Grant: Discovery Launch Supplement

Acute increases in either metabolic CO2 production (exercise) or arterial CO2 tension (hypercapnia) lead to increases in ventilatory drive and output. During severe physiological stress in humans, total minute ventilation (VE) can increase 10-15-fold, with relatively mild increases in respiratory muscle effort. However, at relatively high VE rates, expiratory flow limitation can lead to mechanical ventilatory constraint, which challenges the respiratory system to generate sufficient VE, despite compensatory increases in the ventilatory neural drive. Thus, a dissociation in the ratio between ventilatory output and ventilatory neural drive (neural activation of respiratory musculature), termed neuroventilatory uncoupling, can occur. Importantly, the severity of neuroventilatory uncoupling has been linked to increased perceived shortness of breath (termed dyspnea) in humans. Females have smaller lungs, narrower airways, and decreased ventilatory capacity compared to males. During exercise, females have a greater work of breathing than males at a given level of VE, secondary to decreased airways diameter and heightened airways resistance. Several studies have shown that the hypercapnic VE response is lower in females than males. Although not fully understood, sex differences in respiratory structure may predispose females to increased mechanical constraint in conditions of heightened ventilatory drive (hypercapnia and/or exercise), which could blunt the increase in VE, ultimately leading to neuroventilatory uncoupling. However, the causal relationship between biological sex, mechanical constraint, and neuroventilatory control during physiological stress is poorly understood. Further, it is unclear how natural aging, including the known natural decline in lung function, may interact with biological sex and affect dynamic respiratory mechanics and neuroventilatory control. The overall objective of this proposal is to advance our understanding of the neurophysiological mechanisms that contribute to the control of breathing during physiological stress.  My specific objectives are as follows: AIM 1. To characterize the effect of biological sex on dynamic respiratory mechanical and neuroventilatory responses to progressive hypoxic hypercapnia. AIM 2. To determine the effect of biological sex on respiratory mechanical and neuroventilatory responses to selective manipulation of airways resistance during progressive hypoxic hypercapnia. AIM 3. To determine the effect of biological sex on respiratory mechanical and neuroventilatory responses, dyspnea, and exercise performance, following selective manipulation of airways resistance during whole-body exercise. AIM 4. To determine if the natural aging exacerbates the biological sex differences in neuroventilatory control during physiological stress. This proposal will use sex, aging, and physiological stress paradigms to advance our understanding of mechanisms regulating neuroventilatory control in humans.