Inhaled Corticosteroids as Rescue Medication in Acute Severe Asthma

Gustavo J Rodrigo

Disclosures

Expert Rev Clin Immunol. 2008;4(6):723-729. 

In This Article

Defining the Biological Bases of CS Actions: The Nongenomic Actions

The understanding of the effects of CS is a fundamental aspect in order to interpret the evidence from clinical trials on the use of inhaled CS in acute asthma. In fact, the mechanisms of action of CS on the inflammatory process are complex (Figure 1). On the one hand, the classic anti-inflammatory effects implicate the activation or repression of multiple genes involved in the inflammatory process. Thus, CS produce their effects on cells by activating receptors for CS, which alter transcription through direct DNA binding or transcription factor inactivation.[15,16] As a consequence, CS increase the synthesis of anti-inflammatory proteins, or inhibit the synthesis of many inflammatory proteins through suppression of the genes that encode them. This effect is also denominated the genomic effect because it implies the participation of the cellular genome, it affects gene expression and it may be sensitive to protein synthesis inhibitors. The length of time between CS entry into the cell and the production of new proteins is in the order of hours or even days. This fact is in concordance with clinical evidence that shows a 4-12 h delay before the beneficial effects of systemic CS are able to be detected (Figure 1).[3,4]

Figure 1.

Mechanisms of action of CS. In the anti-inflammatory (or genomic) effect, depicted on the left of the diagram, a CS molecule enters the cell cytoplasm and binds with GR. The complex then diffuses within the cell nucleus, binds to specific DNA sequences and increases the synthesis of mRNA and new protein molecules. Nongenomic effects, depicted on the right of the diagram, are the result of the CS molecule binding to a receptor (R) on the cell surface. This receptor then increases the value of second messengers, such as cAMP; which, in turn, increase the cell permeability of a number of ions.
CS = Corticosteroid; GR = Corticosteroid receptor; R = Receptor.
Modified with permission from [1].

Although the major part of the investigation has been carried out in the last decade, already in 1942, Selye had observed that some CS-induced effects (anesthesia) occurred only minutes after their application, constituting the first notification of a nongenomic effect of CS.[17] Two decades later, acute cardiovascular effects of aldosterone (within 5 min of its administration) were reported in humans.[18] Lately, CS have also been shown to acutely decrease nasal itching in allergic rhinitis patients.[19] These rapid effects are initiated by specific interactions with membrane-bound or cytoplasmic CS receptors, or nonspecific interactions with the cell membrane,[20,21] and the responses are much more rapid (seconds or minutes). Membrane receptor inactivation has been shown to induce rapid effects on a variety of second-messenger systems.[16] In addition, CS could bind to other receptors, ion channels, enzymes or transporters.

In the last decade, research has been focused on the rapid, or nongenomic, effects of inhaled CS on airway smooth muscle tone, and particularly on the study of the mucosal blood flow of asthmatic and healthy people.[20,21,22,23,24] Thus, membrane-binding sites for CS have been demonstrated in smooth muscle cells isolated from human airway blood vessels.[25] Studies also show that asthmatics have a significant increase in airway mucosal blood flow in comparison with healthy subjects (24-77% higher in asthmatics), and that inhalation of one dose of fluticasone (880 µg) or budesonide (400 µg) decreases blood flow in both groups.[20,21,22,23,24,25,26] This effect is transient, reaching a maximum approximately 30 min after inhalation, and returning to basal values after 60-90 min. This blood-flow decrease is dose dependent (doses of 880 and 1700 µg caused a significant decrease), with a greater effect in asthmatics than in healthy subjects (Figure 2). Finally, the effect was not specific for fluticasone or budesonide, and it was also demonstrated for beclometasone. However, fluticasone and budesonide had a greater effect than beclometasone.[22] Evidence suggests that inhaled CS decrease airway blood flow by modulating sympathetic control of vascular tone, potentiating noradrenergic neurotransmission in the airway vasculature.[23,24] After release from sympathetic terminals, norepinephrine must be taken up by postsynaptic cells for inactivation by intracellular enzymes. Because uptake of norepinephrine is inhibited by CS, this could lead to an increased norepinephrine concentration at the neuromuscular junction, explaining the CS-induced vasoconstriction. Furthermore, this decrease in airway blood flow is likely to enhance the action of inhaled bronchodilators by diminishing their clearance from the airway.[27] Thus, simultaneous administration of inhaled CS and bronchodilators could be of clinical significance. To distinguish genomic actions from the effects occurring acutely following steroid administration, the latter effects have been referred to as nongenomic. Very useful in this matter is the definition of nongenomic effects recently given by Losel and Wehling: "any action that does not directly and initially influence gene expression, but rather drives more rapid effects such as the activation of signaling cascades".[16] This definition recognizes that the distinction between the two modes of action is not always clear cut. It is certain that there is no direct proof to support the involvement of either nongenomic pathways or airway blood-flow responses in the observed clinical or spirometric responses.[20,21] However, because the use of genomic-pathway inhibitors in clinical trials is not possible, a short timeframe (minutes) is one of the strongest pieces of evidence in favor of a nongenomic effect. Thus, this initial effect is a good candidate by covering the link between molecular pathways and the clinical effects of the actions of CS, and it is unlikely that early clinical effects (seen as early as 60 min) are due to a genomic mechanism.

Figure 2.

Effect produced by 880 µg of inhaled fluticasone on airway mucosal blood flow (Qaw) in ten asthmatic subjects and ten healthy subjects (mean ± standard error).
*Healthy subjects: p = 0.01 in relation to baseline. Asthmatic subjects: p = 0.01 in relation to baseline. Redrawn with permission from [20].

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