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-min dyspnea challenge (T1), and at 30 and 60 min postchallenge (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 α-amylase, FGF-2, TNF-α, IL-1β, IL-8, or indoleamine/tryptophan 2,3-dioxygenase (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.NEW & NOTEWORTHY Dyspnea can be induced through different types of respiratory challenges, including inspiratory loading and carbon dioxide stimulation with restricted ventilation. These paradigms elicit different physiological, perceptual, and psychological responses, suggesting distinct modes of engagement of respiratory-related brain suffering. This study shows that the associated biological responses also differ: Substance P levels were higher during the CO₂ challenge, whereas β-endorphin changes were more closely linked to effortful breathing. These results open new avenues toward biology-guided research into respiratory-related brain suffering.