RESUMEN

Fanconi anemia (FA) is a chromosome instability syndrome with congenital abnormalities, cancer predisposition and bone marrow failure (BMF). Although hematopoietic stem and progenitor cell (HSPC) transplantation is the recommended therapy, new therapies are needed for FA patients without suitable donors. BMF in FA is caused, at least in part, by a hyperactive growth-suppressive transforming growth factor ß (TGFß) pathway, regulated by the TGFß1, TGFß2, and TGFß3 ligands. Accordingly, the TGFß pathway is an attractive therapeutic target for FA. While inhibition of TGFß1 and TGFß3 promotes blood cell expansion, inhibition of TGFß2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGFß1- and TGFß3-specific inhibitor, on FA hematopoiesis. AVID200 promoted the survival of murine FA HSPCs in vitro. AVID200 also promoted in vitro the survival of human HSPCs from patients with FA, with the strongest effect in patients progressing to severe aplastic anemia or myelodysplastic syndrome (MDS). Previous studies have indicated that the toxic upregulation of the nonhomologous end-joining (NHEJ) pathway accounts, at least in part, for the poor growth of FA HSPCs. AVID200 downregulated the expression of NHEJ-related genes and reduced DNA damage in primary FA HSPC in vitro and in in vivo models. Collectively, AVID200 exhibits activity in FA mouse and human preclinical models. AVID200 may therefore provide a therapeutic approach to improving BMF in FA.

Asunto(s)

Anemia de Fanconi/tratamiento farmacológico , Hematopoyesis/efectos de los fármacos , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta3/antagonistas & inhibidores , Adolescente , Adulto , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Niño , Preescolar , Anemia de Fanconi/metabolismo , Anemia de Fanconi/fisiopatología , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Masculino , Ratones , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta3/metabolismo

RESUMEN

BACKGROUND: Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33. OBJECTIVE: We sought to test the hypothesis that pulmonary RAGE is necessary for allergen-induced ILC2 accumulation in the lung. METHODS: AAI was induced in wild-type and RAGE knockout mice by using IL-33, house dust mite extract, or Alternaria alternata extract. RAGE's lung-specific role in type 2 responses was explored with bone marrow chimeras and induction of gastrointestinal type 2 immune responses. RESULTS: RAGE was found to drive AAI by promoting IL-33 expression in response to allergen and by coordinating the inflammatory response downstream of IL-33. Absence of RAGE impedes pulmonary accumulation of ILC2s in models of AAI. Bone marrow chimera studies suggest that pulmonary parenchymal, but not hematopoietic, RAGE has a central role in promoting AAI. In contrast to the lung, the absence of RAGE does not affect IL-33-induced ILC2 influx in the spleen, type 2 cytokine production in the peritoneum, or mucus hypersecretion in the gastrointestinal tract. CONCLUSIONS: For the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s.

Asunto(s)

Asma/inmunología , Inmunidad Innata , Interleucina-33/inmunología , Pulmón/inmunología , Linfocitos/inmunología , Receptor para Productos Finales de Glicación Avanzada/inmunología , Alérgenos/administración & dosificación , Alérgenos/inmunología , Alternaria/química , Animales , Antígenos Dermatofagoides/administración & dosificación , Antígenos Dermatofagoides/inmunología , Asma/inducido químicamente , Asma/genética , Asma/patología , Médula Ósea/inmunología , Médula Ósea/patología , Proliferación Celular , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Regulación de la Expresión Génica , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-33/genética , Interleucina-5/genética , Interleucina-5/inmunología , Pulmón/patología , Linfocitos/patología , Ratones , Especificidad de Órganos , Peritoneo/inmunología , Peritoneo/patología , Pyroglyphidae/química , Receptor para Productos Finales de Glicación Avanzada/genética , Transducción de Señal , Bazo/inmunología , Bazo/patología , Quimera por Trasplante

RESUMEN

Ionizing radiation triggers mitochondrial overproduction of H(2)O(2) with concomitant induction of intrinsic apoptosis, whereby clearance of H(2)O(2) upon overexpression of mitochondrial catalase increases radioresistance in vitro and in vivo. As an alternative to gene therapy, we tested the potential of Mn((III))-porphyrin complexes to clear mitochondrial H(2)O(2). We report that triphenyl-[(2E)-2-[4-[(1Z,4Z,9Z,15Z)-10,15,20-tris(4-aminophenyl)-21,23-dihydroporphyrin-5-yl]phenyl]iminoethyl]phosphonium-Mn((III)) compartmentalizes preferentially into mitochondria of mouse embryonic cells, reacts with H(2)O(2), impedes γ-ray-induced mitochondrial apoptosis, and increases the survival of mice exposed to whole body irradiation with γ-rays.