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• W2607178172 abstract "Physiological gases such as oxygen (O2) and carbon dioxide (CO2) are central to the regulation of physiological and pathophysiological processes. These two gases are inextricably linked in physiology but are seldom discussed together at scientific symposia, particularly in the context of altered transcriptional responses. O2 is a substrate of aerobic metabolism in order to produce sufficient quantities of ATP to maintain physiological function. It is acutely sensed by chemoreceptors in the carotid body, and cellular adaptation to hypoxia is driven by the hypoxia-inducible factor (HIF) transcription factor. HIF is capable of regulating > 200 genes associated with surviving a hypoxic insult. Similarly, CO2 is sensed acutely by central chemoreceptors in the brainstem and recent evidence suggests that altered CO2 levels can regulate many genes, notably those associated with inflammatory and immune signalling. To date, a CO2-inducible factor analogous to that which exists for the oxygen-sensing pathway has not been identified, with multiple transcription factors including NF-κB, CREB, FOXO3a and HIF postulated to be involved in CO2-dependent gene regulation (Cummins & Keogh, 2016). Hypoxia is a well-understood condition that can profoundly influence physiological processes. It can occur in a variety of settings, e.g. increased O2 demand due to elevated metabolic activity and disruption of vascular supply. In these instances, hypoxia and hypercapnia are likely to coexist as CO2 production is increased and CO2 removal impaired. One explanation for the lack of attention to microenvironmental CO2 concentrations is a paucity of reliable methods for measuring or quantifying in vivo CO2 concentrations in cells and tissues, with a reliance instead on more systemic measurements in the arterial circulation. Thus, this issue of The Journal of Physiology contains a set of papers based on platform presentations that discussed the role of physiological gases in health and disease. They were presented at the recent Joint Meeting of the Physiological Society and the American Physiological Society in Dublin, Ireland (29–31 July 2016). The papers focus on (i) the impact of intermittent hypoxia on adipose tissue, (ii) the impact of hypercapnia on the lung, and (iii) the impact of hypoxia and cellular metabolism on tumour pathophysiology. Notably, while the focus of the review articles is on individual stimuli, e.g. hypercapnia or hypoxia, the potential cross-talk between oxygen-dependent pathways and CO2-dependent pathways is discussed. Obstructive sleep apnoea syndrome (OSAS) is a disease that is characterised by repeated cycles of decreased oxygen saturation during the sleep cycle of affected patients. As well as profound daytime sleepiness, OSAS patients are at risk of Type 2 diabetes and insulin resistance, which is at least in part independent of the effects of obesity (which is common in this patient group). This has led to research focusing on how OSAS might regulate glycaemic control and indeed whether obesity and OSAS are acting synergistically in the regulation of glucose metabolism. Dr Silke Ryan's group has focused their attention on investigating the effects of intermittent hypoxia (IH) (a major feature of OSAS) on adipose tissue. Adipose tissue, in addition to its energy storage function, is regulated by hypoxia-driven signalling pathways and has important endocrine and immune functions. In her article, Ryan (2017) proposes that IH as it occurs in OSAS augments hypoxia/inflammation obesity-induced adipose tissue dysfunction. The mechanisms underpinning these effects are not yet fully characterised but may involve HIF, NF-κB and reactive oxygen species signalling. Hypercapnia (elevated blood CO2) is a feature of several lung pathologies including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and OSAS. Prof. Sznajder's group has been to the fore for several years in describing and dissecting the effects of elevated CO2, particularly in the context of the lung, the primary site of CO2 elimination. Protective ventilation strategies, involving lower tidal volumes have been documented to be protective in patients with acute respiratory distress syndrome (ARDS). This protective approach leads to hypercapnic acidosis, which has been associated with better outcome in acute lung injury/ARDS and has led to discussions regarding the efficacy of permissive and/or therapeutic hypercapnia in the treatment of patients. However, while there is evidence of CO2-dependent protective effects mediated by suppression of inflammatory signalling, in their article Shigemura et al. (2017) sound a word of caution. Hypercapnia is also implicated in impaired alveolar fluid reabsorption, impaired epithelial cell repair, decreased bacterial killing and impaired airway function. Interestingly, several of these responses appear to be a direct effect of CO2-dependent signalling and not due to changes in pH, even though hypercapnia and acidosis frequently occur together. Shigemura et al. advocate further clinical and pre-clinical work to try and unravel the beneficial effects of CO2 from the deleterious effects in the context of managing patients with serious lung diseases. The laboratory of Dr Scott Parks and Dr Jacques Pouyssegur is interested in metabolic adaptations of tumour cells to the challenge of increased nutrient demand. Highly metabolic tumour cells have a greatly elevated requirement for key nutrients and oxygen. It is well established that solid tumours reside within a hypoxic and acidotic tumour microenvironment. Key tumour cell adaptations include (i) expression of increased amino acid transporters, e.g. L-type amino acid transporter 1 (LAT1); (ii) increased glycolytic metabolism, e.g. pyruvate dehydrogenase kinase 1 (PDK1); (iii) altered lactic acid transport, e.g. monocarboxylate transporter 4 (MCT4); (iv) enhanced proton export, e.g. carbonic anhydrase 9 (CA9); and (v) effective HCO3− re-capture, e.g. bicarbonate transporters such as SLC4A. Several of these tumour cell enhanced gene targets are regulated by HIF-1, which is stabilised and activated within hypoxic regions. Interestingly, Parks et al. (2017) comment on an important role for CO2 in acidifying the tumour microenvironment and highlight the presence of both altered CO2 levels and altered O2 levels in tumour cells. While lactic acid is traditionally considered a main driver of the acidic tumour microenvironment, tumour acidosis is still evident in glycolysis-deficient tumours. This indicates a role for CO2 in extracellular acidification by tumour cells in conjunction with the HIF-regulated CA9 (which catalyses the dissociation of carbonic acid into H+ and HCO3−). Linking nicely with Shigemura et al.’s article, Parks et al. propose that altered CO2 in the tumour microenvironment may be an influencing factor in the tumour immune response and potentially provide new therapeutic opportunities. The author has no competing interests. The author is supported by a Science Foundation Ireland award 15/CDA/3490 and by UCD School of Medicine." @default.
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• W2607178172 date "2017-04-13" @default.
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• W2607178172 title "Physiological gases in health and disease - key regulatory factors, not just a lot of hot air" @default.
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