Risk Factors Analysis And Prevention Of ALI/ARDS After Liver Transplantation

Background:Liver transplant is a fast-changing field. Recipients and donors presented to OLT are very different today from a decade ago. This is particularly true after the model for end-stage liver disease (MELD) based organ allocation system has been implemented in 2002. Orthotopic Liver Transplantation (OLT) is an acceptable therapy for certain categories of end-stage liver disease at present. Acute lung injury (ALI)/Acute respiratory distress syndrome (ARDS) is a serious complication with substantial mortality after OLT. ALI/ARDS after OLT was reported previously. Since ARDS was first described in 1967, the diagnostic criteria and definition of ARDS have evolved greatly. In 2012, the Berlin Definition of ARDS was introduced and has been rapidly adopted by the pulmonary and critical care communities. According to the Berlin Definition of ARDS 2012, ALI is mild ARDS. Using a uniform term is essential in clinical research and practice. The latest definition has eliminated the discrepancies and limitations of the previous versions. Study using the Berlin Definition of ARDS in patients undergoing OLT has not been reported. Due to paucity of development of effective treatments for ARDS, current efforts are focusing on identification of risk factors and prevention. Identification of risk factors would allow clinicians to implement the preventive interventions in early stage. This research is divided into two parts. First, According to the Berlin Definition of ARDS 2012, We sought to use our large perioperative database to determine the incidence and risk factors (for both preoperative, intraoperative and postoperative periods) of ARDS in adult patients who underwent OLT. Effect of these risk factors on outcomes. Second, the basic research aimed corresponding risk factors of ARDS after OLT was going. Early research suggests that rejection is a risk factor, Serum total bilirubin(TBIL) level is a risk factor affecting the postoperative occurrence of ARDS, the higher the level of TBIL, the higher the risk of ARDS after OLT. Early prevention and treatment of rejection may be affect the incidence of ARDS and outcome. Acute liver allograft rejection is a serious complication after liver transplantation. The relationship between acute liver allograft rejection and ALI/ARDS was not studied. Interferon regulatory factor 4 (IRF4), is expressed predominantly in the immune system and plays an important role in its development and function. However, the role of 1RF4 in liver transplantation has never been investigated. The aims of this study were to identify the role of IRF4 in liver transplantation. Our findings may be useful to stratify patients and to guide preventive interventions in patients at high risk of developing postoperative ARDS.Part I, Acute Respiratory Distress Syndrome(ARDS) after Orthotopic Liver Transplantation. Objective:The aims of this study were to identify the incidence, preoperative. in traoperative and postoperative risk factors, and impact of ARDS on outcomes in patients after OLT. Methods:Design:Retrospective case-control study. Patients:After institutional review board approval, clinical data of all adult OLT patients between Jan.2004 and Jan,2014 at the UCLA Medical Center were reviewed. Postoperative ARDS was determined using the criteria proposed by the Berlin Definition. Multivariate logistic models were used to identify preoperative and intraoperative risk factors for ARDS. Results:Of 1726 patients who underwent OLT during the study period,71 (4.1%) developed ARDS. The majority of ARDS occurred on the first postoperative day. In preoperative logistic model, encephalopathy (Odds ratio (OR) 2.07, p=0.049), preoperative requirement of intubation (OR 1.97. p=0.043), and preoperative total bilirubin (OR 2.06. p=0.021) were independent risk factors. In intraoperative logistic model, large pressor bolus was the sole risk factor for ARDS (OR 2.691 and 95% CI 1.523-4.755, p=0.001). Postoperatively. patients with ARDS had a two-fold increase in one-year mortality, mechanical ventilation time, and length of hospital stay. Severe ARDS was associated with the highest one-year mortality. In the analysis, the risk factors of postoperative of ARDS were infection and acute rejection after OLT. Conclusion: ARDS occurred at a rate of 4.1% following OLT in adult patients and was associated with preoperative encephalopathy, requirement of intubation, and total bilirubin concentration and intraoperative large pressor bolus. ARDS is closely related to the postoperative acute rejection. ARDS was also associated with increased mortality, longer ventilation time, and hospital stay.Part Ⅱ, the basic research aimed corresponding risk factors of ARDS after OLT -Inhibition of interferon regulatory factor 4 attenuates acute liver allograft rejection in mice. Objective:Acute liver allograft rejection is a serious complication after liver transplantation. Interferon regulatory factor 4 (IRF4), is expressed predominantly in the immune system and plays an important role in its development and function. However, the role of IRF4 in liver transplantation has never been investigated. Methods:In our current study, to evaluate the effect of IRF4 inhibition on recipient survival, IRF4 siRNA, or control siRNA, or PBS was injected into the liver allograft recipients through caudal vein. Results:The survival time of mice treated with IRF4 siRNA (MST= 31.5 days) was prolonged significantly compared with that of mice treated with PBS (MST= 6 days) or control siRNA (MST= 6.5 days) (P< 0.001). IRF4 siRNA treatment displays lower induction of proinflammatory levels, including TNF-α, IL-6 and IFN-γ, and higher induction of anti-inflammatory IL-10 levels. Administration of anti-IL-10 into IRF4 siRNA-treated mice resulted in shortened allograft survival and increased rejection scores. Furthermore, IRF4 inhibition promotes M2 macrophage differentiation in vivo and in vitro. And inhibition of macrophages with GdCl3 reverses the prolonged liver allograft survival and decreased liver rejection scores induced by IRF4 siRNA.Conclusion:Inhibition of IRF4 attenuates acute liver allograft rejection in mice, and this is associated with promoted M2 macrophage differentiation.In a word, the risk factors of ARDS after liver transplantation were analyzed, the study of inhibition of interferon regulatory factor 4 attenuates acute liver allograft rejection in mice and got the corresponding positive effect. These provided reference and new ideas for the prevention and treatment of ALI/ARDS.