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Congenital diaphragmatic hernia (CDH) is a common cause of severe neonatal respiratory distress. Mortality and morbidity are determined by the amount of pulmonary hypoplasia (PH) that occurs and by the development of therapy-resistant pulmonary hypertension. The pathogenesis and aetiology of CDH and its associated anomalies are still largely unknown despite all research efforts. The pathogenesis of CDH is based on an assumption linking herniation of abdominal viscera into the thorax with compression of the developing lung. PH, however, can also result from reduced distension of the developing lung secondary to impaired fetal breathing movements. Our understanding of CDH has also been aided by basic research with the use of dietary, teratogen-induced, and knockout models of CDH. These studies indicate that lung hypoplasia may involve disturbances of mitogenic signalling pathways fundamental to embryonic lung development. Recent data reveal the role of disruption of a retinoid-signalling pathway in the pathogenesis of CDH. Although multifactorial inheritance may best explain most cases of CDH in humans, much has been learned about the genetic factors that play a role in the development of CDH by studies of patients with CDH caused by specific genetic syndromes and chromosome anomalies. More research is warranted to improve our understanding of normal and abnormal lung development in relation to CDH. Such investigations will help in the design of new treatment strategies to improve the natural course or even to prevent this anomaly., (Copyright © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Retinoic acid plays an essential role in lung development and is involved in all stages of embryogenesis and morphogenesis. We aimed to determine whether the human foetal lung is able to synthesize retinoic acid., Methods: ADH3, RALDH1 and CYP26B1 RNA were studied by qualitative and semi-quantitative RT-PCR in human lungs at different stages of development. In human alveolar epithelial cells (lines A549), RAR beta (induced by retinoic acid) was quantified, after treatment by retinol, by q-PCR at 24h and 48 h., Results: The expression of the RNA of ADH3, RALDH1 and CYP26B1 was detected for each of the four stages studied and in the A549 cell line. Only the level of RALDH1 RNA changed during the course of lung development. In the A549 cell line, treatment by retinol induced transcription of the RAR beta gene at 24 and 48 hours., Conclusion: The presence of ADH3, RALDH1 and CYP26B1 during the four stages of normal lung development and in the A549 cell line, as well as the capacity to convert retinol to retinoic acid in these cells, indicate that foetal human lung has the ability to regulate the supply of vitamin A from the pseudoglandular stage., (Copyright © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Retinoids, vitamin A derivatives, are natural or synthetic molecules with pleiotropic effects, which regulate cell differentiation, proliferation and apoptosis. In target cell, the active natural metabolites retinoic acid (RA) and 9-cis-retinoic acid are synthetized from retinol by a two-step process with intermediate metabolite retinaldehyde. In 1987, the identification of the nuclear retinoic acid receptors that belong to the superfamily of nuclear receptors led to a significant progress in the comprehension of the mechanism of action of retinoids. There are two families of Retinoid Nuclear Receptors (RNR), the RA receptors (RAR), which natural ligand is RA, and the Retinoid X Receptors (RXR), which natural ligand is 9-cis-retinoic acid. Among synthetic retinoids, isotretinoin, acitretin, tazarotene and adapalene are ligands of the RAR, bexarotene is the first rexinoid (ligand of the RXR), alitretinoin the first panagonist (RAR+ RXR). For each family, there are 3 isotypes (α, β, γ), and for each isotype several isoforms. Each NRR is composed of 6 regions (A-F). 3 regions are of importance: the A/B region has a ligand-independent transcriptional activation function, the C region harbors the DNA binding domain, the E region harbors the ligand binding domain. To regulate the expression of target genes, NRR have to dimerize. RXR are obligatory in dimers (heterodimers RAR-RXR, homodimers RXR-RXR). Dimers binds specific sequences of DNA, present in the promoters of target genes. When the ligand, natural or synthetic, bind to RNR, coactivators are recruited and transcription factors are activated. In target cell, retinoids not utilized are degradated in polar metabolites by enzymes of cytochrome P450., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Maternal alcohol drinking during pregnancy is a reality in France leading to new-born specific clinical signs called "Fetal alcoholic syndrome/FAS" in 1.5 per 1000 births and to common clinical signs grouped into "Fetal Linked to Alcohol Spectrum Disorders" in 5 per 1000 births. Our works presented for the attribution of the SFBC 2007 price talked about two aspects of this public health problem. The first presented the recent evaluation of the alcohol consumption during pregnancy in Auvergne by the realization of the DATAMATER clinical and biological study on more than 800 "mother/baby" couples. We confirmed the reality of such maternal drinking (1.8 FAS per 1000 births) and also the useless of biological tools to help the diagnosis of the clinician where the clinical signs did not clearly belonged to FAS and when the maternal consumption was asked. The second aspect reviewed the placental abnormalities occurring during the FAS, which could explain the intra-uterine growth retardation. To better understand the genesis of such alterations, we proposed a new physio-pathological mechanism. The alcohol could alter the retinol (vitamin A) activation into retinoic acid, a fundamental morphogenic molecule for the optimal development and functions of the placenta.

Retinoids play important roles in cell differentiation and apoptosis, notably in epithelial tissues. Their utility in cancer therapy has been demonstrated in specific cancer types. Use of retinoic acid (RA) in the treatment of acute promyelocytic leukemia was the first successful example of retinoid-based differentiation therapy. RA has since been evaluated for treatment of other cancers, revealing variable effectiveness. The observation that expression of enzymes involved in RA biosynthesis is suppressed during tumorigenesis suggests that intra-tumor depletion in RA levels may contribute to tumor development and argues for the use of retinoids in cancer treatment. However, the induction of RA-inactivating enzymes is one of the mechanisms that may limit the efficacy of retinoid therapy and contribute to acquired resistance to RA treatment, suggesting that retinoic acid metabolism blocking agents may be effective agents in differentiation therapy.

Retinoic acid (RA) and interferons (IFN) are negative regulators of cell proliferation. A number of clinical trials were thus carried out in cancer therapy with RA and/or IFN. In vitro and in vivo, their combination leads to a more potent cell growth inhibition. Moreover, RA and IFN act cooperatively to increase the expression of many IFN-stimulated genes, leading also to a higher cell differentiation and inhibition of viral replication. However, the molecular mechanisms by which RA and IFN potentiate each other are not fully understood. The cooperative effects by RA and IFN are mediated through multiple pathways. RA causes the induction and secretion of IFN alpha. RA also stimulates the IFN regulatory factor gene expression (IRF1 and p48). Additional mechanisms could be involved as RA increases the level of signal transducing activators of transcription (Stat) proteins, and thus enhances the IFN-induced Stat activation.

Acute promyelocytic leukemia is a key model system in Cancer biology. Its ability to differentiate upon exposure to retinoic acid constitutes the first example of differentiation therapy. The molecular basis of leukemogenesis is the PML/RAR fusion resulting from the t(15, 17) translocation. The fusion protein likely acts through interference with the function of nuclear receptors (resulting in a differentiation block) and also through interference with PML which appear to be a growth suppressor. The exquisite sensitivity of this disease to retinoic acid represents the first example of a therapy directly targeted at a specific and causative genetic lesion.

Some possible applications of chimeric cellular models, specifically responding to an effector through firefly luciferase induction are presented with the help of examples in relation with the biological activity of estradiol or retinoic acid, or phorbol ester. A comparison of experiments on either chimeric or natural responses shows that: i) the responses of both type of cellular models are effector concentration-dependent; ii) these concentrations are in the same order of magnitude; partial agonist compounds and antagonist compounds; iv) potencies (EC50) of test-compounds are similarly classified. Moreover we show that a chimeric cellular model allows the observation of interactions between hormone or effector pathways: it allows readily performed kinetic studies and long-term experiments in intact cells that permit to investigate the effect of a given effector, its reversibility and time-dependent action. Therefore, various steps of a cellular signalling pathway involved in the action of an effector may be observed with such a valuable tool.

Acute promyelotic leukemia is characterized by a t(15;17) chromosomal translocation which results in fusion products between PML (chromosome 15) and RAR-alpha (chromosome 17). We describe 2 classes of patients which possess different PMLRAR and RARPML fusion transcripts. We then discuss the functional properties of PML and show that PMLRAR can interfere with both PML and RAR-alpha functions.

We have previously shown that all-trans retinoic acid therapy is an alternative therapy for acute promyelocytic leukemia (AML3) via differentiation of the leukemic cells. The t(15;17) translocation is specifically found in this leukemia. We and others have shown that through this translocation the RAR alpha gene is rearranged and its expression altered in AML3 cells. The gene is truncated and fused to a novel gene (PLM). This results in a fusion protein whose transactivating properties may be implicated in the leukemogenesis of this disease. Retinoic acid cytoplasmic binding proteins (CRABP and CRBP) are not detected by PAGE chromatography in normal or malignant hematopoietic cells. During all-trans RA therapy, a) all-trans RA plasma concentrations are within in vitro differentiating concentration (med. 0.4 microgram/ml); b) increased expression of the normal remaining RAR alpha allele is rapidly observed and may explain the paradoxical induction of RA differentiation in these cells; c) CRABPII is induced in the bone marrow cells of AML3 patients and remains detectable 1 month after withdrawal of RA. AML3 in relapse after RA therapy is always less sensitive to RA in vitro and in vivo. Our data suggest that modification of the metabolisation pathways of RA may be one of parameters linked to this resistance. It appears that the efficacy of all-trans RA is the resultant of multiple parameters (RA concentration, ratio of PML/RAR alpha transcripts to normal RAR alpha, CRABP) which need to be defined to efficiently monitor all-trans RA therapy in APL.

The aromatic retinoic acid derivative Ro 10-9359 was administered orally to 25 severe psoriatic patients (14 with generalized plaques, 7 erythrodermic, 4 pustular). The initial dose was 25 mg/20 kg body weight daily for 4 weeks; afterwards the same posology was given every other day during several months (Max : 18 months). Excellent results were obtained in 16 patients (64 p. 100) particularly in severe erythrodermic and pustular psoriasis. However, under follow-up therapy relapses sometimes occurred leading to temporary resumption of initial posology. The most important side effects are cheilitis, palmoplantar scaling with thinning of the skin, hyperhidrosis and diffuse hair loss. A slight increase of transaminases and of alkaline phosphatases was found in a few patients. The Ro 10-9359 compound is a very useful new therapy of severe psoriasis.