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Can GPCRs Be Targeted to Control Inflammation in Asthma?

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Lung Inflammation in Health and Disease, Volume II

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1304))

Abstract

Historically, the drugs used to manage obstructive lung diseases (OLDs), asthma, and chronic obstructive pulmonary disease (COPD) either (1) directly regulate airway contraction by blocking or relaxing airway smooth muscle (ASM) contraction or (2) indirectly regulate ASM contraction by inhibiting the principal cause of ASM contraction/bronchoconstriction and airway inflammation. To date, these tasks have been respectively assigned to two diverse drug types: agonists/antagonists of G protein-coupled receptors (GPCRs) and inhaled or systemic steroids. These two types of drugs “stay in their lane” with respect to their actions and consequently require the addition of the other drug to effectively manage both inflammation and bronchoconstriction in OLDs. Indeed, it has been speculated that safety issues historically associated with beta-agonist use (beta-agonists activate the beta-2-adrenoceptor (β2AR) on airway smooth muscle (ASM) to provide bronchoprotection/bronchorelaxation) are a function of pro-inflammatory actions of β2AR agonism. Recently, however, previously unappreciated roles of various GPCRs on ASM contractility and on airway inflammation have been elucidated, raising the possibility that novel GPCR ligands targeting these GPCRs can be developed as anti-inflammatory therapeutics. Moreover, we now know that many GPCRs can be “tuned” and not just turned “off” or “on” to specifically activate the beneficial therapeutic signaling a receptor can transduce while avoiding detrimental signaling. Thus, the fledging field of biased agonism pharmacology has the potential to turn the β2AR into an anti-inflammatory facilitator in asthma, possibly reducing or eliminating the need for steroids.

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Abbreviations

AHR:

Airway hyperresponsiveness

ASM:

Airway smooth muscle

AERD:

Aspirin-exacerbated respiratory disease

COPD:

Chronic obstructive pulmonary disease

CaSR:

Calcium-sensing receptor

CysLT:

Cysteinyl leukotriene

IL:

Interleukin

GPCR:

G protein-coupled receptor

OLD:

Obstructive lung diseases

mAChR:

Muscarinic acetylcholine receptor

mPGES-1:

microsomal prostaglandin E synthase-1

LABA:

Long-acting beta-2 agonist

PG:

Prostaglandin

LPS:

Lipopolysaccharide

PAR-2:

Protease-activated receptor-2

PMNT:

Phenylethanolamine-N-mthyltransferase

PKA:

Protein kinase A

SABA:

Short-acting beta-2 agonist

TGFβ1:

Transforming growth factor beta 1

TAS2R:

Type II taste receptors

TNF-α:

Tumor necrosis factor alpha

TRPV4:

Transient receptor potential vanilloid 4

β2AR:

beta-2 adrenoceptor

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Acknowledgments

Dr. Penn is supported by National Institutes of Health (NIH) grants HL58506, AI110007, AI161296, HL136209, HL145392, and HL114471. The authors thank Dr. Richard Bond for permission to utilize previously published figures.

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  1. Center for Translational Medicine, Division of Pulmonary, Allergy, & Critical Care Medicine Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA, USA

    Pawan Sharma & Raymond B. Penn

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  1. Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA

    Yong-Xiao Wang

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Sharma, P., Penn, R.B. (2021). Can GPCRs Be Targeted to Control Inflammation in Asthma?. In: Wang, YX. (eds) Lung Inflammation in Health and Disease, Volume II. Advances in Experimental Medicine and Biology, vol 1304. Springer, Cham. https://doi.org/10.1007/978-3-030-68748-9_1

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