Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model

Heim, Christian; Motsch, B.; Jalilova, Sabina; Bernhardt, Wanja M.; Ramsperger-Gleixner, M.; Burzlaff, Nicolai; Weyand, Michael; Eckardt, Kai‐Uwe; Ensminger, Stephan

doi:10.1016/j.trim.2016.08.007

Cited by 8 publications

(6 citation statements)

References 51 publications

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“…Beyond the correction of renal anemia, preclinical evidence suggests that PHD inhibition offers novel opportunities for organ protection, an area of unmet clinical need. We showed potent PHD inhibition by 2‐(1‐chloro‐4‐hydroxyisoquinoline‐3‐carbox‐amido)acetate (ICA) with beneficial effects in murine models of kidney ischemia‐reperfusion injury, allotransplantation, and chronic kidney disease 207–210 . Tissue and organ protective effects of PHD inhibition have also been demonstrated in models of myocardial injury, 211 brain injury, 212 lung injury, 213 and—as mentioned earlier—inflammatory bowel disease 169,172 .…”

Section: Pharmacologic Hif Modifiersmentioning

confidence: 65%

“…We showed potent PHD inhibition by 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido)acetate (ICA) with beneficial effects in murine models of kidney ischemia-reperfusion injury, allotransplantation, and chronic kidney disease. [207][208][209][210] Tissue and organ protective effects of PHD inhibition have also been demonstrated in models of myocardial injury, 211 brain injury, 212 lung injury, 213 and-as mentioned earlier-inflammatory bowel disease. 169,172 AKB-4924 is evaluated for the treatment of inflammatory bowel disease (NCT02914262).…”

Section: Hif Stabilizationmentioning

confidence: 74%

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Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets

Kling

Schreiber

Kettritz

2020

Journal of Leukocyte Biology

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Hypoxia describes limited oxygen availability at the cellular level. Myeloid cells are exposed to hypoxia at various bodily sites and even contribute to hypoxia by consuming large amounts of oxygen during respiratory burst. Hypoxia-inducible factors (HIFs) are ubiquitously expressed heterodimeric transcription factors, composed of an oxygen-dependent and a constitutive subunit. The stability of HIF-1 and HIF-2 is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1 and HIF-2 modify the innate immune response and are context dependent. We provide a historic perspective of HIF discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions. HIFs enable myeloid-cell adaptation to hypoxia by up-regulating anaerobic glycolysis. In addition to effects on metabolism, HIFs control chemotaxis, phagocytosis, degranulation, oxidative burst, and apoptosis. HIF-1 enables efficient infection defense by myeloid cells. HIF-2 delays inflammation resolution and decreases antitumor effects by promoting tumor-associated myeloid-cell hibernation. PHDs not only control HIF degradation, but also regulate the crosstalk between innate and adaptive immune cells thereby suppressing autoimmunity. HIF-modifying pharmacologic compounds are entering clinical practice. Current indications include renal anemia and certain cancers. Beneficial and adverse effects on myeloid cells should be considered and could possibly lead to drug repurposing for inflammatory disorders. K E Y W O R D S hypoxia-inducible factor, hypoxia, innate immunity, myeloid cells This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Pharmacologic Hif Modifiersmentioning

confidence: 65%

Section: Hif Stabilizationmentioning

confidence: 74%

Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets

Kling

Schreiber

Kettritz

2020

Journal of Leukocyte Biology

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“…Genetically-upregulating HIF-2 in airway allografts provides robust protection from microvascular destruction and diminishes alloimmune inflammation. Transient upregulation of the HIFs in the peri-transplant period at the anastomosis site or during acute rejection episodes in the more distal airways have therapeutic potential for the two major vascular injuries described in Figures 1 and 2 [24,27,28]. To this end, iron-chelators are FDA-approved therapies for iron-overload-related disorders which stabilize the HIFs and their potential as a treatment is described in the Therapeutic Opportunities section below.…”

Section: Vascular Injury and Airway Hypoxia In Lung Transplantationmentioning

confidence: 99%

Airway hypoxia in lung transplantation

Pasnupneti

Nicolls

2019

Current Opinion in Physiology

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Lung transplantation is a life-saving operation for patients with advanced lung disease. Pulmonary allografts eventually fail because of infection, thromboembolism, malignancy, airway complications, and chronic rejection, otherwise known as chronic lung allograft dysfunction (CLAD). Emerging evidence suggests that a highly-compromised airway circulation contributes to the evolution of airway complications and CLAD. There are two significant causes of poor perfusion and airway hypoxia in lung transplantation: an abnormal bronchial circulation which causes airway complications and microvascular rejection which induces CLAD. At the time of transplantation, the bronchial artery circulation, a natural component of the airway circulatory anatomy, is not surgically connected, and bronchi distal to the anastomosis become hypoxic. Subsequently, the bronchial anastomosis is left to heal under ischemic conditions. Still later, the extant microvessels in transplant bronchi are subjected to alloimmune insults that can further negatively impact pulmonary function. This review describes how airway tissue hypoxia evolves in lung transplantation, why depriving oxygenation in the bronchi and more distal bronchioles contributes to disease pathology and what therapeutic interventions are currently emerging to address these vascular injuries. Improving anastomotic vascular healing at the time of transplantation and preventing microvascular loss during acute rejection episodes are two steps that could limit airway hypoxia and improve patient outcomes.

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“…60,61 A study by our own working group analyzed the connection between hypoxia and the development of CLAD. 62 Ischemic preconditioning using PHD inhibitor ICA to induce the accumulation of HIF with respective activation of tissue protective target genes under normoxic conditions showed positive effects in the context of chronic rejection after heart transplantation with a significant reduction of CAV. 14 For evaluating the role of HIF with regard to the development of CLAD, trachea donor mice were treated with ICA shortly before graft removal.…”

Section: Treatment Options Based On Inhibiting Ischemia and Oxidativementioning

confidence: 99%

New Targets for the Prevention of Chronic Rejection after Thoracic Organ Transplantation

Heim

Gocht

Weyand

et al. 2017

Thorac cardiovasc Surg

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The gold standard for the treatment of terminal heart failure and irreversible lung diseases includes thoracic organ transplantation. The major obstacle for long-term survival after successful transplantation is chronic rejection, an ongoing immunomodulatory disease so far without effective therapy. Therefore, the aim of this review is to elucidate scientific efforts targeting different new mechanisms of cardiac allograft vasculopathy (CAV) and chronic lung allograft dysfunction (CLAD). For this purpose, we performed a systematic review of the literature to assess recent strategies in transplant immunology research. We searched MEDLINE from 2015 up to date for articles addressing the following keywords: CAV, transplant vasculopathy, transplant arteriosclerosis, CLAD, bronchiolitis obliterans transplant, and obliterative bronchiolitis transplant. All articles including experimental models in the field of transplant immunology addressing new aspects for the prevention of chronic rejection after heart and lung transplantation were included in this review. The prevention of chronic rejection would clearly improve the survival of patients after heart and lung transplantation. Interesting targets were addressed in recent research, but further research is necessary to effectively treat this life-threatening disease in transplant recipients.

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Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model

Cited by 8 publications

References 51 publications

Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets

Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets

Airway hypoxia in lung transplantation

New Targets for the Prevention of Chronic Rejection after Thoracic Organ Transplantation

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