Human airway musculature on a chip: an in vitro model of allergic asthmatic bronchoconstriction and bronchodilation

Abstract

Many potential new asthma therapies that show promise in the pre-clinical stage of drug development do not demonstrate efficacy during clinical trials. One factor contributing to this problem is the lack of human-relevant models of the airway that recapitulate the tissue-level structural and functional phenotypes of asthma. Hence, we sought to build a model of a human airway musculature on a chip that simulates healthy and asthmatic bronchoconstriction and bronchodilation in vitro by engineering anisotropic, laminar bronchial smooth muscle tissue on elastomeric thin films. In response to a cholinergic agonist, the muscle layer contracts and induces thin film bending, which serves as an in vitro analogue for bronchoconstriction. To mimic asthmatic inflammation, we exposed the engineered tissues to interleukin-13, which resulted in hypercontractility and altered relaxation in response to cholinergic challenge, similar to responses observed clinically in asthmatic patients as well as in studies with animal tissue. Moreover, we reversed asthmatic hypercontraction using a muscarinic antagonist and a β-agonist which are used clinically to relax constricted airways. Importantly, we demonstrated that targeting RhoA-mediated contraction using HA1077 decreased basal tone, prevented hypercontraction, and improved relaxation of the engineered tissues exposed to IL-13. These data suggest that we can recapitulate the structural and functional hallmarks of human asthmatic musculature on a chip, including responses to drug treatments for evaluation of safety and efficacy of new drugs. Further, our airway musculature on a chip provides an important tool for enabling mechanism-based search for new therapeutic targets through the ability to evaluate engineered muscle at the levels of protein expression, tissue structure, and tissue function.

IL-4 and IL-13 signaling in allergic airway disease

“…Moreover, Shore and colleagues recently reported that mice lacking one allele of ROCK-2 (+/−) had partial abrogation of OVA-induced AHR, whereas AHR was completely abrogated in mice lacking a single allele of ROCK-1 (+/−)[101]. Evidence that IL-13 may induce a hypercontractile state in ASM, through direct activation of ROCK pathways in human ASM cells, was recently provided by Nesmith and colleagues [102]. They showed that IL-13-treated human airway muscle strips on a chip, developed hypercontractile responses to cholinergic agonist stimulation [102].…”

“…Evidence that IL-13 may induce a hypercontractile state in ASM, through direct activation of ROCK pathways in human ASM cells, was recently provided by Nesmith and colleagues [102]. They showed that IL-13-treated human airway muscle strips on a chip, developed hypercontractile responses to cholinergic agonist stimulation [102]. Moreover, they demonstrated that incubation of the chip muscle tissues with the ROCKII inhibitor (HA1077) prevented the hypercontractile response of the IL-13-treated tissues and promoted relaxation of tissues.…”

Microfluidics in Malignant Glioma Research and Precision Medicine

“…[174] Several organ-on-a-chip models designed to study the inflammatory responses could serve as templates to further study the role of immune and inflammatory cells and molecules on glioma. [175] Microfluidic assays can prove effective in these contexts and facilitate the high-throughput assessment of combination therapies based on molecular profiling of GBM patient biopsy. These platforms can also be used to evaluate the efficacy of potential immunotherapies and their ability to bolster the adoptive immune response to cancer.…”

Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model

“…Significant efforts have been aimed at the development of in vitro models for the human airway (Huang et al, 2013;Nesmith et al, 2014). Progress in basic mechanisms of important airway functions (Thompson et al, 2006;Pohl et al, 2009;Prytherch et al, 2011;Sellgren et al, 2014;Farsani et al, 2015) has been obtained with these models; however, many airway models rely on cell lines rather than human primary epithelial cells and are often cultured in laboratory systems that are difficult to scale or implement in an automated fashion.…”