title: 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.
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering and the School of Engineering and Applied Sciences, Harvard University, 29 Oxford St., Pierce Hall 321, Cambridge, MA 02138, USA. kkparker@seas.harvard.edu.
authors.forename: Alexander Peyton
authors.initials: AP
authors.lastname: Nesmith
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Agarwal
authors.forename: Megan Laura
authors.initials: ML
authors.lastname: McCain
authors.forename: Kevin Kit
authors.initials: KK
authors.lastname: Parker
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods*; D005898:Glass; D006801:Humans; D056656:Lab-On-A-Chip Devices; D008954:Models, Biological; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001993:Bronchodilator Agents; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases
references.citation: J Allergy Clin Immunol. 2008 Mar;121(3):685-91
references.pmid: 18328894
references.citation: Eur Respir J. 2000 Apr;15(4):782-9
references.pmid: 10780774
references.citation: Chest. 1997 Apr;111(4):852-7
references.pmid: 9106559
references.citation: N Engl J Med. 2006 May 11;354(19):1985-97
references.pmid: 16687711
references.citation: Pediatr Pulmonol. 1999 Feb;27(2):117-23
references.pmid: 10088935
references.citation: N Engl J Med. 2011 Sep 22;365(12):1088-98
references.pmid: 21812663
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15346-51
references.pmid: 18832176
references.citation: Nat Med. 2012 Mar 04;18(4):547-54
references.pmid: 22388091
references.citation: Am J Physiol Cell Physiol. 2002 Mar;282(3):C606-16
references.pmid: 11832346
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Jan 1;304(1):L4-16
references.pmid: 23125251
references.citation: Neurol Med Chir (Tokyo). 2011;51(10):679-83
references.pmid: 22027241
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12705-10
references.pmid: 21765001
references.citation: Am J Physiol. 1998 May;274(5):L803-9
references.pmid: 9612296
references.citation: Biochem Biophys Res Commun. 2009 May 15;382(4):697-703
references.pmid: 19327344
references.citation: N Engl J Med. 2011 May 26;364(21):2006-15
references.pmid: 21612469
references.citation: Respir Med. 2000 Aug;94(8):806-14
references.pmid: 10955758
references.citation: Am Rev Respir Dis. 1992 Sep;146(3):565-9
references.pmid: 1519829
references.citation: J Pediatr. 1995 Apr;126(4):639-45
references.pmid: 7699549
references.citation: Science. 1997 May 30;276(5317):1425-8
references.pmid: 9162012
references.citation: Am J Respir Cell Mol Biol. 2009 Feb;40(2):159-67
references.pmid: 18688040
references.citation: Thorax. 2000 Oct;55 Suppl 2:S42-4
references.pmid: 10992556
references.citation: Clin Ophthalmol. 2014 May 09;8:883-90
references.pmid: 24872673
references.citation: Lancet. 2009 May 30;373(9678):1905-17
references.pmid: 19482216
references.citation: Lab Chip. 2013 Sep 21;13(18):3599-608
references.pmid: 23807141
references.citation: Am Rev Respir Dis. 1993 Sep;148(3):720-6
references.pmid: 8368645
references.citation: J Appl Physiol (1985). 1997 Jan;82(1):70-7
references.pmid: 9029200
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L214-9
references.pmid: 18487358
references.citation: Nat Med. 2002 Aug;8(8):885-9
references.pmid: 12091879
references.citation: Lab Chip. 2014 Sep 7;14(17):3181-6
references.pmid: 24828385
references.citation: Chest. 2002 Aug;122(2):409-15
references.pmid: 12171810
references.citation: Cell Motil Cytoskeleton. 2008 Aug;65(8):641-51
references.pmid: 18561184
references.citation: Clin Exp Allergy. 1993 Feb;23(2):81-96
references.pmid: 8448686
references.citation: J Allergy Clin Immunol. 2006 Jan;117(1):18-24; quiz 25
references.pmid: 16387578
references.citation: Biomaterials. 2010 May;31(13):3613-21
references.pmid: 20149449
references.citation: Nature. 1997 Oct 30;389(6654):990-4
references.pmid: 9353125
references.citation: Am J Physiol Lung Cell Mol Physiol. 2002 Mar;282(3):L520-8
references.pmid: 11839548
references.citation: Integr Biol (Camb). 2011 Nov;3(11):1063-70
references.pmid: 21993765
references.citation: Lab Chip. 2011 Dec 21;11(24):4165-73
references.pmid: 22072288
references.citation: J Investig Allergol Clin Immunol. 2010;20(7):542-50; quiz 2p following 550
references.pmid: 21313993
references.citation: Am J Respir Crit Care Med. 2001 Jul 1;164(1):141-8
references.pmid: 11435252
references.citation: Drug Discov Today. 2013 Dec;18(23-24):1323-33
references.pmid: 24076262
references.citation: Pulm Pharmacol Ther. 2013 Feb;26(1):24-36
references.pmid: 22967819
references.citation: J Clin Invest. 2008 Nov;118(11):3546-56
references.pmid: 18982161
references.citation: Am J Respir Crit Care Med. 2004 Oct 15;170(8):836-44
references.pmid: 15256389
references.citation: Pediatrics. 2002 Aug;110(2 Pt 1):315-22
references.pmid: 12165584
references.citation: PLoS Med. 2010 Mar 30;7(3):e1000245
references.pmid: 20361020
references.citation: Am J Physiol Lung Cell Mol Physiol. 2011 Jun;300(6):L958-66
references.pmid: 21460123
references.citation: Biochem Pharmacol. 2011 Sep 15;82(6):586-99
references.pmid: 21745459
references.citation: J Pharmacol Exp Ther. 1992 Jul;262(1):119-26
references.pmid: 1625190
references.citation: Am J Physiol. 1996 Jun;270(6 Pt 1):L1040-51
references.pmid: 8764231
references.citation: Am Rev Respir Dis. 1988 Jul;138(1):145-50
references.pmid: 2849336
references.citation: Thorax. 1992 Mar;47(3):162-6
references.pmid: 1519192
references.citation: Clin Exp Allergy. 2007 Jul;37(7):973-88
references.pmid: 17581191
references.citation: Br J Pharmacol. 1994 May;112(1):179-87
references.pmid: 8032639
references.citation: J Allergy Clin Immunol. 1997 May;99(5):657-65
references.pmid: 9155833
references.citation: Science. 2007 Sep 7;317(5843):1366-70
references.pmid: 17823347
references.citation: Sci Transl Med. 2012 Nov 7;4(159):159ra147
references.pmid: 23136042
references.citation: Am J Physiol. 1997 Jun;272(6 Pt 1):C1960-7
references.pmid: 9227425
references.citation: J Appl Physiol (1985). 2001 Aug;91(2):986-94
references.pmid: 11457818