RESUMO
Microvascular injury and increased vascular leakage are prominent features of radiation-induced lung injury (RILI), and often follow cancer-associated thoracic irradiation. Our previous studies demonstrated that polymorphisms in the gene (MIF) encoding macrophage migratory inhibition factor (MIF), a multifunctional pleiotropic cytokine, confer susceptibility to acute inflammatory lung injury and increased vascular permeability, particularly in senescent mice. In this study, we exposed wild-type and genetically engineered mif(-/-) mice to 20 Gy single-fraction thoracic radiation to investigate the age-related role of MIF in murine RILI (mice were aged 8 wk, 8 mo, or 16 mo). Relative to 8-week-old mice, decreased MIF was observed in bronchoalveolar lavage fluid and lung tissue of 8- to 16-month-old wild-type mice. In addition, radiated 8- to 16-month-old mif(-/-) mice exhibited significantly decreased bronchoalveolar lavage fluid total antioxidant concentrations with progressive age-related decreases in the nuclear expression of NF-E2-related factor-2 (Nrf2), a transcription factor involved in antioxidant gene up-regulation in response to reactive oxygen species. This was accompanied by decreases in both protein concentrations (NQO1, GCLC, and heme oxygenase-1) and mRNA concentrations (Gpx1, Prdx1, and Txn1) of Nrf2-influenced antioxidant gene targets. In addition, MIF-silenced (short, interfering RNA) human lung endothelial cells failed to express Nrf2 after oxidative (H2O2) challenge, an effect reversed by recombinant MIF administration. However, treatment with an antioxidant (glutathione reduced ester), but not an Nrf2 substrate (N-acetyl cysteine), protected aged mif(-/-) mice from RILI. These findings implicate an important role for MIF in radiation-induced changes in lung-cell antioxidant concentrations via Nrf2, and suggest that MIF may contribute to age-related susceptibility to thoracic radiation.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Raios gama/efeitos adversos , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Lesões Experimentais por Radiação/metabolismo , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Envelhecimento/efeitos da radiação , Animais , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio/efeitos adversos , Peróxido de Hidrogênio/farmacologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/farmacologia , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Oxidantes/efeitos adversos , Oxidantes/farmacologia , Lesões Experimentais por Radiação/genética , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/prevenção & controleRESUMO
PURPOSE: To evaluate multidetector computed tomographic (CT) images to investigate the prevalence, morphology, natural course, and prognostic effect of intramural blood pools (IBPs) in patients with acute intramural hematoma (IMH). MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Sixty-five patients (41 men; mean age, 65.9 years ± 11.3 [standard deviation]) with acute IMH undergoing three or more multidetector CT examinations during follow-up for 12 months or longer (median = 18 months), except for those undergoing surgery (n = 16), were enrolled. Associated factors of developing and resorption of IBP in IMH were analyzed by using logistic regression. RESULTS: There were 40 IBPs in 10 patients at initial multidetector CT, and 15 new IBPs developed in 11 patients during follow-up. IBPs occurred most in the descending thoracic (55% [31 of 56]) and abdominal (41% [23 of 56]) aorta in 28% (18 of 65) of patients. During 33.8 months (range, 2.8-50 months) of follow-up in these 18 patients, 57% (32 of 56) of IBPs showed complete resorption in 15 patients, 29% (16 of 56) of IBPs showed incomplete resorption in eight patients, and 14% (eight of 56) of IBPs had interrupted follow-up because of surgery or death in three patients. Logistic regression showed that age younger than 70 years (odds ratio [OR], 8.74; 95% confidence interval [CI]: 1.03, 76.9) and IMH wall thickness greater than 10 mm (OR, 4.93; 95% CI: 1.04, 23.0) were associated with developing IBP at initial multidetector CT, while IBP with larger transmural diameter (OR, 1.16; 95% CI: 1.02, 1.31) and multidetector CT-demonstrated connection with intercostal or lumbar artery (63% [35 of 56]) (OR, 5.44; 95% CI: 1.43, 20.9) were associated with incomplete resorption. CONCLUSION: IBPs are frequently observed at multidetector CT in patients with IMH. They may resolve over time or appear during follow-up. These findings are not associated with a poor prognosis, and IBPs should be distinguished from ulcerlike projections.