HMGB1 is upregulated in the airways in asthma and potentiates airway smooth muscle contraction via TLR4

Airway smooth muscle (ASM) contributes to asthma pathophysiology via hypercontractility, increased mass, and inflammatory mediator release.1 Clinical studies and animal models demonstrate a role for high-mobility group box 1 (HMGB1) and its receptors in airway inflammation and asthma.2,3 HMGB1's activity and receptor interactions is determined by its redox state, with oxidation rendering HMGB1 inactive.4 We have investigated the redox state of airway HMGB1 and the role of HMGB1 in ASM function. Reduced recombinant HMGB1, at concentrations equivalent to those in sputum, caused a concentration-dependent increase in intracellular ROS production in ASMCs from controls, but not in ASMCs from those with asthma (Fig 2, D), which was reduced by the RAGE decoy receptor soluble RAGE (sRAGE) and the Toll-like receptor (TLR) 4 antagonist LPS from Rhodobacter sphaeroides (LPS-RS) (Fig 2, E). Characteristic Healthy control(n = 10) Asthma severe(n = 19) t test/χ2 test∗ GINA classification, n GINA 4, n = 11GINA 5, n = 5 Age (y)† 46.7 ± 6.2 55 ± 2.8 P = .17 Sex: male, n (%) 5 (50) 8 (42.1) P = .71∗ Smoking status, current smoker, n (%) 1 (10) 5 (26.3) P = .63∗ ICS (μg/d BDP equivalent)‡ 0 (0) 1600 (125)§ P < .001 Pre-BD FEV1 % predicted‡ 93.5 (28.6) 76.0 (54.7) P = .065 Pre-BD FEV1/FVC‡ 90.5 (13.3) 71.1 (24.9)§ P = .0009 % Sputum neutrophils† 50.5 ± 18.7 52.6 ± 6.1 P = .9 % Sputum eosinophils‡ 0.4 (0.8) 5.3 (16.8)§ P = .002 1 D.C. Doeing, J. Solway, Airway smooth muscle...