One special question to start with: can HIF/NFkB be a target in inflammation?

Hypoxia and Inflammation are strictly interconnected with important consequences at clinical and therapeutic level. While cell and tissue damage due to acute hypoxia mostly leads to cell necrosis, in chronic hypoxia, cells that are located closer to vessels are able to survive adapting their phenotype through the expression of a number of genes, including proinflammatory receptors for alarmins. These receptors are activated by alarmins released by necrotic cells and generate signals for master transcription factors such as NFkB, AP1, etc. which control hundreds of genes for innate immunity and damage repair. Clinical consequences of chronic inflammatory reparative response activation include cell and tissue remodeling, damage in the primary site and, the systemic involvement of distant organs and tissues. Thus every time a tissue environment becomes stably hypoxic, inflammation can be activated followed by chronic damage and cell death or repair with vessel proliferation and fibrosis. This pathway can occur in cancer, myocardial infarction and stroke, diabetes, obesity, neurodegenerative diseases, chronic and autoimmune diseases and age-related diseases. Interestingly, proinflammatory gene expression can be observed earlier in hypoxic tissue cells and, in addition, in activated resident or recruited leukocytes. Herewith, the reciprocal relationships between hypoxia and inflammation will be shortly reviewed to underline the possible therapeutic targets to control hypoxia-related inflammation in a number of epidemiologically important human diseases and conditions

Hypoxic regulation of ion channel function and expression

Acute hypoxia regulates the activity of specific ion channels in a rapid and reversible manner. Such effects underlie appropriate cellular responses to hypoxia which are designed to initiate cardiorespiratory reflexes and contribute importantly to other tissue responses, all of which are designed to improve tissue O2 supply. These responses include excitation of chemoreceptors as well as pulmonary vasoconstriction and systemic vasodilatation. However, such responses may also contribute to the adverse responses to hypoxia, such as excitotoxicity in the central nervous system. Whilst numerous ion channel types are known to be modulated by acute hypoxia, the nature of the O2 sensor in most tissues remains to be identified. Prolonged (chronic) hypoxia regulates functional expression of ion channels, and so remodels excitability of various cell types. Whilst this may contribute to adaptive responses such as high-altitude acclimatization, such altered channel expression may also contribute to the onset of pathological disorders, including Alzheimer's disease. Indeed, evidence is emerging that production of pathological peptides associated with Alzheimer's disease is increased during prolonged hypoxia. Such effects may account for the known increased incidence of this disease in patients who have previously endured hypoxic episodes, such as congestive heart failure and stroke. Identification of the mechanisms coupling hypoxia to the increased production of these peptides is likely to be of therapeutic benefit

The paradox between resistance to hypoxia and liability to hypoxic damage in hyperglycemic peripheral nerves. Evidence for glycolysis involvement

Isolated ventral and dorsal rat spinal roots incubated in normal (2.5 mM) or high glucose (25 mM) concentrations or in high concentrations of other hexoses were exposed transiently to hypoxia (30 min) in a solution of low buffering power. Compound nerve action potentials, extracellular direct current potentials, and interstitial pH were continuously recorded before, during, and after hypoxia. Ventral roots incubated in 25 mM D-glucose showed resistance to hypoxia. Dorsal roots, on the other hand, revealed electrophysiological damage by hyperglycemic hypoxia as indicated by a lack of posthypoxic recovery. In both types of spinal roots, interstitial acidification was most pronounced during hyperglycemic hypoxia. The changes in the sensitivity to hypoxia induced by high concentrations of D-glucose were imitated by high concentrations of D-mannose. In contrast, D-galactose, L-glucose, D-fructose, and L-fucose did not have such effects. Resistance to hypoxia, hypoxia-generated interstitial acidification, and hypoxia-induced electrophysiological damage were absent after pharmacological inhibition of nerve glycolysis with iodoacetate. These observations indicate 1) that enhanced anaerobic glycolysis produces resistance to hypoxia in hyperglycemic peripheral nerves and 2) that acidification may impair the function of peripheral axons when anaerobic glycolysis proceeds in a tissue with reduced buffering power

Eigenspectra optoacoustic tomography achieves quantitative blood oxygenation imaging deep in tissues

Light propagating in tissue attains a spectrum that varies with location due to wavelength-dependent fluence attenuation by tissue optical properties, an effect that causes spectral corruption. Predictions of the spectral variations of light fluence in tissue are challenging since the spatial distribution of optical properties in tissue cannot be resolved in high resolution or with high accuracy by current methods. Spectral corruption has fundamentally limited the quantification accuracy of optical and optoacoustic methods and impeded the long sought-after goal of imaging blood oxygen saturation (sO2) deep in tissues; a critical but still unattainable target for the assessment of oxygenation in physiological processes and disease. We discover a new principle underlying light fluence in tissues, which describes the wavelength dependence of light fluence as an affine function of a few reference base spectra, independently of the specific distribution of tissue optical properties. This finding enables the introduction of a previously undocumented concept termed eigenspectra Multispectral Optoacoustic Tomography (eMSOT) that can effectively account for wavelength dependent light attenuation without explicit knowledge of the tissue optical properties. We validate eMSOT in more than 2000 simulations and with phantom and animal measurements. We find that eMSOT can quantitatively image tissue sO2 reaching in many occasions a better than 10-fold improved accuracy over conventional spectral optoacoustic methods. Then, we show that eMSOT can spatially resolve sO2 in muscle and tumor; revealing so far unattainable tissue physiology patterns. Last, we related eMSOT readings to cancer hypoxia and found congruence between eMSOT tumor sO2 images and tissue perfusion and hypoxia maps obtained by correlative histological analysis

Hypoxia in the Initiation and Progression of Neuroblastoma Tumours

Neuroblastoma is the most frequent extracranial solid tumour in children, causing 10% of all paediatric oncology deaths. It arises in the embryonic neural crest due to an uncontrolled behaviour of sympathetic nervous system progenitors, giving rise to heterogeneous tumours. Low local or systemic tissue oxygen concentration has emerged as a cellular stimulus with important consequences for tumour initiation, evolution and progression. In neuroblastoma, several evidences point towards a role of hypoxia in tumour initiation during development, tumour cell differentiation, survival and metastatic spreading. However, the heterogeneous nature of the disease, its developmental origin and the lack of suitable experimental models have complicated a clear understanding of the effect of hypoxia in neuroblastoma tumour progression and the molecular mechanisms implicated. In this review, we have compiled available evidences to try to shed light onto this important field. In particular, we explore the effect of hypoxia in neuroblastoma cell transformation and differentiation. We also discuss the experimental models available and the emerging alternatives to study this problem, and we present hypoxia-related therapeutic avenues being explored in the field.Spanish Ministry of Science and Innovation SAF program (grant number SAF2016-80412-P

Effect of hypoxia on lung gene expression and proteomic profile: insights into the pulmonary surfactant response

Exposure of lung to hypoxia has been previously reported to be associated with significant alterations in the protein content of bronchoalveolar lavage (BAL) and lung tissue. In the present work we have used a proteomic approach to describe the changes in protein complement induced by moderate long-term hypoxia (rats exposed to 10% O2 for 72h) in BAL and lung tissue, with a special focus on the proteins associated with pulmonary surfactant, which could indicate adaptation of this system to limited oxygen availability. The analysis of the general proteomic profile indicates a hypoxia-induced increase in proteins associated with inflammation both in lavage and lung tissue. Analysis at mRNA and protein levels revealed no significant changes induced by hypoxia on the content in surfactant proteins or their apparent oligomeric state. In contrast, we detected a hypoxia-induced significant increase in the expression and accumulation of hemoglobin in lung tissue, at both mRNA and protein levels, as well as an accumulation of hemoglobin both in BAL and associated with surface-active membranes of the pulmonary surfactant complex. Evaluation of pulmonary surfactant surface activity from hypoxic rats showed no alterations in its spreading ability, ruling out inhibition by increased levels of serum or inflammatory proteins.Ministerio de Ciencia BIO2012-30733Ministerio de Ciencia CSD2007-00010Gobierno de la Comunidad de Madrid S2009MAT-1507National Institutes of Health NIH HL3478

Hooray for Hypoxia?

The mortality of critically ill patients rises steadily as the partial pressure of arterial oxygen falls below about 11 kPa (80 mm Hg). A new animal study in the May 2005 issue of PLoS Biology showing a potential benefit for hypoxia is thus a challenge to current thinking

GBM radiosensitizers: dead in the water…or just the beginning?

The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers. However, many of  the previous radiosensitizing strategies were not based on clear pre-clinical evidence, and in many cases blood-barrier penetration was not considered. Furthermore, DNA repair inhibitors have only recenly arrived in the clinic, and likely represent potent agents for glioma radiosensitization. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization