Am J Respir Cell Mol Biol
October 2024
Leucine-rich repeat containing 8A (LRRC8A) is an obligatory constituent of the volume-regulated anion channel (VRAC) that is fundamental to a wide range of biological processes, including regulating cell size, proliferation, and migration. Here we explored the physiological role for VRAC in excitation-contraction (E-C) coupling and shortening of human airway smooth muscle (HASM). In HASM cells, pharmacological inhibition of VRAC with DCPIB (0.
View Article and Find Full Text PDFBronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β adrenergic receptor (βAR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is a single-molecule, dual pharmacology agent combining muscarinic antagonist and βAR agonist functions, currently in development as a COPD therapeutic.
View Article and Find Full Text PDFBronchomotor tone modulated by airway smooth muscle shortening represents a key mechanism that increases airway resistance in asthma. Altered glucose metabolism in inflammatory and airway structural cells is associated with asthma. Although these observations suggest a causal link between glucose metabolism and airway hyperresponsiveness, the mechanisms are unclear.
View Article and Find Full Text PDFAm J Physiol Lung Cell Mol Physiol
September 2022
Obesity can aggravate asthma by enhancing airway hyperresponsiveness (AHR) and attenuating response to treatment. However, the precise mechanisms linking obesity and asthma remain unknown. Human airway smooth muscle (HASM) cells exhibit amplified excitation-contraction (EC) coupling and force generation in obesity.
View Article and Find Full Text PDFAm J Respir Cell Mol Biol
January 2022
In most living cells, the second-messenger roles for adenosine 3',5'-cyclic monophosphate (cAMP) are short-lived, confined to the intracellular space, and tightly controlled by the binary switch-like actions of Gα (stimulatory G protein)-activated adenylyl cyclase (cAMP production) and cAMP-specific PDE (cAMP breakdown). Here, by using human airway smooth muscle (HASM) cells in culture as a model, we report that activation of the cell-surface βAR (β-adrenoceptor), a G-coupled GPCR (G protein-coupled receptor), evokes cAMP egress to the extracellular space. Increased extracellular cAMP levels ([cAMP]) are long-lived in culture and are induced by receptor-dependent and receptor-independent mechanisms in such a way as to define a universal response class of increased intracellular cAMP levels ([cAMP]).
View Article and Find Full Text PDFBackground: Asthma exacerbations evoke emergency room visits, progressive loss of lung function and increased mortality. Environmental and industrial toxicants exacerbate asthma, although the underlying mechanisms are unknown. We assessed whether 3 distinct toxicants, salicylic acid (SA), toluene diisocyanate (TDI), and 1-chloro-2,4-dinitrobenzene (DNCB) induced airway hyperresponsiveness (AHR) through modulating excitation-contraction coupling in human airway smooth muscle (HASM) cells.
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