RESUMEN
There have been reports of marrow cells converting into pulmonary epithelial cells after marrow transplantation in irradiated mice. We evaluated the impact of whole bone marrow (WBM) infusion in mice, with or without total body irradiation (TBI), treated with saline or monocrotaline (MCT), which induces pulmonary hypertension (PH). C57BL/6 mice were injected with MCT or saline weekly for 4 weeks. Cohorts were then infused with saline vehicle (vehicle) or WBM from C57BL/-Tg(UBC-GFP)30Scha/J mice, with or without previous TBI (WBM or WBM/TBI). Four weeks later, right ventricular peak pressures (RVPP), right ventricular free wall-to-body weight ratios (RV/BW), and pulmonary vessel wall thickness-to-blood vessel diameter ratios (PVWT/D) were determined. WBM infusion and WBM following TBI induced increases in RVPP and RV/BW in saline-treated mice, while only TBI-exposed mice showed additional increases in PVWT/D. MCT increased RVPP, RV/BW, and PVWT/D in mice given vehicle or WBM alone, but not in mice given WBM/TBI. RVPP and RV/BW were not significantly lower in MCT mice given WBM/TBI than in MCT mice treated with vehicle, but MCT-treated mice given WBM or TBI/WBM had significantly lower PVWT/D compared to MCT-treated mice given saline vehicle. No donor WBM-derived pulmonary vascular cells were detected, suggesting that the observed effects of WBM infusion may be due to paracrine effects separate from cell conversions. The observation of PH after marrow infusion suggests an additional mechanism for lung toxicity seen in marrow transplantation. In conclusion, WBM alone appears to increase RVPP and RV/BW in normal mice but the combination of WBM and TBI attenuates MCT-induced PH.
Asunto(s)
Vasos Sanguíneos/fisiopatología , Células de la Médula Ósea/citología , Trasplante de Médula Ósea , Hipertensión Pulmonar/fisiopatología , Animales , Presión Sanguínea , Modelos Animales de Enfermedad , Femenino , Hemodinámica , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Monocrotalina , Cloruro de Sodio , Vimentina/metabolismo , Irradiación Corporal TotalRESUMEN
Numerous animal studies have demonstrated that adult marrow-derived cells can contribute to the cellular component of the lung. Lung injury is a major variable in this process; however, the mechanism remains unknown. We hypothesize that injured lung is capable of inducing epigenetic modifications of marrow cells, influencing them to assume phenotypic characteristics of lung cells. We report that under certain conditions, radiation-injured lung induced expression of pulmonary epithelial cell-specific genes and prosurfactant B protein in cocultured whole bone marrow cells separated by a cell-impermeable membrane. Lung-conditioned media had a similar effect on cocultured whole bone marrow cells and was found to contain pulmonary epithelial cell-specific RNA-filled microvesicles that entered whole bone marrow cells in culture. Also, whole bone marrow cells cocultured with lung had a greater propensity to produce type II pneumocytes after transplantation into irradiated mice. These findings demonstrate alterations of marrow cell phenotype by lung-derived microvesicles and suggest a novel mechanism for marrow cell-directed repair of injured tissue.
Asunto(s)
Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea , Regulación de la Expresión Génica , Pulmón/citología , Fenotipo , Biosíntesis de Proteínas , Esferoides Celulares/fisiología , Animales , Diferenciación Celular , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Femenino , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: To describe patients with rheumatoid arthritis (RA) who subsequently developed bronchiectasis (BR) and to review the literature on biologic response modifiers (BRM) in relation to infectious complications in the management of these patients. METHODS: We describe 4 patients with RA who were diagnosed with BR out of a cohort of 170 patients. We then performed a comprehensive review of the English language literature on the major clinical trials for RA that involved the BRMs etanercept, infliximab, anakinra, and adalimumab. We focused on inclusion/exclusion criteria involving pulmonary disease and infectious complications in these trials. RESULTS: Of the 4 patients we describe, all developed BR after the diagnosis of RA was established, had positive cyclic citrullinated peptide antibodies, had extra-articular manifestations, and had clinical courses complicated by pneumonia. Management strategies were influenced by these factors in all of the patients described. Of the 16 clinical trials on BRMs reviewed, few studies mentioned BR as an exclusion criteria or reported pneumonia as a specific infectious complication. CONCLUSIONS: BR may be considered as an extra-articular pulmonary manifestation of RA. The infectious complications associated with BR in these patients underscore the management challenge, especially in choosing whether or not to treat with BRMs. Further studies are needed to analyze the infectious complications in RA trials with BRMs, specifically, to assess the risk of patients with BR. Risk stratification in these patients may require screening them for the presence of underlying BR.