HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity.

Pharmacologic HIF hydroxylase inhibitors (HIs) are effective for the treatment of anemia in chronic kidney disease patients and may also be beneficial for the treatment of diseases such as chronic inflammation and ischemia-reperfusion injury. The selectivities of many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the translation from preclinical studies to clinical trials. We developed a novel assay that discriminates between the inhibition of HIF-α prolyl-4-hydroxylase domain (PHD) enzymes and HIF-α asparagine hydroxylase factor inhibiting HIF (FIH). We characterized 15 clinical and preclinical HIs, categorizing them into pan-HIF-α hydroxylase (broad spectrum), PHD-selective, and FIH-selective inhibitors, and investigated their effects on HIF-dependent transcriptional regulation, erythropoietin production, and cellular energy metabolism. While energy homeostasis was generally maintained following HI treatment, the pan-HIs led to a stronger increase in pericellular pO2 than the PHD/FIH-selective HIs. Combined knockdown of FIH and PHD-selective inhibition did not further increase pericellular pO2 . Hence, the additional increase in pericellular pO2 by pan- over PHD-selective HIs likely reflects HIF hydroxylase independent off-target effects. Overall, these analyses demonstrate that HIs can lead to oxygen redistribution within the cellular microenvironment, which should be considered as a possible contributor to HI effects in the treatment of hypoxia-associated diseases.

Early and late abdominal surgeries after lung transplantation: incidence and outcome.

OBJECTIVES: Abdominal surgery after lung transplantation is an important factor for major morbidity and mortality. Herein, we describe the incidence and outcome of abdominal surgery occurring early or late after transplantation. METHODS: Overall, 315 patients who underwent lung transplantation between January 2000 and December 2013 at our institution were included in a prospective database. Perioperative parameters were assessed, and complications were graded according to the Clavien-Dindo Classification. RESULTS: Among 315 patients after lung transplantation, 52 patients underwent abdominal surgery, 16 during the early postoperative phase and 42 at later time points. Bowel ischaemia and perforation of the right colon were the most common reason for early surgery, with a median interval of 7 days after lung transplantation. The median survival time for patients with early abdominal surgery was 31 months compared to 40 and 90 months for patients with no or late abdominal surgery (P = 0.001 and P = 0.002, respectively). The most common late indications for surgery were perforated diverticulitis, ileus and hernia, with a median interval of 37.9 months after lung transplantation and a median survival comparable with patients without any abdominal surgery (P = 0.9). However, prior hospitalization due to a non-abdominal disease was associated with increased morbidity (P = 0.006) after late surgery. CONCLUSIONS: Early abdominal surgeries after lung transplantation are associated with a significant mortality risk. Abdominal operations at late time points have a favourable outcome unless patients were hospitalized prior to the abdominal complication. Clinical trial registration number: ZH-KEK-Nr. 2014-0244.