Orfanos S, Jude J, Deeney BT, Cao G, Rastogi D, van Zee M, Pushkarsky I, Munoz HE, Damoiseaux R, Di Carlo D, Panettieri R Jr (2018) Am J Physiol Lung Cell Mol Physiol. 2018 Aug. doi: 10.1152/ajplung.00459.2017. [Epub ahead of print]
The asthma-obesity syndrome represents a major public health concern that disproportionately contributes to asthma severity and induces insensitivity to therapy. To date, no study has shown an intrinsic difference between human airway smooth muscle (HASM) cells derived from non-obese subjects and those derived from obese subjects. The objective of this study was to address whether there is a greater response to agonist-induced calcium mobilization, phosphorylation of myosin light chain (MLC) and greater shortening in HASM cells derived from obese subjects.
HASM cells derived from non-obese and obese subjects were age and gender matched. Phosphorylation of MLC was measured after having been stimulated by carbachol. Carbachol or histamine-induced mobilization of calcium and cell shortening was assessed in HASM cells derived from non-obese and obese donors.
Agonist-induced MLC phosphorylation, mobilization of calcium and cell shortening was greater in obese as compared to non-obese-derived HASM cells. The MLC response was comparable in HASM cells derived from obese non-asthma and non-obese fatal asthma subjects. HASM cells derived from obese female subjects were more responsive to carbachol than HASM cells derived from obese male subjects. Insulin pre-treatment had little effect on these responses.
Our results show an increase in agonist-induced calcium mobilization associated with an increase in MLC phosphorylation and an increase in ASM cell shortening in favor of agonist-induced hyperresponsiveness in HASM cells derived from obese subjects. Our studies suggest that obesity induces a retained phenotype of hyperresponsiveness in cultured human airway smooth muscle cells.