cytological preparations. They were analysed by 17 observers who assessed 17 cytological features including nuclear features (chromatin texture, nuclear outline, nuclear shape, etc.), cytoplasmic features (cell shape, cytoplasmic staining, cytoplasmic clearing, etc.) and group characteristics (nuclear polarity, cellular density, etc.). A total of 43,350 data scores were collected in a database using a web-based survey. Kendall's W and relative entropy indexes were utilized to compute concordance indexes of respectively ordinal and nominal variables. RESULTS: Nuclear features have significantly lower reproducibility (0.46) compared with other cytological features (0.59). The feature with least agreement is assessment of chromatin texture. A small but significant difference in concordance was found between two subsets of observers with different levels of experience. CONCLUSION: Most previous studies assessing reproducibility of cytological diagnoses show, at best, moderate reproducibility among observers. This study focused on agreement regarding the presence of constituent morphological features used to recognize dyskaryosis and various grades of squamous intraepithelial lesions. A map of reproducibility indexes is presented that highlights, for daily practice or teaching, the robustness of features used for cytological assessment, recognizing that diagnosis is always based on a combination of features.

Relevance of a scoring system including CD11c expression in the identification of splenic diffuse red pulp small B-cell lymphoma (SRPL).

'Splenic red pulp lymphoma with numerous basophilic villous lymphocytes' (SRPL), recently described, is characterized by clinical, morphologic, immunologic, cytogenetic and molecular features distinct from SMZL/SLVL and HCL. In particular, the intensity of CD11c staining (expressed as fluorescence intensity -RFI-) in SRPL is significantly different from the RFI in SMZL/SLVL and HCL. Moreover the use of a scoring system based on the expression of CD11c, CD22, CD76, CD38 and CD27 appears to improve the differential diagnosis between SRPL and SMZL/SLVL and emphasizes that SRPL is an entity closed to but distinct from SMZL/SLVL.

Synergetic bitherapy in mice with xenografts of human prostate cancer using a methional mimic (METLICO) and an aldehyde dehydrogenase 3 inhibitor (MATE): systemic intraperitoneal (IP) and targeted intra-tumoral (IT) administration.

An intraperitoneal (IP) monotherapy in nu/nu mice with subcutaneous xenografts of a human prostate epithelial cancer cell line:DU145 was undertaken with an aldehyde dehydrogenase 3 inhibitor MATE, that is a potent apoptogen on (DU145) in culture but not on their human prostate epithelial normal counterparts [13] . Tumour growth was slowed down but treatment had to be done 5days/week. To try to potentiate the action of MATE in vivo, a bitherapy was undertaken based on the synergetic apoptotic effect that had been observed previously in culture on DU145 treated with a methional mimic METLICO and DIMATE, an inhibitor of ALDH1 and ALDH3 [19]. The bitherapy with METLICO/MATE administered IP was as effective as the monotherapy with MATE alone by IP, but at a 2-fold lower dose of MATE and at a dose of METLICO that had no growth-inhibitory effect as a monotherapy . Hence there was definite synergism with bitherapy. To try to increase the efficacy of bitherapy, it was administered by the intra-tumoral (IT) route using the recently developed 20-bars-pressurized microinjection system from CERMA [16, 17]. IT administration of the bitherapy was indeed more effective than that by IP as regards tumour volumes are concerned. Histopathological analysis of IT-treated tumours confirmed that there were many necrotized zones but intact cells were still present. Approaches for treating a wider zone of tumour tissue by IT-bitherapy are discussed.

Implication of dipeptidylpeptidase IV activity in human bronchial inflammation and in bronchoconstriction evaluated in anesthetized rabbits.

BACKGROUND: Decreased dipeptidylpeptidase IV (DPPIV) activity within the human nasal mucosa has previously been shown to contribute to the severity of chronic inflammatory rhinosinusitis. OBJECTIVE: To investigate and correlate the role of DPPIV activity with regard to bronchial inflammation. METHODS: DPPIV/CD26 activity/concentration was investigated in the bronchial tissue of human subjects suffering from chronic bronchial inflammation. In addition, the effect of a recombinant Aspergillus fumigatus DPPIV (fuDPPIV) was investigated on histamine-induced bronchoconstriction in anesthetized rabbits. RESULTS AND CONCLUSIONS: DPPIV/CD26 was present in submucosal seromucous glands, in leukocytes and to a very low degree in endothelial cells of human bronchi. DPPIV activity was correlated with tissue CD26 content measured by immunoassay. As previously reported for the nasal mucosa, DPPIV/CD26 activity was inversely correlated with the degree of airway inflammation. Systemic pretreatment with recombinant fuDPPIV markedly reduced the increase in histamine-induced airway resistance in rabbits. In conclusion, DPPIV activity modulates lower airway tone by degrading unknown peptidic substrates released by histamine in response to an allergen. Contrasting with our observations in the nose, this modulation is apparently not mediated via a neurokinin (NK1) receptor.

Identification of circulating CD10 positive T cells in angioimmunoblastic T-cell lymphoma.

In most cases of lymphomas with blood dissemination, the careful cytological analysis of peripheral blood smears provides a rapid orientation to diagnosis, even if the final subtyping is achieved by histology and eventually other techniques. Here, we evaluated if the analysis of blood smears may suggest the blood dissemination of angioimmunoblastic T-cell lymphoma (AITL) and if CD10 expression on neoplastic T cells, as recently reported on AITL, may contribute to the diagnosis. In all, 11 lymph nodes and six peripheral blood samples from 12 patients with AITL were studied using four-colour flow cytometry associated to histological, cytological and molecular data. According to previous results, a fraction of T cells expressed CD10 in 10/11 lymph nodes. Interestingly, all blood smears showed atypical lymphoid cells and a fraction of T cells expressed CD10 with a mean percentage of 18.75% (range 5.00-47.00%), regardless of lymphocytosis level and of rate of CD10 T cells in corresponding lymph node. In contrast, in all control samples (100), none CD10-positive T cell was identified. This is to our knowledge the first description of circulating CD10 neoplastic T cells in AITL. Therefore, they ought to be explored in further studies when aggressive lymphoma, in particular with lymphopenia and circulating atypical cells, is suspected.

Time and tidal volume-dependent ventilator-induced lung injury in healthy rats.

BACKGROUND AND OBJECTIVE: We evaluated the effect of duration of mechanical ventilation with different tidal volumes (VT) on ventilator-induced lung injury in healthy rats. METHODS: Anaesthetized rats were ventilated with VT between 9 and 45 mL kg[-1] for 1 or 7 h with a positive end-expiratory pressure of 2.5 cmH2O. RESULTS: After 1 h, rats ventilated even with the highest applied VT (36 and 45 mL kg[minus sign]1, resulting in average peak airway pressures of 30 +/-3 and 37 +/- 4 cmH2O), had no detectable alterations in dynamic or static lung mechanics, gas exchange or pulmonary permeability, but a moderate degree of lung inflammation (neutrophil accumulation in broncho-alveolar lavage) observed in all groups. In contrast, after 3 h of ventilation, rats ventilated with the highest VT (36 and 45 mL kg[minus sign]1) died from progressive circulatory failure and high-permeability pulmonary oedema, manifested by hypoxaemia, an increased alveolar-arterial protein concentration ratio and a reduced static lung compliance (mortality rate at 7 h, 62.5% and 100%). Animals with lower VT all survived and presented no changes in the measured variables. CONCLUSION: These results in normal rats demonstrate the preponderant effect of the duration (>3 h) of 'aggressive' ventilation and the cut-off value of the level of VT applied (>27 mL kg[minus sign]1).

Cytogenetic analysis delineates a spectrum of chromosomal changes that can distinguish non-MALT marginal zone B-cell lymphomas among mature B-cell entities: a description of 103 cases.

The purpose of this study was to document the frequency and distribution of karyotypic changes present at diagnosis in 103 non-MALT marginal zone cell lymphoma (MZL) patients. This cytogenetic analysis of a large cohort extends previous observations and allows the identification of new cytogenetic features. Abnormalities identified in more than 15% of patients included +3/+3q (37%), 7q deletions (31%), +18/+18q (28%), 6q deletions (19%), +12/+12q (15%) and 8p deletions (15%). Trisomy 3/3q, 7q deletions, +18 and +12 were seen in different combinations in more than 30% of patients in comparison to 2% in lymphocytic lymphomas/chronic lymphocytic leukemias, 1% in mantle cell lymphomas and 7% in follicular lymphomas. The marked propensity of these abnormalities to be recurrently associated with the same tumoral clone of individual karyotypes allowed the delineation of a cytogenetic profile that may help to distinguish non-MALT MZL among other mature B-cell neoplasms. If +3/3q, +12/+12q, and 6q, 7q and 8p deletions were significantly associated with clinical prognostic factors previously reported to influence survival and time to progression, patients displaying these abnormalities did not experience a significantly shorter time to progression.

An unusual endocarditis-induced crescentic glomerulonephritis treated by plasmapheresis.

A 58-year-old man presented with fever and a rapidly progressive glomerulonephritis. An infective endocarditis due to Streptococcus parasanguis was diagnosed. A renal biopsy revealed type III pauci-immune crescentic glomerulonephritis. As first-line therapy, antibiotics were administered alone. Faced to the unsuccessful anti-infective approach, corticosteroid therapy was added as a second-line therapy. Finally, plasmapheresis introduced as the third-line therapy, significantly improved renal function. This case is an original type III rapidly progressive glomerulonephritis, since ANCA were repeatedly found negative. In very few cases, plasmapheresis was successfully used for the treatment of infective endocarditis-induced crescentic glomerulonephritis. The pathophysiology and the potential efficiency of plasmapheresis are discussed.

Hemodynamics induced after acute reduction of proximal thoracic aorta compliance.

OBJECTIVE: to investigate the affect of reduced aortic compliance on cardiovascular hemodynamics. MATERIALS AND METHOD: fourteen Yucatan miniature swine were divided into two equal groups, a Sham Operated Group and a Banding Group. A Teflon prosthesis was wrapped around the aortic arc in order to limit proximal aortic compliance (Banding Group). Data were recorded operatively (after implantation of a pressure sensor and a flow probe in the ascending aorta), after banding (only in the Banding Group) and at 2 days postoperatively. RESULTS: after banding, compliance decreased by 52 +/- 13% ((-)X +/- SEM) (p < 0.01) while systolic and pulse pressure increased by 37 +/- 8% (p < 0.05) and 87 +/- 31% (p < 0.01), respectively. Diastolic pressure, mean blood pressure, cardiac output and systemic vascular resistance did not change significantly. Aortic characteristic impedance increased nearly 2.5 times. Amplitudes of forward and reflected pressure waves (derived from the aortic pressure wave) increased by 96 +/- 41% and 174 +/- 46%, respectively (p < 0.05), while the time delay between the two decreased by 36 +/- 7% (p < 0.05). CONCLUSIONS: about half of the total arterial compliance is located in the proximal thoracic aorta. Arterial reconstruction of the proximal aorta with a non-compliant graft results in a significant decrease in systemic arterial compliance, which in turn increases systolic and pulse pressure. The development of more compliant prosthesis, which matches the host artery compliance, is expected to reduce the hemodynamic changes induced after their implantation.

Somato-sympathetic vasoconstriction to intranasal fluid administration with consecutive decrease in nasal nitric oxide.

AIM: Patients suffering from non-allergic chronic rhinosinusitis (NACRS) increasingly use intranasal saline sprays. They report better nasal comfort. METHODS: In order to better understand this phenomenon, we studied intranasal laser Doppler flowmetry (LDF) and nasal nitric oxide (NO) variations evoked by local administration of saline, histamine, N-acetylcysteine (NAC) and lidocaine at room temperature (22 degrees C). RESULTS: There was a significant (P < 0.05) 14 +/- 3.8% decrease in LDF signal after 30 s, which lasted for 60-90 s, for all the substances applied at 22 degrees C. This pharmaco-independent vasoconstriction was further studied in patients under general anaesthesia (GA), with saline at 37 degrees C and after intranasal adrenaline treatment. While GA did not influence the vasoconstriction, saline at 37 degrees C and adrenaline pre-treatment abolished it. Nasal NO is influenced by vasoconstriction. Therefore we investigated, whether the observed vasoconstriction also changes nasal NO. A significant (P < 0.001) 8.03 +/- 0.59% decrease in nasal NO was recorded 60 s after administration of all the substances, and under GA after 22 degrees C saline application. This NO decrease was absent after intranasal adrenaline pre-treatment. An additional experiment tested the effect of nose blowing on nasal NO concentration. We registered an NO decrease with a similar pattern than observed with the other substances. CONCLUSIONS: Intranasal fluid nebulization at 22 degrees C induces a sympathetic mediated, transient vasoconstrictor reflex response. This somato-sympathetic vasoconstriction induces a decrease in nasal NO. Both could be related to the subjective comfort experienced by NACRS patients using intranasal saline sprays.

[mTOR and FTY 720 inhibitors]. / Les inhibiteurs de la mTOR et le FTY 720.

SIROLIMUS: The leading member of the mTOR inhibitor family, sirolimus or rapamycin, has dose-dependent side effects that can generally be well controlled. Sirolimus can be combined with tacrolimus at therapeutic doses; likewise for the sirolimus-cyclosporine combination at moderate dosage. Effective plasma concentrations of sirolimus vary from 5 to 20 ng/ml depending on the combination of immunosuppressant agents used. Sirolimus has been shown to inhibit metastatic diffusion of renal adenocarcinoma in the mouse. Its complex side effects on angiogenesis, fibrosis processes and chronic rejection are still being investigated. EVEROLIMUS: Everolimus, or RAD, has a very short half-life, but induces fewer hematologic effects. The therapeutic dose must reach at least 3 ng/ml to prevent rejection. Doses above 15 ng/ml increase the risk of thrombocytopenia. FTY 720: A new immunosuppressant agent, FTY 720, does not belong to any known family. It has a totally different mechanism of action compared with currently available immunosuppressants. FTY 720 increases the expression of chemokine receptors on the surface of T cells making them unavailable for the rejection reaction. FTY 720 has a very long half-life (108 hours). Due to its particular liver metabolism, there is a very low risk of drug interactions.

Long-term (> or =20 yr) status of 14 cadaveric kidney-transplant recipients.

The aim of this study was to analyze the status of patients with a successful long-term (> or =20 yr) kidney graft. Nineteen (8.1%) of the 234 recipients who received a cadaveric kidney transplant between 1968 and 1978 in our center are still alive 21.7+/-1.6 yr (mean+/-standard error of the mean) later with a functioning allograft. Function, including measurement of the renal functional reserve (RFR), histological status, and morbidity were evaluated. Fourteen patients agreed to participate in this study. Their current immunosuppressive regimens combined prednisone (P)+azathioprine (AZA) (n=9), P+AZA+cyclosporine (CsA) (n=3) or P+CsA (n=2). Although they described their quality of life as good, 10 patients had mild hypertension, 5 developed 10 malignancies (9 cutaneous), 5 had replicative hepatitis, 8 had osteopenia, and 6 had cataracts, but none had diabetes mellitus. Proteinuria was detected in 6 patients, but was always less than 1 g/d. Mean serum creatinine was 1.28+/-0.28 mg/dL and glomerular filtration rate was 54.5+/-5.3 mL/min/1.73 m2. RFR was present for 4 patients with a mean value of +14.8+/-1.9 mL/min. Their functional status was not correlated with the histological lesions observed in concomitant transplant biopsies. Kidney grafts are able to function well even more than 20 yr post-transplantation, with some having a RFR whose significance remains unknown. Morbidity is of minor clinical severity, but could be further reduced with optimized management. Moreover, transplantation is much less costly than hemodialysis.

Effects of abdominal Co2 insufflation on renal and hepatic blood flows during acute hemorrhage in anesthetized pigs.

OBJECTIVE: To evaluate the consequences of laparoscopy during hemorrhage, we studied the respiratory, renal, and hepatic blood flow changes induced by abdominal Co2 insufflation during severe hemorrhage in anesthetized pigs. DESIGN: Prospective animal study. SETTING: University research laboratory. SUBJECTS: Anesthetized and ventilated pigs (n = 18). INTERVENTIONS: The right carotid artery was cannulated to measure mean arterial pressure. A pulmonary artery catheter was inserted to measure mean pulmonary arterial pressure and cardiac output. After a midline abdominal incision, three flow probes were positioned around the portal vein, the hepatic artery, and the renal artery to measure portal vein blood flow, hepatic artery blood flow, and renal blood flow. To induce hemorrhage, blood was withdrawn until mean arterial pressure reached 50 mm Hg. Laparoscopy was mimicked by insufflating Co2 until intra-abdominal pressure reached approximately 15 mm Hg. Measurements were collected during hemorrhage, Co2 abdominal insufflation, and the combination of both interventions. MEASUREMENTS AND MAIN RESULTS: Severe pulmonary hypertension and hypercapnic acidosis occurred during abdominal Co2 insufflation. However, the abdominal Co2 insufflation did not aggravate the cardiac output and total hepatic blood flow changes induced by acute hemorrhage, whereas the combination of hemorrhage and abdominal Co2 insufflation markedly altered renal blood flow. CONCLUSIONS: These results suggest that renal function must be monitored carefully when performing laparoscopy in trauma patients. In contrast, hepatic perfusion seems well preserved.

A proliferation control network model: the simulation of two-dimensional epithelial homeostasis.

Despite the recent progress in the description of the molecular mechanisms of proliferation and differentiation controls in vitro, the regulation of the homeostasis of normal stratified epithelia remains unclear in vivo. Computer simulation represents a powerful tool to investigate the complex field of cell proliferation regulation networks. It provides huge computation capabilities to test, in a dynamic in silico context, hypotheses about the many pathways and feedback loops involved in cell growth and proliferation controls. Our approach combines a model of cell proliferation and a spatial representation of cells in 2D using the Voronoi graph. The cell proliferation model includes intracellular (cyclins, Cyclin Dependent Kinases - CDKs. Retinoblastoma protein - Rb, CDK inhibitors) and extracellular controls (growth and differentiation factors, integrins). The Voronoi graph associates a polygon with every cell and the set of these polygons defines the tissue architecture. Thus, the model provides a quantitative model of extracellular signals and cell motility as a function of the neighborhood during time dependent simulations. The 2D simulations illustrate the influence of the microenvironment on cell proliferation in basal layers of stratified epithelia and of differential adherence in keratinocytes differentiation and related upward migration. Our results particularly show the role of CDK inhibitors (mainly the protein p27) in the Rb dependent control pathway of the transition from the G1 to S phase of the cell cycle.

Aprotinin does not impair renal haemodynamics and function after cardiac surgery.

Patients undergoing cardiac surgery with moderate hypothermic cardiopulmonary bypass (CPB) were allocated randomly to receive either saline (control group, n = 29) or a high-dose regimen of aprotinin (aprotinin group, n = 28). In both groups, CPB was associated with similar and transient increases in effective renal plasma flow (+54% in controls and +48% in aprotinin-treated patients) and in fractional excretion of sodium and potassium, but glomerular filtration rate remained unchanged. Plasma and urinary ratios of 6-keto-PGF1 alpha to thromboxane B2 (TxB2) increased significantly, indicating systemic and renal release of vasodilatory prostaglandins. Osmolar clearance correlated with urinary excretion of cyclic GMP (r = 0.79 and 0.86 in the control and aprotinin groups, respectively) and 6-keto-PGF1 alpha (r = 0.63 and 0.69 in the control and aprotinin groups, respectively). Compared with preoperative values, plasma atrial natriuretic peptide increased after weaning from CPB (+71% and +93% in the control and aprotinin groups, respectively). Aprotinin had no apparent adverse effect on renal function and it did not alter mechanisms involving prostanoids and atrial natriuretic peptide during cardiac surgery.

Renal synthesis of leukaemia inhibitory factor (LIF), under normal and inflammatory conditions.

Leukaemia inhibitory factor (LIF) is a pleiotropic cytokine that is particularly involved in nephrogenesis and repair of the extracellular matrix. Transgenic mice overexpressing LIF have mesangial proliferative glomerulonephritis. Also, during local inflammatory reactions, such as kidney graft rejection or urinary tract infections, urinary LIF excretion is enhanced. The aim of the study therefore was to study LIF production by normal and inflammatory diseased kidneys (glomerulonephritis or graft rejection), maintained in short cultures. To determine the responsibility of the kidney itself in LIF synthesis, we measured LIF secretion into the culture supernatants of human mesangial or renal tubular epithelial cells. Fragments from diseased kidneys, whether grafts or not, released more LIF than normal human kidney fragments, mesangial or renal tubular epithelial cells. However, LIF production was delayed in renal transplants compared to glomerulonephritic samples taken from untreated patients. In every case, LIF production was enhanced by interleukin 1beta (IL-1beta) and inhibited by IL-4 or dexamethasone, except in two severe rejection episodes. So, LIF appeared to respond to pro- and anti-inflammatory stimuli, in vitro and in vivo. Considering its biological effects, LIF could play a role in inflammatory renal diseases.

Type IV phosphodiesterase inhibitor is effective in prevention and treatment of experimental crescentic glomerulonephritis.

BACKGROUND: Tumour necrosis factor alpha (TNF-alpha) has an important role in acute glomerular inflammation. Rolipram, a type IV phosphodiesterase inhibitor, has multiple anti-inflammatory effects including inhibition of TNF-alpha synthesis. METHODS: We investigated the effects of rolipram in prevention and delayed treatment of crescentic glomerulonephritis in Wistar Kyoto rats. Glomerulonephritis was induced by injection of nephrotoxic serum. RESULTS: In the preventive study, rolipram (6.25 mg/kg i.p. twice daily) was started 2.5 h before injection of nephrotoxic serum. Rolipram reduced the expression of TNF-alpha in glomeruli and renal tubules and abrogated glomerular injury on day 4 (99.7% reduction in albuminuria and 96.4% reduction in fibrin deposition). In the delayed-treatment experiment, rolipram was started 4 days after injection of nephrotoxic serum. Rolipram reduced renal excretion of TNF-alpha by 63% on day 7. TNF-alpha was not detected in the sera of treated or control rats. Delayed treatment was effective in crescentic glomerulonephritis, as shown by reduction in albuminuria by 38.1%, fibrin deposition by 60.8%, and crescent formation by 67% on day 7. CONCLUSIONS: Rolipram is effective both in prevention and treatment of experimental crescentic glomerulonephritis. This was associated with a reduction of renal production of TNF-alpha.