Assuntos
Hispânico ou Latino/estatística & dados numéricos , Transplante de Órgãos/efeitos adversos , Dermatopatias/epidemiologia , Neoplasias Cutâneas/epidemiologia , Transplantados/estatística & dados numéricos , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Asiático/estatística & dados numéricos , Humanos , Incidência , Pessoa de Meia-Idade , Estudos Retrospectivos , Dermatopatias/etiologia , Neoplasias Cutâneas/etiologia , Estados Unidos/epidemiologiaRESUMO
Rationale: Alveolar epithelial cell (AEC) injury and dysregulated repair are implicated in the pathogenesis of pulmonary fibrosis. Endoplasmic reticulum (ER) stress in AEC has been observed in idiopathic pulmonary fibrosis (IPF), a disease of aging.Objectives: To investigate a causal role for ER stress in the pathogenesis of pulmonary fibrosis (PF) and therapeutic potential of ER stress inhibition in PF.Methods: The role of ER stress in AEC dysfunction and fibrosis was studied in mice with tamoxifen (Tmx)-inducible deletion of ER chaperone Grp78, a key regulator of ER homeostasis, in alveolar type II (AT2) cells, progenitors of distal lung epithelium, and in IPF lung slice cultures.Measurements and Main Results:Grp78 deletion caused weight loss, mortality, lung inflammation, and spatially heterogeneous fibrosis characterized by fibroblastic foci, hyperplastic AT2 cells, and increased susceptibility of old and male mice, all features of IPF. Fibrosis was more persistent in more severely injured Grp78 knockout (KO) mice. Grp78 KO AT2 cells showed evidence of ER stress, apoptosis, senescence, impaired progenitor capacity, and activation of TGF-ß (transforming growth factor-ß)/SMAD signaling. Glucose-regulated protein 78 is reduced in AT2 cells from old mice and patients with IPF, and ER stress inhibitor tauroursodeoxycholic acid ameliorates ER stress and fibrosis in Grp78 KO mouse and IPF lung slice cultures.Conclusions: These results support a causal role for ER stress and resulting epithelial dysfunction in PF and suggest ER stress as a potential mechanism linking aging to IPF. Modulation of ER stress and chaperone function may offer a promising therapeutic approach for pulmonary fibrosis.
Assuntos
Células Epiteliais Alveolares/metabolismo , Estresse do Retículo Endoplasmático/genética , Proteínas de Choque Térmico/genética , Fibrose Pulmonar/genética , Células-Tronco/metabolismo , Fatores Etários , Células Epiteliais Alveolares/patologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/genética , Senescência Celular/genética , Dasatinibe/farmacologia , Chaperona BiP do Retículo Endoplasmático , Técnicas de Inativação de Genes , Proteínas de Choque Térmico/metabolismo , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/efeitos dos fármacos , Glicoproteínas de Membrana/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Inibidores de Proteínas Quinases/farmacologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Quercetina/farmacologia , Quinolinas/farmacologia , Proteínas Smad/metabolismo , Ácido Tauroquenodesoxicólico/farmacologia , Fator de Transcrição CHOP/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
CASE PRESENTATION: A 63-year-old woman with a history of neurofibromatosis type-1 (NF-1) and pulmonary arterial hypertension (PAH) thought to be secondary to the NF-1 presented with a few weeks of worsening dyspnea on exertion. She took no medications other than sildenafil for her pulmonary hypertension (PH). She denied tobacco, alcohol, and illicit or anorectic drug use. She had previously worked as a waitress. Her mother and her brother had NF-1 but no PH or lung disease.
Assuntos
Hemangioma Capilar/diagnóstico , Hipertensão Pulmonar/complicações , Hipóxia/etiologia , Neoplasias Pulmonares/diagnóstico , Neurofibromatose 1/complicações , Biópsia , Diagnóstico Diferencial , Ecocardiografia , Feminino , Hemangioma Capilar/complicações , Hemangioma Capilar/terapia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/terapia , Hipóxia/diagnóstico , Hipóxia/terapia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , Imagem Cinética por Ressonância Magnética , Pessoa de Meia-Idade , Oxigenoterapia , Pressão Propulsora Pulmonar/fisiologia , Tomografia Computadorizada por Raios XRESUMO
Posttransplant lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation with an annual incidence rate of 3-5% in lung-transplant recipients. Pathogenesis indicates a strong association with functional over-immunosuppression and EBV infection. Clinical improvement is generally observed with reduction in immunosuppression intensity alone. We present a case of a 24-year-old woman with EBV-associated PTLD following lung transplant where decreasing the immunosuppression improved PTLD but was ineffective against controlling the EBV infection. Foscarnet in combination with immunoglobulins was successfully administered to cause a remission of the EBV infection. This is the second case reported of a persistent EBV infection after reducing immunosuppression levels and evidence of PTLD remission that required foscarnet for EBV infection control.