Fine particulate matter increases airway hyperresponsiveness through kallikrein-bradykinin pathway.

Epidemiological studies have reported short-term fine particulate matter (PM2.5) exposure to increase incidence of asthma, related to the increase of airway hyperresponsiveness (AHR); however, the underlying mechanism remains unclear. Aim of this study was to elucidate the role of kallikrein in PM2.5-induced airway hyperresponsiveness and understand the underlying mechanism. Nose-only PM2.5 exposure system was used to generate a mouse model of airway hyperresponsiveness. Compared with the control group, PM2.5 exposure could significantly increase airway resistance, lung inflammation, kallikrein expression of bronchi-lung tissue and bradykinin (BK) secretion. However, these changes could be alleviated by kallikrein inhibitor. In addition，PM2.5 could increase the viability of human airway smooth muscle cells (hASMCs), accompanied by increased expression of kallikrein 14 (Klk14), bradykinin 2 receptor (B2R), bradykinin secretion and cytosol calcium level, while kallikrein 14 gene knockdown could significantly amelioratethe above response induced by PM2.5. Taken together, the data suggested kallikrein to play a key role in PM2.5-induced airway hyperresponsiveness, and that it could be a potential therapeutic target in asthma. Mechanisms involved in PM2.5-induced airway hyperresponsiveness. PM2.5 induces alleviated expression of kallikrein, which is the precursor of bradykinin. Bradykinin can bind to GPCR and induce downstream Ca²⁺ release from endoplasmic reticulum of airway smooth muscle cells. Airway smooth muscle contracts, followed by overall tracheal and bronchial contraction; eventually, airway resistance increases and airway hyperresponsiveness occurs. GPCR: G protein coupled receptor. Image 1 • Mouse model of hyper-responsive airway was generated by a nasal inhalation system. • PM2.5-induced airway hyperresponsiveness and lung inflammation were inhibited by kallikrein inhibitor. • PM2.5 could increase the contraction of human aiway smooth muscle cells dependent of Kallikrein. • Kallikrein-bradykinin-Ca²⁺ signal play a key role in PM2.5 induced airway smooth muscle contraction. • Kallikrein could be a potential therapeutic target in asthma. [ABSTRACT FROM AUTHOR]