Sensing molecular carbon dioxide: a translational focus for respiratory disease

The last two decades of research on carbon dioxide have demonstrated that CO₂ is far more than a waste product of aerobic metabolism leading to acidosis and that it elicits biological responses directly via non-pH-dependent molecular interactions. New specialized methodologies have mapped CO₂ incorporation into specific regions of CO₂-sensitive proteins and linked these events to altered cellular function. CO₂ affects a host of biological responses related to respiratory disease, including control of respiration, protein maturation, alveolar fluid homeostasis, wound repair, innate immunity, host defense, and airway contractility. Elevated CO₂ (hypercapnia) appears to be primarily deleterious in pulmonary diseases, leading to a heightened interest in strategies to reduce excess CO₂ in patients with hypercapnic respiratory failure. Here, we summarize recently generated knowledge on molecular CO₂ sensing and signaling and the potential translational relevance of these processes in the context of respiratory disease. We need to grow this field further by encouraging experts in basic and translational science to contribute to more fully elucidating CO₂ sensing, signaling, and downstream effects. Understanding the biology and clinical consequences of perturbations in CO₂ homeostasis should no longer be considered secondary to studying oxygen sensing and signaling in respiratory medicine.