RESUMEN
BACKGROUND: Dysregulation of inflammation-resolution pathways leads to postlung transplant (LTx) ischemia-reperfusion (IR) injury and allograft dysfunction. Our hypothesis is that combined treatment with specialized pro-resolving lipid mediators, that is, Resolvin D1 (RvD1) and Maresin-1 (MaR1), enhances inflammation-resolution of lung IR injury. METHODS: Expression of RvD1 and MaR1 was analyzed in bronchoalveolar lavage (BAL) fluid of patients on days 0, 1, and 7 post-LTx. Lung IR injury was evaluated in C57BL/6 (WT), FPR2-/-, and LGR6 siRNA treated mice using a hilar-ligation model with or without administration with RvD1 and/or MaR1. A donation after circulatory death and murine orthotopic lung transplantation model was used to evaluate the protection by RvD1 and MaR1 against lung IR injury. In vitro studies analyzed alveolar macrophages and type II epithelial cell activation after treatment with RvD1 or MaR1. RESULTS: RvD1 and MaR1 expressions in BAL from post-LTx patients was significantly increased on day 7 compared to days 0 and 1. Concomitant RvD1 and MaR1 treatment significantly mitigated early pulmonary inflammation and lung IR injury in WT mice, which was regulated via FPR2 and LGR6 receptors. In the murine orthotopic donation after cardiac death LTx model, RvD1 and MaR1 treatments significantly attenuated lung IR injury and increased PaO2 levels compared to saline-treated controls. Mechanistically, RvD1/FPR2 signaling on alveolar macrophages attenuated HMGB1 and TNF-α secretion and upregulated uptake of macrophage-dependent apoptotic neutrophils (efferocytosis), whereas MaR1/LGR6 signaling mitigated CXCL1 secretion by epithelial cells. CONCLUSIONS: Bioactive proresolving lipid mediator-dependent signaling that is, RvD1/FPR2 and MaR1/LGR6- offers a novel therapeutic strategy in post-LTx injury.
Asunto(s)
Ácidos Docosahexaenoicos , Enfermedades Pulmonares , Trasplante de Pulmón , Daño por Reperfusión , Animales , Ratones , Células Epiteliales Alveolares/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Ácidos Docosahexaenoicos/análisis , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/genética , Inflamación/metabolismo , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/cirugía , Trasplante de Pulmón/efectos adversos , Macrófagos Alveolares/efectos de los fármacos , Ratones Endogámicos C57BL , Receptores Acoplados a Proteínas G , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/etiología , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , ARN Interferente PequeñoRESUMEN
BACKGROUND: Hemodialysis machine-generated circuit pressures and clearance profiles are potential predictors of quality assurances. In our practice, we previously we observed that elevated static access pressures were associated with abnormal Kt/V values, high access recirculation and deviation of the Kt/V profile (Abnormal Kt/V profile) from normally expected values (Normal Kt/V profile). AIM: To hypothesize that static or derived access pressures would correlate with direct intra-access blood flow rates and that clearance (Kt/V) profiles would correlate with measured Kt/V values. METHODS: Static access pressures, real-time adequacy of dialysis and intra-access blood flow were investigated in end stage renal disease patients undergoing hemodialysis. Wilcoxon-Mann-Whitney test, chi-square test or Fisher's exact test was used to investigate differences between the groups; Spearman's rank correlation test to investigate relationships between static pressures, direct intra-access pressures and Kt/V profiles; and multinomial logistic regression models to identify the independent effect of selected variables on Kt/V profiles. Odds ratio were calculated to measure the association between the variables and Kt/V profiles. RESULTS: One hundred and seven patients were included for analysis. There were no significant differences between genders, and types of vascular access between the normal vs. abnormal clearance (Kt/V) profile groups. No significant correlation could be demonstrated between static access pressures and Kt/V profiles, static access pressures and intra-access blood flow, intra-access blood flow and Kt/V profiles, measured Kt/V and Kt/V profiles or recirculation and Kt/V profiles. CONCLUSION: In this study utilizing measured versus estimated data, we could not validate that dialysis machine generated elevated static pressures predict intra-access blood flow disturbances or that abnormal Kt/V profiles predict access recirculation or inadequate dialysis. These parameters, though useful estimates, cannot be accepted as quality assurance for dialysis adequacy or access function without further evidences.