Can the anti-inflammatory activities of β2-agonists be harnessed in the clinical setting?

Figures & data

Table 1 Types of commonly used β₂-agonists: their activity, partition coefficients, and duration of action

Types	Agonist activity	Partition coefficient (Log P)	Duration of action (hours)
Short acting
Salbutamol^Citation5^–^Citation7,Citation11	Partial	0.34–0.6	4–6
Terbutaline^Citation7,Citation11	Partial	0.44–0.55	4–8
Fenoterol^Citation5,Citation7,Citation8,Citation11	Full	1.36–1.47	6–8
Long acting
Salmeterol^Citation5^–^Citation7,Citation11	Partial	3.61–3.82	12
Formoterol^Citation5^–^Citation7,Citation11	Full	1.06–1.91	12
Ultra-long acting
Indacaterol^Citation5,Citation7,Citation9^–^Citation11	Full	3.26–3.31	24

Table 2 The number of receptors per cell and dissociation constants of β₂-agonists in various immune and inflammatory cells

Cell type	Number of receptors/cell (Bmax)	Dissociation constant (Kd) (pM)
Neutrophils^Citation12	20878±2470 (females) 7331±3179 (males)
Macrophages^Citation13	5643±942	29±9
Monocytes^Citation14	1000–3000	38±29
Mast cells^Citation15	Variable btw preparations	40±10
Epithelial cells^Citation16	9908±1127 (Calu-3 cells) 6423±895 (16HBE14o(-) cells)
Eosinophils^Citation17	4333±318	25.3±1.4
T-cells^Citation18,Citation19	776±183*	19.7±1.6

Note: The results are expressed as the mean ± standard error of the mean or *standard deviation.

Abbreviation: btw, between.

Table 3 The effects of β₂-agonists on various immune and inflammatory cells

Neutrophils^Citation2,Citation38,Citation39

↓ O2 ^−

↓ Elastase release

↓ LTB4

↓ CR3

↓ IL-8

↓ Chemotaxis

↑ Ca^2+ clearance from cytosol

↓ Adhesion to bronchial epithelial cells

↓ Bacterial permeability-increasing protein

↑ Membrane-stabilizing effects

Monocytes/macrophages^Citation2,Citation38,Citation39

↓ iNOS

↓ ERK 1/2

↓ LTB4, PGE2, TBX B2

↓ GM-CSF, TNF-α, IL-1β

↓ IL-2, IL-6, IL-8, IL-12, IL-18

↑ IL-10

Mast cells^Citation2,Citation38,Citation39

↓ Histamine release

↓ IL-5, TNF-α, GM-CSF, MIP-1α

↓ LTC4, LTD4 and PGD2

Epithelial cells^Citation39

↓ GM-CSF, VEGF

↓ IL-8, RANTES, eotaxin, IP-10

↓ ICAM-1, VCAM-1

Eosinophils^Citation2,Citation36,Citation37

↓ O2 ^−

↓ Eosinophil cationic protein

↓ Eosinophil peroxidase release

↓ LTC4

↓ Chemotaxis

↓ Adherence to fibronectin-coated plates

↓ Eosinophil-derived neurotoxin

Basophils^Citation2

↓ Histamine release

↓ IL-4, IL-13

T-cells^Citation2,Citation38,Citation39

↓Proliferation in response to anti-CD3 Ab

↓ IL-2, IL-3, IL-4, IL-5, IL-13

↓ IFN-γ, GM-CSF, TNF-α

↑ IL-10

Abbreviations: O₂ ⁻, superoxide anion; iNOS, inducible nitric oxide synthase; ERK, extracellular-regulated kinase; LTB₄, leukotriene B4; PGE₂, prostaglandin E2; TBX B₂, thromboxane B2; GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin-1 beta; IL-; interleukin-; MIP-1α, macrophage inflammatory protein 1 alpha; LTD₄, leukotriene D4; PGD₂ prostaglandin D2; VEGF, vascular endothelial growth factor; RANTES, regulated upon activation normal T cell expressed and secreted; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion protein 1; anti-CD3 Ab, anti-CD3 monoclonal antibody; IFN-γ, interferon gamma; CR3, complement receptor 3; LTC₄ leukotriene C₄; IP-10, interferon γ inducible protein.

Table 4 cAMP-mediated mechanisms of anti-inflammatory activity

Target	Effect
Protein kinase A-mediated
• Regulation of Ca^2+mobilization and cytosolic clearance in activated immune and inflammatory cells	Downregulation of Ca^2+-dependent proinflammatory activities^Citation40^–^Citation48
• Antagonism of proinflammatory transcription factors (NFκB, AP-1, others)	Decreased expression of genes encoding proinflammatory proteins^Citation51,Citation52
• Interaction of CREB with the promoter region of the IL-10 gene	Activation of synthesis of IL-10^Citation53^–^Citation56
• Potentiation of GR/GRE-mediated gene transcription (trans-activation)	Activation of synthesis of other anti-inflammatory proteins^Citation58^–^Citation69
• Inhibition of 5′-lipoxygenase	Decreased production of proinflammatory leukotrienes, and antagonism of glucocorticoid-mediated anti-apoptotic effects on neutrophils^Citation47,Citation48,Citation72
Epac1-mediated
• Antagonism of NFκB and glycogen synthase kinase	Decreased production of TNF^Citation75,Citation77

Abbreviations: cAMP, cyclic adenosine monophosphate; NFκB, nuclear factor kappa B; AP-1, activator protein-1; CREB, cAMP response element-binding protein; IL-10, interleukin 10; GR, glucocorticoid receptor; GRE, glucocorticoid response element; TNF, tumor necrosis factor; Epac1, guanine nucleotide exchange protein directly activated by cAMP-1.

Table 5 Inhaled bronchodilator therapies that may be used alone or in combination for the management of chronic stable COPD

Class of agent	Onset of action	Therapeutic efficacy	Adverse effects
LABA*
Formoterol^Citation98^–^Citation111	10 minutes	↑ Lung functions	Tremor
Salmeterol^Citation97,Citation112	3 hours	↑ Quality of life	Headache
		↓ Symptoms	Cough Cardiac toxicity
LABA + ICS*
Formoterol/budesonide^Citation98,Citation100,Citation103,Citation113	As above for	↑ Lung functions	Tremor
Salmeterol/fluticasone^Citation97,Citation104,Citation106,Citation108,Citation109,Citation114	LABAs	↑ Quality of life	Headache
		↓ Symptoms	Cough
		↓ Exacerbations	Cardiac toxicity Pneumonia
LAMA
Tiotropium^Citation97,Citation107,Citation110,Citation112,Citation113,Citation115^–^Citation120	3–4 hours	↑ Lung functions	Dry mouth
		↑ Quality of life	Hoarseness
		↓ Symptoms	Cardiac toxicity
		↓ Exacerbations	Pneumonia
LABA + LAMA
Formoterol + tiotropium^Citation121^–^Citation124,Citation125	As above	As above	As above
Salmeterol + tiotropium^Citation126,Citation127	As above	As above	As above
LABA + LAMA + ICS^Citation126,Citation128 Ultra-LABA	As above	As above	As above
Indacaterol^Citation99,Citation129,Citation130	5 minutes	↑ Lung functions	Cough
		↑ Quality of life	Nasopharyngitis
		↓ Symptoms	Worsening
		↓ Exacerbations	COPD
Experimental agents
Various Ultra-LABAs^Citation129	To be established	See Ultra-LABA	See Ultra-LABA
New LAMAs^Citation127		See LAMA	See LAMA
Glycopyrronium	To be established
GSK-573719
BEA-2180BR
Aclidinium bromide
Darotropium bromide

Notes:

* Randomized placebo-controlled trials of duration >24 weeks have been selected, as this duration allows the best assessment of treatment effects. Data from Decramer et al.¹¹¹

Abbreviations: COPD, chronic obstructive pulmonary disease; LABA, long-acting beta agonist; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic agent.

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