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.