Differential biological responses to dyspnea-inducing experimental respiratory challenges in healthy humans

Dyspnea is the symptom that conveys the upsetting or distressing awareness of respiratory sensations. It is part of an ensemble of respiratory, neurovegetative, and behavioral manifestations resulting from the brain's reaction to abnormal respiratory-related afferents. This attests to a systemic phenomenon and suggests the existence of measurable biological changes. Different types of experimental respiratory challenges evoke different perceptual, physiological and psychological responses, suggesting distinct mechanisms and the possibility of varied systemic biological responses. We investigated this hypothesis in 34 healthy volunteers (17 women) exposed to inspiratory threshold loading (ITL) and carbon dioxide stimulation with restricted ventilation (CO2-rv), in a randomized cross-over design. Blood and saliva samples were collected at baseline (T0), at the end of a 5-minute dyspnea challenge (T1), and at 30 and 60 minutes post-challenge (T2 and T3). They were analyzed for neuromodulators and inflammatory biomarkers. Substance P levels rose at all time points during both challenges, but were significantly higher after CO2-rv than after ITL. β-endorphin levels rose similarly after both challenges, with a correlation to affective dyspnea ratings during ITL only (R=0.527, p=0.0023). Brain-derived neurotrophic factor (BDNF) decreased after both stimuli, with lower values following ITL. There were no significant changes in salivary alpha-amylase, FGF-2, TNF-α, IL-1β, IL-8, or IDO/TDO activity, and salivary cortisol decreased. These results provide a biological substrate for the differences between responses to respiratory challenges. They open new avenues toward biology-guided research into respiratory-related brain suffering.