Cough hypersensitivity risk increases during heatwaves and can be reduced by inhalation of alkaline aerosols of endogenous ions

Abstract Heat wave burden is rapidly rising and exacerbating human respiratory illnesses. Yet, how to protect human airways, short of deep and sustained reductions in greenhouse gas emissions, remains unclear. Here, we find, by theoretical, in vitro experimental, and human clinical studies, that heatwave exposure elevates risks of cough hypersensitivity, which can be reversed by the inhalation of alkaline hypertonic divalent salts (HDS). We find that upper-airway mucosal collapse occurs on exposing human bronchial epithelial (HBE) cell cultures to an arid heatwave atmosphere (35 ºC, 30% RH), resulting in elevated (p < 0.05) expression of genes associated with cough hypersensitivity, including TRPV4, PIEZO1, P2X3R and ENaC subunit proteins α and β (SCNN1A, SCNN1B) post 8 h—while not post 3 h—relative to baseline. We find by continuum mechanic analysis, and confirm experimentally in HBE cell cultures, that airway mucosal collapse reverses for greater than 3 h post deposition of HDS (magnesium) aerosols with pH above the cysteine pKa (approximately 8.3), while not at pH 7 or 8, nor by hypertonic saline at any pH. In a randomized, double-blind, placebo controlled study (REACH) in Riyadh, Saudi Arabia, HDS pH 9 aerosols reduced daily cough bout rate relative to placebo by 59% (p = 0.03) after 2 weeks treatment (n = 6), while, in a preceding RCC study, HDS pH 8 aerosols reduced cough bout rate by only 4% (p > 0.05) (n = 7). Alkaline HDS aerosols may be protective of human respiratory health with global warming.