Striae distensae (SD; stretch marks) are well-recognized skin lesions that occur in a large percentage of the population. Although they rarely cause significant medical concern, they can be a source of extreme physiological stress to affected patients. They occur commonly in pregnancy, puberty and obesity, but also become manifest following various medical conditions and therapeutic interventions. The precise etiological mechanism of SD has yet to be determined, however numerous theories have been proposed and risk factors have been identified. To date, there are many different treatment modalities to improve size and color of striae including diet and exercise, topical and laser therapies and surgery but none have demonstrated a consistent effectiveness. This unmet medical need may be addressed by the use of Pirfenidone. Pirfenidone is a small synthetic non-peptide molecule of low molecular weight (185.2 Daltons) that has been identified to have immuno-modulatory and anti-inflammatory properties. Clinical evidence indicates that Pirfenidone can modulate collagenase and fibroblastic activity by the modulation of cytokines in the wound healing process, such as TFG-β and TNF-α, which lead to effective collagen remodeling. Pirfenidone has exhibited low-toxicity in pre-clinical and clinical studies. These in vitro and in vivo findings suggest that Pirfenidone may be a safe and effective treatment of patients with SD.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21627号 / 医博第4433号 / 新制||医||1033(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 松原 和夫, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown etiology, in which excessive accumulation of scar tissue in the interstitial spaces of the lung obstruct normal pulmonary function. Currently, the only curative treatment is lung transplantation. While pharmaceutical therapeutics have been recently approved for use in IPF in 2014, they are still unable to provide a truly curative treatment. While genetic risk factors have been identified, the most commonly occurring mutation is only detected in approximately 38% of IPF patients, leaving an uncertainty in the very existence of a common genetic factor in IPF. Cigarette smoke and other environmental particulates have been significantly linked to the diagnosis of IPF, implicating an initial immunological response to trigger the pathogenesis of IPF. Nintedanib, a potent tyrosine kinase receptor inhibitor was first developed in 1998 as a candidate for cancer treatment. Investigation of its effects in fibrosis in the past few decades has led to a significant discovery of its application in IPF. Nintedanib significantly inhibits the fibrotic activity of fibrotic myofibroblasts in the lungs by inhibiting signaling cascades necessary for cell proliferation and progression of the disease. However, nintedanib falls short in that it cannot fully inhibit the advancement of the disease and mortality rates of IPF still remain high. Pirfenidone, the other currently available pharmaceutical therapeutic, was discovered in 1976 as a potent inhibitor of inflammation. Subsequent experiments further reviled its potency as an anti-fibrotic drug. After decades of research, pirfenidone’s mechanism of antifibrotic characteristics were revealed as a potent inhibitor of fibrocyte recruitment and chemotaxis, and as an inhibitor of transcription growth factor beta (a growth factor heavily implicated in the activity of myofibroblasts) mediated pathways. However, like nintedanib, pirfenidone fails as a curative treatment, only delaying the progression of the disease. In the search for new molecular targets for pharmaceutical therapy, forkhead box M1 (FOXM1), programmed cell death protein-1 (PD-1), and prostaglandin E2, have been identified to play a mediatory role in many of the pathways involved in myofibroblast activity. Many of these targets have also been identified in other disease models such as cancer and immunological inflammatory disease. Avasimibe has been recently identified as a potent inhibitor of aldo-ketoreductase through a FOXM1 mediated pathway. Its molecular mechanism in osteosarcoma cancer disease model may prove to be a novel pharmaceutical therapeutic for IPF. BI 853250, a novel focal adhesion kinase (FAK) inhibitor also demonstrates potential to be a new pharmaceutical therapeutic for IPF patients. Exploring signaling pathways that involve these newly found targets and collaborative research with cancer and immunological diseases shows promise in providing steps to cure IPF in the future.

Introduction. L’encéphalopathie hépatique (HE) est une complication commune mais sévère des insuffisances hépatiques. La physiopathologie de l’HE provient essentiellement de l’ammoniac dérivé du métabolisme des bactéries intestinales. Le traitement standard pour les patients qui subissent des épisodes manifestes d’HE est le lactulose mais son observance est faible du fait d’effets secondaires inconfortables. La rifaximine est un candidat potentiel mais il n’y a pas de données issues d’essais cliniques suffisamment robustes pour supporter sa seule utilisation. Les traitements anti-fibrotiques sont une autre piste de traitement dans le sens où s’il est possible de prévenir l’avancement de la défaillance hépatique il est alors possible de diminuer la probabilité et la sévérité des épisodes. Deux études indépendantes ont été réalisées dans un modèle de ligature de la voie biliaire, la première étude pour évaluer l’efficacité de traitements thérapeutiques de l’HE (lactulose et rifaximine) utilisés seuls ou en combinaison pour réduire le taux d’ammoniac et améliorer le statut de l’HE; et la seconde étude, pour évaluer des traitements utilisés individuellement pour prévenir l’établissement de la fibrose (acide obéticholique, rapamycine, pirfénidone, acide ursodésoxycholique). Matériel et méthodes. Les deux projets utilisent un modèle murin de ligature de la voie biliaire. Pour l’évaluation de la rifaximine, trois semaines après la chirurgie, les animaux sont séparés en cinq groupes en fonction du traitement reçu quotidiennement et du modèle : SHAM-VEH, pour les animaux ayant subi un simulacre de chirurgie de ligature de la voie biliaire (SHAM) et traité par le véhicule (VEH); BDL-VEH, pour les animaux ayant subi la chirurgie de ligature de la voie biliaire et traité par le véhicule; BDL-RIF, pour les animaux traités par la rifaximine (RIF); BDL-LAC, pour les animaux traités par le lactulose (LAC); BDL-LAC+RIF, pour les animaux traités par le lactulose et la rifaximin (LAC+RIF). Pour l’évaluation des composés anti-fibrotiques, une semaine après la chirurgie, les animaux sont séparés en six groupes en fonction du traitement reçu quotidiennement et du modèle : SHAM-VEH; BDL-VEH; BDL-OCA pour les animaux traités par l’obéticholique acide (OCA); BDL-RPM, pour les animaux traités par la rapamycine (RPM); BDL-UDCA, pour les animaux traités par l’acide ursodésoxycholique (UDCA); BDL-PFN pour les animaux traités par la pirfenidone (PFN). Les animaux sont alors évalués au cours du modèle pour leur survie, leur consommation de nourriture et leur poids. Les paramètres biochimiques de la fonction hépatiques sont évalués en fin de modèle. Plus particulièrement, le projet sur les composés anti-fibrotiques comprend une analyse plus approfondie de la fibrose par histologie avec établissement du score MÉTAVIR et par mesure du contenu hépatique en hydroxyproline. Le projet rifaximine comprend des analyses comportementales pour évaluer l’HE mais également une mesure de l’œdème cérébral. Résultats. Pour le projet rifaximine, aucun des deux composés testés (i.e. rifaximin et lactulose) seuls ou combinaison n’ont pas eu d’effets bénéfiques globaux en termes de survie, de croissance, de consommation de nourriture, de tests comportementaux, d’œdème cérébral, de paramètres biochimiques incluant l’ammoniac. Aucun des traitements pris séparément ou en combinaison n’a montré d’efficacité pour le traitement de l’HE. Pour le projet des composés anti-fibrotiques, certains composés ont entrainé une mortalité plus élevée. Aucune différence entre les traitements ne fut observée en termes de croissance, de consommation de nourriture, de paramètres biochimiques, d’histologie et de contenu en hydroxyproline. Conclusions. Globalement, l’étude sur la rifaximine ne présente pas de résultats suffisamment concluants pour recommander l’utilisation de la rifaximine en remplacement ou en concomitance avec le lactulose. L’étude sur les composés anti-fibrotiques ne permet pas de mettre en évidence un composé capable de limiter la progression de la fibrose. / Introduction. Hepatic encephalopathy (HE) is a major but common complication of liver failures diseases. The physiopathology of HE mainly involves intestinal bacteria metabolism derived ammonia. The golden standard for patients who experience overt episodes of HE is lactulose but its observance is poor due to uncomfortable side effects. On the other hand, Rifaximin is a potent candidate but there is a lack of relevant data from clinical trials to support its sole use. Antifibrotic drugs are another category of treatment that can be useful in the setting of HE since it can prevent the onset of cirrhosis and thus of the liver failure, this can decrease the appearance and severity of the episodes. The aim of this study is to evaluate in a murine model of bile duct ligation the efficiency of therapeutic treatments (lactulose and rifaximin) alone or in combination to decrease blood ammonia and ameliorate HE status; and of prophylactic treatments (obeticholic acid, rapamycin, pirfenidone, ursodeoxycholic acid) individually to prevent the onset of fibrosis. Materials and methods. The two projects used a murine model of bile duct ligation. For the evaluation of the efficiency of rifaximin, three weeks after surgery, the animals were sorted into five groups according to the treatment they received daily and according to the model : SHAM-VEH, for animals that underwent a mock surgery (SHAM) and were treated with vehicle (VEH); BDL-VEH, for animals that underwent a bile duct ligation surgery (BDL) and were treated with vehicle; BDL-RIF, for animals that were treated with rifaximin (RIF); BDLLAC, for animals that were treated with lactulose (LAC); BDL-LAC+RIF for animals that were treated with lactulose and rifaximin (LAC+RIF);. For the evaluation of the effect of antifibrotic drugs, one week after surgery, the animals were sorted into six groups according to the treatment they received daily and according to the model : SHAM-VEH, BDL-VEH, BDL-OCA for animals that were treated with obeticholic acid (OCA); BDL-RPM, for animals that were treated with rapamycine (RPM); BDL-UDCA, for animals that were treated with ursodeoxycholic acid (UDCA); BDL-PFN, for animals that were treated with pirfenidone (PFN). All animals were evaluated during the model for survival, food consumption and growth. The biological parameters of the liver function were evaluated at the end of the model. More specifically, this project includes a deeper analysis on fibrosis through histological analysis with establishment of the METAVIR score and measure of the content on hydroxyproline. The rifaximin project includes behavioural analysis to evaluate the HE status and measurement of cerebral edema. Results. Concerning the rifaximin project, no difference can be established between the treatments in term of survival, growth, food consumption, behavioural tests, cerebral edema, biochemistry parameters including ammonia. No treatment, taken alone or in combination, showed efficacy to treat HE. Concerning the antifibrotic drug study, some compounds have shown an increase in mortality, although no difference can be observed on growth, food consumption, biochemistry parameters, histology or hydroxyproline content. Conclusions. Overall, the study on rifaximin does not present strong and conclusive results on the sole use of rifaximin. According to the study on the antifibrotic drugs, no compounds show evidence of prevention of the onset of the fibrosis.