Respiratory gases and the regulation of transcription

Abstract

Eoin obtained a bachelor's degree in Pharmacology (2002) and a PhD (2007) from University College Dublin (UCD). During his postdoctoral career, Eoin became interested in the potential role for carbon dioxide as a modulator of inflammatory and immune signalling, in particular in relation to nuclear factor-κB signalling. The first paper on this work was published in the Journal of Immunology in 2010. In 2013, Eoin obtained his first faculty position as a Lecturer/Assistant Professor in Physiology in the School of Medicine UCD, and he currently leads a research group focused on the effects of hypercapnia on inflammation and immunity. New Findings r What is the topic of this review? This review highlights the transcriptional consequences for decreased cellular O 2 levels (hypoxia) and increased cellular CO 2 levels (hypercapnia). r What advances does it highlight?We discuss recent advances in our understanding of the cellular response to hypoxia and consider the potential cross-talk between O 2 -and CO 2 -dependent transcriptional regulation.Oxygen and carbon dioxide are the substrate and product of aerobic metabolism, respectively. Thus, the levels of these physiological gases are inextricably linked in physiological and pathophysiological conditions. Increased mitochondrial consumption of O 2 (to produce ATP) will produce more CO 2 . Furthermore, in lung pathologies such as chronic obstructive pulmonary disease, sleep apnoea and central hypoventilation syndrome, hypoxia and hypercapnia are co-incident. Acute responses to hypoxia involve carotid body-mediated changes in the rate and depth of breathing. Chronic adaptation to hypoxia involves a multitude of changes on a transcriptional level, which simultaneously increases oxygen utilization (via hypoxia-inducible factor and others), while suppressing superfluous energy-demanding processes. Acute responses to CO 2 affect breathing primarily via central chemoreceptors. The nature of hypercapnia-dependent transcriptional regulation is an emerging area of research, but at present the mechanisms underpinning this response are not fully characterized and understood. Thus, given the juxtaposition of hypoxia and hypercapnia in health and disease, this manuscript reviews the current evidence for transcriptional responses to hypoxia and hypercapnia. Finally, we discuss the potential cross-talk between hypoxia and hypercapnia on a transcriptional level.

Minocycline alters expression of inflammatory markers in autonomic brain areas and ventilatory responses induced by acute hypoxia

“…The present study shows that AH induced an increase in the mRNA levels of IL‐6, IL‐1β, TNFα and MMP9 in specific brain regions involved with cardiorespiratory control, corroborating previous data in the literature that suitable oxygen perfusion in cells is extremely important for the maintenance of their vital functions, whereas low oxygen levels trigger the induction of transcription factors (Cummins & Keogh, ; Hocker et al., ; Prabhakar & Semenza, ; Stokes, Arbogast, Moya, Fu, & Powell, ; Taylor & Cummins, ).…”

“…NF‐κB and the transcription factor HIF are important regulators of oxygen homeostasis and are involved in the cellular signalling mechanisms observed after hypoxia. Under hypoxia, HIF translocates to the nucleus and directly activates a number of genes in order to restore oxygen homeostasis and adapt cells to low oxygen availability (Cummins & Keogh, ; Cummins et al ., ; Taylor & Cummins, ). At the same time, it has also been proposed that the development of inflammation in response to hypoxia also involves the key regulator of immunity and apoptosis, NF‐κB (Eltzschig & Carmeliet, ; Taylor & Cummins, ).…”

“…In addition, increasing evidence supports a dynamic role for inflammation either by promoting or by inhibiting different forms of plasticity within the brain (Hocker, Stokes, Powell, & Huxtable, ). Physiological perturbations such as hypoxia promote transcriptional responses that initiate gene‐specific regulation to improve cellular oxygenation and decrease ATP expenditure (Cummins & Keogh, ; Cummins et al ., ; Kiernan, Smith, Mitchell, & Watters, ; Oliver et al., ; Taylor & Cummins, ). Although neuroinflammatory mechanisms have scarcely been studied in the cardiorespiratory field, correlations between these complex systems may be essential to gaining valuable insights and a better understanding of the regulation of breathing and blood pressure in various physiological conditions.…”

α-Tocopherol transfer protein mediates protective hypercapnia in murine ventilator-induced lung injury

“…Microarray analyses have led to identification of key molecular pathways in VILI9 and of genes regulated by hypercapnia in neonatal lung development,10 and provide the possibility of identifying a specifically upregulated mechanistic pathway. Hypercapnia-dependent transcriptional responses have been recently reviewed 11. While not fully characterised, they include inhibition of NFκB12 and hypoxia-inducible factor 1α (HIF-1α)13 responses, and activation of CREB14 and FoxO3a 15…”

A time of change: out with the old, in with the new

“…The award of this Inaugural Review Prize is marked by publication of a major review article. To date, we have been delighted to honour two outstanding young researchers (Padilla et al 2015;Cummins & Keogh, 2016). Experimental Physiology has also continued its longstanding Early Author Prize, which recognizes authors publishing a first paper that makes a particularly important research contribution in physiology (Ono et al 2015).…”