Mechanisms and Consequences of Oxygen and Carbon Dioxide Sensing in Mammals

Abstract

Molecular oxygen (O2) and carbon dioxide (CO2) are the primary gaseous substrate and product of oxidative phosphorylation in respiring organisms, respectively. Variance in the levels of either of these gasses outside of the physiological range presents a serious threat to cell, tissue, and organism survival. Therefore, it is essential that endogenous levels are monitored and kept at appropriate concentrations to maintain a state of homeostasis. Higher organisms such as mammals have evolved mechanisms to sense O2 and CO2 both in the circulation and in individual cells and elicit appropriate corrective responses to promote adaptation to commonly encountered conditions such as hypoxia and hypercapnia. These can be acute and transient nontranscriptional responses, which typically occur at the level of whole animal physiology or more sustained transcriptional responses, which promote chronic adaptation. In this review, we discuss the mechanisms by which mammals sense changes in O2 and CO2 and elicit adaptive responses to maintain homeostasis. We also discuss crosstalk between these pathways and how they may represent targets for therapeutic intervention in a range of pathological states.

Hypercapnia Impairs Na,K-ATPase Function by Inducing Endoplasmic Reticulum Retention of the β-Subunit of the Enzyme in Alveolar Epithelial Cells

“…In patients with ARDS, disruption of the alveolar-capillary barrier causes pulmonary edema that severely alters gas exchange and leads to hypoxia and hypercapnia. Since patients with ARDS require ventilation with low tidal volumes to limit ventilator-induced lung injury, hypercapnia is often further aggravated in this patient group [11,12], which has been tolerated in the last two decades. This is a concept termed "permissive hypercapnia."…”

“…Carbon dioxide (CO 2 ) is a byproduct of mitochondrial respiration and cellular metabolism. Excess of CO 2 , in mammals, is eliminated by the lungs under physiological conditions [11,12]. Thus, any condition that leads to alveolar hypoventilation or impairs diffusion of CO 2 across the alveolar-capillary barrier results in retention of CO 2 in the blood, which is termed hypercapnia.…”

Dynamic Brain-Body Coupling of Breath-by-Breath O2-CO2Exchange Ratio with Resting State Cerebral Hemodynamic Fluctuations

“…Lahiri et al (1978) reported that the stimulus thresholds of arterial PO 2 and PCO 2 for peripheral chemoreceptors were largely interdependent under normoxic conditions where a drop in arterial PO 2 was routinely accompanied by increased chemoreceptor activities as well as an enhanced sensitivity of carotid chemoreceptors to arterial PCO 2 . While research on the mechanisms of interaction between peripheral and central chemoreceptors to optimize systemic gases is on-going (Cummins et al, 2019;Kumar and Prabhakar, 2012;Rocha and Branco, 1998), our findings here suggest that PO 2 and PCO 2 work synergistically to regulate blood supply to the brain. bER is one of the appropriate metrics to be used to study such synergism of ΔPO 2 and ΔPCO 2 .…”

“…According to concept of homeostasis, homeostatic regulatory system is formed with arterial PO 2 and PCO 2 as regulated variables, peripheral and central chemoreceptors as sensors, brain stem as control center, and diaphragm and respiratory muscles as effectors, to optimize systemic blood gases. While the detailed mechanisms between the change in central chemoreceptor activities and the change in CBF are topics of on-going research (Cummins et al, 2019;Kumar and Prabhakar, 2012;Rocha and Branco, 1998), arterial PO 2 and PCO 2 which are sensed by chemoreceptors are maintained within a range (or fluctuate) around the physiological 'set point' (i.e. mean) by the feedback control of diaphragm and respiratory muscles for ventilation in the homeostatic regulatory system.…”

Hypercapnia: An Aggravating Factor in Asthma

“…Cells possess the ability to sense and respond to changes in concentration of gaseous molecules through evolutionarily conserved pathways [ 50 ]. CO 2 is a small non-polar molecule and produced in the mitochondria of eukaryotic cells during oxidative phosphorylation and its physiological levels in mammalian tissues (~5%) [ 7 ] are significantly higher than those found in the atmosphere (~0.04%) [ 51 , 52 ].…”