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Abstract: Airway hyperreactivity (AHR) is a major feature of asthmatic and inflammatory airways. Cigarette smoke exposure, and bacterial and viral infections are well-known environmental risk factors for AHR, but knowledge about the underlying molecular mechanisms on how these risk factors lead to the development of AHR is limited. Activation of intracellular mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) and their related signal pathways including protein kinase C (PKC), phosphoinositide 3-kinase (PI3K) and protein kinase A (PKA) signaling pathways may result in airway kinin receptor upregulation, which is suggested to play an important role in the development of AHR. Environmental risk factors trigger the production of pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukins (ILs) that activate intracellular MAPK- and NF-κB-dependent inflammatory pathways, which subsequently lead to AHR via kinin receptor upregulation. Blockage of intracellular MAPK/NF-κB signaling prevents kinin B1 and B2 receptor expression in the airways, resulting in a decrease in the response to bradykinin (kinin B2 receptor agonist) and des-Arg9-bradykinin (kinin B1 receptor agonist). This suggests that MAPK- and NF-κB-dependent kinin receptor upregulation can provide a novel option for treatment of AHR in asthmatic as well as in other inflammatory airway diseases. [Copyright &y& Elsevier]

IL levels were correlated with the mRNA levels of HMGB1/TLR-4 from allergic rhinitis patients with the analysis of Spearman correlation. • HMGB1 and TLR-4 were upregulated in AR patients, associating with nasal lavage ILs in AR patients. • TLR4 was associated with HMGB1 in nasal brushing samples from AR patients. • HMGB1/TLR4 pathway was associated with nasal lavage ILs in AR patients. High mobility group box 1 (HMGB1) acts as an inflammatory mediator initiator, and has shown to increase in nasal secretions of allergic rhinitis (AR) patients. The purpose of the present study was to investigate the association of HMGB1 and its receptor, toll-like receptor (TLR) 4 with proinflammatory interleukins in AR patients. The interleukin (IL) −4, −5, −13, −17A, −10 in nasal lavage fluid and the serum IgE were examined with enzyme-linked immunosorbent assay (ELISA) in 125 AR patients or 87 healthy subjects (as control). The mRNA levels of HMGB1, receptor for advanced glycation end products (RAGE) and TLR 2, 3 and 4 were examined in these participants with real-time quantitative PCR (RT-qPCR) method. Spearman rank correlation was adopted to analyze the relationship between any two factors of clinical characteristics and laboratory-examined biomarkers. IL-4, −5, −13 and −17A were significantly higher, whereas IL-10 was markedly lower in the nasal lavage fluid samples from AR patients, compared with the control subjects. High expression of HMGB1, TLR2 and TLR4 were observed in the nasal brushing samples from these AR patients, whereas there was no significant difference for the mRNA levels of TLR3 and RAGE. Besides, HMGB1/TLR4 mRNA levels correlated positively with IL-4, −5, −13 and −17A, whereas negatively with IL-10. A linear regression of HMGB1/TLR4 was also found positively with IL-4, −5 (only for TLR4), −13 or −17A, whereas negatively with IL-10. High mRNA levels of HMGB1 and TLR4 were found in the nasal brushing samples in AR patients, correlating positively with IL-4, −5, −13 or −17A, wheareas negatively with IL-10. HMGB1/TLR4 signaling pathway might be well responsive targets as immunotherapy for allergic rhinitis. [ABSTRACT FROM AUTHOR]