Targeted delivery of the hydroxylase inhibitor DMOG provides enhanced efficacy with reduced systemic exposure in a murine model of colitis

Tambuwala, Murtaza M.; Manresa, Mario C.; Cummins, Eoin P.; Aversa, Vincenzo; Coulter, Ivan S.; Taylor, Cormac T.

doi:10.1016/j.jconrel.2015.09.022

Cited by 65 publications

(63 citation statements)

References 18 publications

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“…Depending on the cause of the constitutive hypoxia, it may be favorable to either activate or suppress HIF (35). During inflammation and colitis, HIF exerts a protective effect (11,49,50). In contrast, in cancer, intratumoral hypoxia and genetic mutations result in the up-regulation of HIF-1␣, and the activation of HIF can promote tumorigenesis (35).…”

Section: Discussionmentioning

confidence: 99%

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-␣ protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O 2 -dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-␣ protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO 2 . Bafilomycin A1, a specific inhibitor of vacuolar-type H ؉ -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-␣ protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-␣ subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.Current atmospheric CO 2 levels are relatively low when compared with those recorded throughout the natural history of the planet (1). Not surprisingly, therefore, a range of organisms as diverse as bacteria, fungi, plants, and mammals mount physiologic responses to hypercapnia (2). It is now clear that CO 2 , like other physiologic gases such as oxygen and nitric oxide, can be sensed by cells and can elicit adaptive transcriptional responses (2-4).Because O 2 consumption is coupled to CO 2 production, an intimate inverse relationship exists between the levels of these gases in cells and tissues. Furthermore, O 2 and CO 2 levels may become perturbed during certain pathophysiologic states (3, 5). Hypoxia and hypercapnia can co-occur in respiratory disorders such as obstructive sleep apnea syndrome, pneumonia, and chronic obstructive pulmonary disease (6, 7). In acute lung injury hypoxia may arise, whereas permissive hypercapnia is often tolerated as a protective ventilatory strategy in patients presenting with this disorder (8, 9). Hypercapnia and hypoxia also influence inflammatory processes (10 -12). During inflammation, oxygen consumption is significantly elevated, leading to tissue hypoxia. It is likely that this also has consequences for tissue CO 2 levels (3, 11). HIF 8 (which comprises the HIF-1, HIF-2, and HIF-3 isoforms) is the master transcriptional regulator of the cellular response to hypoxia (13). Canonical HIF degradation relies on the activity of O 2 -dependent prolyl hydroxylases 1-3 (14). In normoxia, prolyl hydroxylases enzymatically modify HIF-␣ subunits on proli...

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Section: Discussionmentioning

confidence: 99%

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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“…First, in order to achieve tissue-specific effects without inducing systemic responses (such as unwanted erythropoiesis), the targeted delivery of drugs to niches should be considered. Recent approaches to this have been used in models of IBD 139 . Furthermore, the development of specific reagents, including isoform-specific PHD inhibitors or selective HIF1 versus HIF2 inhibitors, will improve the therapeutic potential of interfering with this pathway.…”

Section: Perspectivementioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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“…Given the crosstalk described above, it is plausible to think that targeting the HIF pathway will impact on NF‐κB function. In fact, a number of studies using both genetic and chemical inhibition of the PHD proteins have demonstrated therapeutic effects in disease models such as colitis and even in response to infection , where inflammation and NF‐κB play an important role. It would therefore be interesting to expand the possible therapeutic effect of both HIF activators and inhibitors to other diseases of the immune system such as RA and COPD.…”

Section: Hif and Nf‐κb Crosstalk In Disease Conditionsmentioning

confidence: 99%

NF‐κB and HIF crosstalk in immune responses

2015

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Hypoxia and inflammation have been associated with a number of pathological conditions, in particular inflammatory diseases. While hypoxia is mainly associated with the activation of hypoxia‐inducible factors (HIFs), inflammation activates the family of transcription factor called nuclear factor‐kappa B (NF‐κB). An extensive crosstalk between these two main molecular players involved in hypoxia and inflammation has been demonstrated. This crosstalk includes common activating stimuli, shared regulators and targets. In this review, we discuss the current understanding of the role of NF‐κB and HIF in the context of the immune response. We review the crosstalk between HIF and NF‐κB in the control of the immune response in different immune cell types including macrophages, neutrophils and B and T cells. Furthermore the importance of the molecular crosstalk between HIFs and NF‐κB for a variety of medical conditions will be discussed.

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Targeted delivery of the hydroxylase inhibitor DMOG provides enhanced efficacy with reduced systemic exposure in a murine model of colitis

Cited by 65 publications

References 18 publications

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Regulation of immunity and inflammation by hypoxia in immunological niches

NF‐κB and HIF crosstalk in immune responses

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