NF-κB mediates IL-1ß- and IL-17A-induced MUC5B expression in airway epithelial cells.

A major pathological feature of chronic airway diseases is the elevated expression of gel-forming mucins. NF-κB activation in airway epithelial cells has been shown to play a proinflammatory role in chronic airway diseases; however, the specific role of NF-κB in mucin gene expression has not been characterized. In this study, we show that the proinflammatory cytokines, IL-1ß and IL-17A, both of which use the NF-κB pathway, are potent inducers of MUC5B mRNA expression in both well differentiated primary normal human bronchial epithelial cells and the human bronchial epithelial cell line, HBE1. MUC5B induction by these cytokines was both time- and dose-dependent, and was attenuated by the small molecule inhibitor, NF-κB inhibitor III, as well as p65 small interfering RNA, suggesting that the regulation of MUC5B expression by these cytokines is via an NF-κB-based transcriptional mechanism. Deletion analysis of the MUC5B promoter demonstrated that IL-1ß- and IL-17A-induced promoter activity resides within the -4.17-kb to -2.56-kb region relative to the transcriptional start site. This region contains three putative κB-binding sites (NF-κB-1, -3,786/-3,774; NF-κB-2, -3,173/-3,161; and NF-κB-3, -2,921/-2,909). Chromatin immunoprecipitation analysis confirmed enhanced binding of the p50 NF-κB subunit to the NF-κB-3 site after cytokine stimulation. We conclude that an NF-κB-based transcriptional mechanism is involved in MUC5B regulation by IL-1ß and IL-17A in airway epithelium. This is the first demonstration of the participation of NF-κB and its specific binding site in cytokine-mediated airway MUC5B expression.

Acute Kidney Injury and Renin-Angiotensin System Inhibition Following Transcatheter Aortic Valve Replacement.

OBJECTIVE: To identify renin-angiotensin system (RAS) inhibition utilization and discontinuation after transcatheter aortic valve replacement (TAVR) and identify predictors of use and discontinuation. BACKGROUND: RAS inhibition after TAVR has been associated with lower cardiac mortality and heart failure readmissions. METHODS: We analyzed 735 consecutive TAVR patients (2014-2019) who survived to hospital discharge at a high-volume TAVR center to determine the utilization and discontinuation of RAS inhibition after TAVR and identify predictors of use and discontinuation. Clinical characteristics, procedural variables, and hospital outcomes were compared between patients receiving vs not receiving discharge RAS inhibitors. Data were compared using t-test and Chi-square test. Multivariable analysis was used to determine independent clinical predictors. RESULTS: Of the 735 patients, 41.9% were discharged with at least 1 RAS inhibitor. In TAVR patients with heart failure with reduced ejection fraction (HFrEF), defined as EF ≤40%, the utilization of RAS inhibitors at discharge was 51.1%. Patients receiving discharge RAS inhibitors had lower incidences of acute kidney injury (AKI) post procedure (8.1% vs 17.8%; P<.01). Discontinuation of RAS inhibition was observed in approximately 1 in 3 patients and was associated with AKI and pacemaker requirement. Three predictors of RAS inhibitor utilization were higher systolic blood pressure, RAS inhibitor use prior to TAVR, and HFrEF. Conversely, new pacemaker and AKI were associated with less utilization of RAS inhibitors; patients developing AKI were 74% less likely to receive RAS inhibitors than those without AKI. CONCLUSION: Decreased RAS inhibition provides a potential mechanism for worse outcomes in TAVR patients who develop AKI.

Patent foramen ovale and neurologic events in patients undergoing liver transplantation.

BACKGROUND: Patent foramen ovale (PFO) is present in approximately 20% of individuals. During liver transplantation (LT), intra-operative transesophageal echocardiography can observe transient intra-cardiac shunting of atheromatous debris via a PFO. Closure of PFOs prior to LT has thus been suggested as a potential treatment to reduce peri-operative cerebral vascular accident (CVA). The objective of this study was to assess if the presence of PFO is associated with CVA in patients undergoing LT. METHODS: Three hundred fifty-eight patients undergoing LT at a single academic institution were included. All patients underwent standardized cardiac evaluation including a detailed cardiovascular history and physical examination, electrocardiogram and transthoracic echocardiogram. Five patients were excluded because of poor transthoracic echocardiographic image quality, and three patients were excluded because of PFO closure prior to LT, yielding a study population of 350 patients. Medical records were reviewed to determine demographics, echocardiographic findings and outcome following LT. Major adverse cardiovascular events, myocardial infarction, CVA and death were collected. RESULTS: Mean age was 53.4 ±â€¯10.2 years; 61% male and 5% of patients had a prior history of CVA. Alcohol and hepatitis C were the most common etiologies for liver disease. Forty-six patients (13.1%) were diagnosed with PFO prior to LT. In-hospital CVA occurred in 6 patients (1.7%). The prevalence of a CVA was not significantly higher in patients with PFO compared to patients without PFO, 2.2% vs 1.6%, p = 0.57. In-hospital mortality was similar in patients with PFO compared to patients without PFO, 4.4% and 5.3%, p = 1.0. CONCLUSIONS: The presence of a PFO in patients undergoing LT is not associated with postoperative CVA. Prophylactic closure of PFOs, in the absence of other indications, does not appear to be warranted in patients undergoing LT.

Circumferential strain acquired by CMR early after acute myocardial infarction adds incremental predictive value to late gadolinium enhancement imaging to predict late myocardial remodeling and subsequent risk of sudden cardiac death.

PURPOSE: Late adverse myocardial remodeling after acute myocardial infarction (AMI) is strongly associated with sudden cardiac death (SCD). Cardiac magnetic resonance (CMR) performed early after AMI can predict late remodeling and SCD risk with moderate accuracy. This study assessed the ability of CMR-measured circumferential strain (CS) to add incremental predictive information to late gadolinium enhancement (LGE). METHODS: Patients with an AMI and LVEF < 50% were screened for inclusion. A total of 27 patients, totaling 432 myocardial segments, prospectively underwent CMR 7 ± 5 days after percutaneous coronary intervention (PCI). LGE, microvascular obstruction (MVO), and myocardial CS were measured for each segment. The primary endpoint was late segmental adverse remodeling defined as segmental wall motion score (WMS) > 1 measured by echocardiography 3 months after PCI. RESULTS: A total of 141 segments experienced the primary endpoint at 3 months. The mean LGE volume was higher in these segments, but LGE was also present in many segments with normal WMS (40 ± 28 versus 20 ± 26%, p < 0.01). Segments that met the primary endpoint also showed greater impairment of CS. Segments with both LGE > 17% and impaired CS >- 7.2% on CMR were more likely to experience late adverse remodeling (73%) as compared to segments with neither (9%, p < 0.001) or one abnormal parameter (36%, p < 0.001). CS >- 7.2% also added incremental accuracy to LGE > 17% for predicting late adverse remodeling (AUC 0.81 from 0.70, p < 0.001). CONCLUSIONS: When performed early after AMI, LGE is a moderate predictor of late remodeling and CS is a powerful predictor of late myocardial remodeling. When combined, they can predict late remodeling, a surrogate of SCD, with high accuracy.

Developmental expression of translocator protein/peripheral benzodiazepine receptor in reproductive tissues.

Translocator protein (TSPO) present in the outer mitochondrial membrane has been suggested to be critical for cholesterol import, a rate-limiting step for steroid hormone biosynthesis. Despite the importance of steroidogenesis in regulating reproductive functions, the developmental profile of TSPO expression in the gonads and accessory sex organs has not been completely characterized. As a first step towards understanding the function of TSPO, we studied its expression in male and female murine reproductive organs. We examined testes and ovaries at embryonic days 14.5 and 18.5, and postnatal days 0, 7, 14, 21 and 56 of development. In the adult testis, TSPO was expressed in both Leydig cells and Sertoli cells. In the developing testes TSPO expression was seen in immature Sertoli cells, fetal Leydig cells and gonocytes. In the ovary, TSPO was expressed in the ovarian surface epithelium, interstitial cells granulosa cells and luteal cells. Corpora lutea of ovaries from pregnant mice showed strong expression of TSPO. In the developing ovary, TSPO expression was seen in the squamous pregranulosa cells associated with germ line cysts, together with progressively increasing expression in interstitial cells and the ovarian surface epithelium. In adult mice, the epithelia of other reproductive tissues like the epididymis, prostate, seminal vesicle, oviduct and uterus also showed distinct patterns of TSPO expression. In summary, TSPO expression in both male and female reproductive tissues was not only restricted to steroidogenic cells. Expression in Sertoli cells, ovarian surface epithelium, efferent ductal epithelium, prostatic epithelium, seminal vesiclular epithelium, uterine epithelium and oviductal epithelium suggest either previously unknown sites for de novo steroidogenesis or functions for TSPO distinct from its well-studied role in steroid hormone production.