Nayak, Ajay P.

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Thomas Jefferson UniversityJefferson Digital CommonsCenter for Translational Medicine Faculty Papers Center for Translational Medicine7-1-2019Glucocorticoids and Airway Smooth Muscle: AFew More Answers, Still More QuestionsAjay P. NayakThomas Jefferson University, Ajay.Nayak@jefferson.eduLet us know how access to this document benefits youFollow this and additional works at: https://jdc.jefferson.edu/transmedfpPart of the Translational Medical Research CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inCenter for Translational Medicine Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, pleasecontact: JeffersonDigitalCommons@jefferson.edu.Recommended CitationNayak, Ajay P., "Glucocorticoids and Airway Smooth Muscle: A Few More Answers, Still MoreQuestions" (2019). Center for Translational Medicine Faculty Papers. Paper 58.https://jdc.jefferson.edu/transmedfp/58EDITORIALSGlucocorticoids and Airway Smooth Muscle: A Few More Answers,Still More QuestionsGlucocorticoids (oral and inhaled corticosteroids) have been criticalfor the management of asthma symptoms owing to their exceptionaltherapeutic efﬁcacy in mitigating airway inﬂammation.Glucocorticoids exert therapeutic effects in asthma primarily viatheir genomic actions in resident or invading lung cells (1), eitherby negatively regulating the expression of genes that promoteinﬂammation or by inducing genes that inhibit inﬂammation.Although inhalation of corticosteroids provides efﬁcient controlof exacerbations in a large number of patients with asthma,corticosteroids have limited efﬁcacy in many patients with asthmawhose disease is severe or refractory (steroid-resistant asthma) (1).Multiple mechanisms have been proposed to explain thecompromised glucocorticoid response in distinct cell typesassociated with asthma pathology, but the precise molecularmechanisms remain ill deﬁned.To date, most studies have emphasized immune cells andepithelial cells as the key targets of glucocorticoid actions in theasthmatic lung. However, glucocorticoids have potentiallyimportant immunomodulatory effects on airway smooth muscle(ASM) cells. Speciﬁcally, glucocorticoid actions in ASM can affectboth airway inﬂammation (i.e., the immunomodulatory role ofASM) and airway remodeling (2–6). Glucocorticoids can alsoregulate the contractile function of ASM by 1) reducing cholinergichypersensitivity in the airways, possibly through regulation of theexpression of G protein–coupled receptors (muscarinic: M2, M3;and histamine: H1) that mediate airway contraction (7–9), or2) augmenting airway relaxation through upregulation of b2AR(b2 adrenergic receptor) and modulation of adenylyl cyclaseactivity (10, 11). Although studies over the last decade haveprovided signiﬁcant insight into the complex molecularinteractions of glucocorticoids in ASM cells, whether ASMfrom individuals with asthma responds differently toglucocorticoids is unknown, as is the contribution of this responseto the phenomenon of steroid resistance in individuals withasthma.In this issue of the Journal, Kan and colleagues (pp. 110–120)take an important step toward addressing this problem bycharacterizing the glucocorticoid-regulated transcriptome of ASMderived from patients with severe asthma (12). Speciﬁcally, theauthors compare differences in mRNA abundance in ASM cellsderived from donors with fatal asthma and donors without asthma,treated or not treated with budesonide. Additionally, the authorscompare the dataset generated in this experiment with thetranscriptomic proﬁle of glucocorticoid response in other cell types(from a publicly available database), and identify signatures uniqueto ASM.Several interesting observations are reported. Somewhatsurprisingly, the transcriptome proﬁles were highly similar in ASMfrom donors with asthma and those without asthma, both at baselineand after stimulation with budesonide. In ASM cells from bothdonor cohorts, glucocorticoid-regulated genes such as TSC22D3,CRISPLD2, and KLF15 were signiﬁcantly upregulated, which isconsistent with previous studies that examined glucocorticoidresponses in bronchial biopsies and isolated ASM cells (13–15).Similarly, FKBP5, which has been previously reported as a negativeregulator of glucocorticoid response in individuals with asthma,was also signiﬁcantly upregulated (13). Two genes, CCK(cholecystokinin) and PMEL (premelanosome protein), weredifferentially expressed between the cohorts with and withoutasthma. The functions of these genes in ASM are poorly deﬁned,and additional studies focused on examining their role in renderingASM cells glucocorticoid resistant are essential to establish theirphysiological relevance in the development of steroid resistance inthe disease state.Although the paper by Kan and colleagues is a critical steptoward identifying glucocorticoid-regulated molecular networksthat are differentially regulated in ASM cells from patients withsevere asthma, the clinical signiﬁcance of these observations isunclear and remains to be determined in future work. As duly notedby the authors, the ASM cells were derived from postmortemspecimens with cursory background information lacking speciﬁcclinical data or comments on steroid usage and resistance, if any. It isalso essential to note here that isolated ASM cells retain molecularand physiological traits that are reﬂective of their behavior in vivoand have been used extensively in basic and translational research.Understandably, the ASM cells used in the current study wereisolated from tracheae or large bronchi. However, ASM cellsfrom smaller airways play a crucial role in inﬂuencing airwayinﬂammation, remodeling, and resistance, and may responddifferently to glucocorticoids and be equally or more importantthan large-airway ASM cells in contributing to steroid resistance inpatients with asthma. Finally, a validation of these targets using asecondary approach (such as real-time qPCR) or biochemicalanalysis of proteins is also lacking. Notwithstanding theselimitations, the current effort by Kan and colleagues shows thatglucocorticoid responses are altered in ASM cells from individualswith severe asthma.Understanding the mechanisms that contribute to steroidresistance in patients with asthma is a profound challenge that ismademore difﬁcult not only by the complexity of the disease asthmaper se but also by the fact that multiple cell types contribute toasthma pathobiology, and the function of each of these cells isregulated by glucocorticoids. Although the clinical effect of steroidtreatment can be readily assessed, the success or failure of steroidtreatment relies on the sum of the effects of the drug on multiplecells, and how steroids impact the singular and cooperative actionsThis article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints please contact Diane Gern (dgern@thoracic.org).Editorials 9of the cells that cause asthma. Given that it is extremely difﬁcult todecipher the relative contributions of individual cell types to drugresponses in integrative human studies (i.e., most clinical research),and despite the inherent limitations of in vitro studies (16), a logicalapproach to understanding these mechanisms is to pursue morereductionist studies in individual cell types and then attemptto piece data from such studies into a understanding of thegestalt. Accordingly, computational biology methods to analyzetranscriptome data (and other omics-based approaches) along withextensive clinical and patient phenotype data would greatly servethis purpose and clearly represent an important path for futureresearch.Careful consideration of the limitations of reductionist/in vitro studies is necessary to inform study design and enableinterpretation. Relevant to Kan and colleagues, the source of cellsfrom patients with asthma is an important consideration. Cellsobtained from ASM tissue collected after an autopsy have potentialviability concerns, but perhaps more importantly, the ability toultimately match experimental data with a patient’s clinical proﬁleor disease phenotype is often limited compared with what canachieved in prospective studies in which tissue can be procuredfrom (live) patients. Yet, the latter situation also has limitations,in that tissue procurement occurs via bronchial biopsies,which are highly variable with respect to the amount and viabilityof ASM collected, and involve a fairly invasive (and expensive)protocol.Despite these and other technical and design challenges ofcell-based studies, studies such as those conducted by Kanand colleagues are critical to the slow inductive process of acquiringsufﬁcient data to gain insight into the pathobiology of asthmaand a patient’s response to asthma drugs. Ultimately, thereﬁnement of experimental designs coupled with better technologywill grow the database and advance this ﬁeld of study. nAuthor disclosures are available with the text of this article atwww.atsjournals.org.Ajay P. Nayak, Ph.D.Center for Translational MedicineandJane and Leonard Korman Respiratory InstituteThomas Jefferson UniversityPhiladelphia, PennsylvaniaORCID ID: 0000-0003-3437-0096 (A.P.N.).References1. Barnes PJ. Severe asthma: advances in current management and futuretherapy. J Allergy Clin Immunol 2012;129:48–59.2. Nayak AP, Deshpande DA, Penn RB. New targets for resolution of airwayremodeling in obstructive lung diseases. F1000 Res 2018;7:F1000Faculty Rev-680.3. Stewart AG, Fernandes D, Tomlinson PR. The effect of glucocorticoidson proliferation of human cultured airway smooth muscle. Br JPharmacol 1995;116:3219–3226.4. Stewart AG, Tomlinson PR, Fernandes DJ, Wilson JW, Harris T. Tumornecrosis factor alpha modulates mitogenic responses of human culturedairway smooth muscle. Am J Respir Cell Mol Biol 1995;12:110–119.5. Saunders MA, Mitchell JA, Seldon PM, Yacoub MH, Barnes PJ,Giembycz MA, et al. Release of granulocyte-macrophage colonystimulating factor by human cultured airway smooth muscle cells:suppression by dexamethasone. Br J Pharmacol 1997;120:545–546.6. Hirst SJ, Lee TH. Airway smooth muscle as a target of glucocorticoidaction in the treatment of asthma. Am J Respir Crit Care Med 1998;158:S201–S206.7. Emala CW, Clancy J, Hirshman CA. Glucocorticoid treatment decreasesmuscarinic receptor expression in canine airway smooth muscle. AmJ Physiol 1997;272:L745–L751.8. Hardy E, Farahani M, Hall IP. Regulation of histamine H1 receptorcoupling by dexamethasone in human cultured airway smoothmuscle. Br J Pharmacol 1996;118:1079–1084.9. Nabishah BM, Morat PB, Khalid BA, Kadir BA. Effect of acetylcholine andmorphine on bronchial smooth muscle contraction and its modulationby steroid hormones. Clin Exp Pharmacol Physiol 1990;17:841–847.10. Davies AO, Lefkowitz RJ. Regulation of beta-adrenergic receptors bysteroid hormones. Annu Rev Physiol 1984;46:119–130.11. Mak JC, Nishikawa M, Shirasaki H, Miyayasu K, Barnes PJ. Protectiveeffects of a glucocorticoid on downregulation of pulmonary beta2-adrenergic receptors in vivo. J Clin Invest 1995;96:99–106.12. Kan M, Koziol-White C, Shumyatcher M, Johnson M, Jester W, PanettieriRA Jr, et al. Airway smooth muscle–speciﬁc transcriptomic signaturesof glucocorticoid exposure. Am J Respir Cell Mol Biol 2019;61:110–120.13. Kelly MM, King EM, Rider CF, Gwozd C, Holden NS, Eddleston J,et al. Corticosteroid-induced gene expression in allergen-challengedasthmatic subjects taking inhaled budesonide. Br J Pharmacol 2012;165:1737–1747.14. Masuno K, Haldar SM, Jeyaraj D, Mailloux CM, Huang X, Panettieri RAJr, et al. Expression proﬁling identiﬁes Klf15 as a glucocorticoidtarget that regulates airway hyperresponsiveness. Am J Respir CellMol Biol 2011;45:642–649.15. Sasse SK, Kadiyala V, Danhorn T, Panettieri RA Jr, Phang TL, GerberAN. Glucocorticoid receptor ChIP-seq identiﬁes PLCD1 as a KLF15target that represses airway smooth muscle hypertrophy. Am JRespir Cell Mol Biol 2017;57:226–237.16. Gerber AN. Glucocorticoids and airway smooth muscle: someanswers, more questions. Am J Respir Crit Care Med 2013;187:1040–1041.EDITORIALS10 American Journal of Respiratory Cell and Molecular Biology Volume 61 Number 1 | July 2019

Glucocorticoids and Airway Smooth Muscle: A Few More Answers, Still More Questions

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Glucocorticoids and Airway Smooth Muscle: A Few More Answers, Still More Questions

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