Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease

Abstract

Airway structure and function are key aspects of normal lung development, growth, and aging, as well as of lung responses to the environment and the pathophysiology of important diseases such as asthma, chronic obstructive pulmonary disease, and fibrosis. In this regard, the contributions of airway smooth muscle (ASM) are both functional, in the context of airway contractility and relaxation, as well as synthetic, involving production and modulation of extracellular components, modulation of the local immune environment, cellular contribution to airway structure, and, finally, interactions with other airway cell types such as epithelium, fibroblasts, and nerves. These ASM contributions are now found to be critical in airway hyperresponsiveness and remodeling that occur in lung diseases. This review emphasizes established and recent discoveries that underline the central role of ASM and sets the stage for future research toward understanding how ASM plays a central role by being both upstream and downstream in the many interactive processes that determine airway structure and function in health and disease.

Calcium sensing receptor in developing human airway smooth muscle

“…We have previously shown that human fASM expresses IP3R (Hartman et al, 2012) and results from our current study with U73122 (PLC inhibitor), PLCβ siRNA, and XeC (IP 3 R blocker) underline the link between CaSR and the PLC-IP 3 pathway in developing ASM. The expression and role of TRPC channels in adult ASM has also been previously demonstrated (Prakash, 2016;Wang & Zheng, 2011) and we have previously reported expression of TRPC channels (Hartman et al, 2012) Our data demonstrate that CaSR promotes proliferation of fASM cells, a novel finding. Here, the PLC pathway appears to be at least one mechanism by which CaSR functions.…”

“…[Ca 2+ ] i regulation is a recognized aspect of ASM contractility (Mahn et al, 2010;Prakash, 2016;Sakai et al, 2017) but compared with adult ASM, regulatory aspects in developing ASM are less understood, partly due to lack of age-appropriate cell/tissue models, particularly in humans.…”

Modulation of the lung inflammatory response to ozone by the estrous cycle

“…A second limitation of our model is the use of whole lung tissue to study gene expression differences. As conducted, our approach cannot identify changes in specific cell types, such as resident or recruited immune cells, as well as in lung compartments such as the endothelium or vascular, which have been identified as important contributors of sexual dimorphism in lung diseases such as asthma (Prakash ). In fact, some of the differential gene expression networks identified display associations with connective tissue disorders, cell‐to‐cell signaling, and hematologic systems.…”

Smooth muscle brain‐derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma

“…Expression of [Ca 2+ ] i regulatory proteins, such as those for SR Ca 2+ release and Ca 2+ influx, are known to be upregulated in ASM of patients with asthma or with inflammatory mediators (52). In the present study, using LCM, we examined mRNA expression of several [Ca 2+ ] i regulatory proteins in the ASM layer.…”

“…[Ca 2+ ] i regulation is central to modulation of ASM contraction/relaxation and to ASM hypercontractility observed in patients with asthma (52). In addition to several inflammatory cytokines that are known to enhance baseline levels and [Ca 2+ ] i responses to bronchoconstrictor agonists, BDNF has emerged as a key regulator of contractility in human ASM (30,35).…”