Traffic-related air pollution induces non-allergic eosinophilic airway inflammation and cough hypersensitivity in guinea-pigs

BackgroundThe pathogenesis and pathophysiology of eosinophilia-related chronic cough such as non-asthmatic eosinophilic bronchitis and cough variant asthma are still not clear. ObjectiveThis study is to examine the potential role of traffic-related air pollution (TRAP) in eosinophilic inflammation and cough responses. MethodsNon-sensitized guinea-pigs were exposed to TRAP in an urban traffic tunnel or kept in a filtered air environment for 7 or 14days. Reflexive cough was measured using citric acid and allyl isothiocyanate (AITC) challenges, respectively. Spontaneous cough counting was determined using audio recording and a waveform analysis. Airway inflammation was evaluated using differential cells in bronchoalveolar lavage fluid (BALF) and lung histopathology. To further elucidate the relationship between airway inflammation and cough hypersensitivity, a subgroup of those exposed for 14days received a dexamethasone treatment. ResultsCompared to reflexive cough count (mean (95% confidence interval) in 10minutes) provoked by the AITC challenge for the unexposed animals (3.1 (1.7-4.5)), those were increased significantly following both the 7-day (12.0 (6.8-17.2), P<0.01) and the 14-day (12.0 (6.4-17.6), P<0.01) TRAP exposure. The effect provoked by the citric acid challenge was more profound following the 14-day exposure (26.0 (19.5-32.5) vs 3.8 (1.5-6.0) for the control, P<0.001). TRAP exposures enhanced spontaneous cough events, caused a significant increase of eosinophils and neutrophils in BALF and resulted in a dramatic eosinophilic infiltration in submucosal layer of trachea and bronchus, which can be inhibited significantly by dexamethasone treatment. Conclusions & Clinical RelevanceTRAP exposures induced cough hypersensitivity and non-allergic eosinophilic inflammation of airways in guinea-pigs. This study highlights the potential mechanisms of eosinophilia-related chronic cough that can be induced by traffic-related air pollution

Small cytosolic double-stranded DNA represses cyclic GMP-AMP synthase activation and induces autophagy

Summary: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a major mediator of inflammation following stimulation with >45 bp double-stranded DNA (dsDNA). Herein, we identify a class of ∼20–40 bp small cytosolic dsDNA (scDNA) molecules that compete with long dsDNA (200–1,500 bp herring testis [HT]-DNA) for binding to cGAS, thus repressing HT-DNA-induced cGAS activation. The scDNA promotes cGAS and Beclin-1 interaction, releasing Rubicon, a negative regulator of phosphatidylinositol 3-kinase class III (PI3KC3), from the Beclin-1-PI3KC3 complex. This leads to PI3KC3 activation and induces autophagy, causing degradation of STING and long cytosolic dsDNA. Moreover, DNA damage decreases, and autophagy inducers increase scDNA levels. scDNA transfection and treatment with autophagy inducers attenuate DNA damage-induced cGAS activation. Thus, scDNA molecules serve as effective brakes for cGAS activation, preventing excessive inflammatory cytokine production following DNA damage. Our findings may have therapeutic implications for cytosolic DNA-associated inflammatory diseases