Asthma airway smooth muscle

Asthma is an extremely complex condition characterized by variable and reversible airways obstmction combiaed with nonspecific bronchial hypersensitivity (1 3). The cause of asthma, which is not always readily diagnosed (4), remains unknown. Days, if not weeks, ate needed to document the spontaneous reversal of the airways obstmction ia some patients. Asthmatics experience both an immediate hypersensitivity response and a delayed late-phase reaction, each mediated by a different pathway. Chronic asthma has come to be viewed as an inflammatory disease (5). The late-phase reaction plays a key role ia iaduciag and maintaining the inflammatory state which ia turn is thought to iaduce the bronchial hyperresponsiveness (6). The airways obstmction results from both contraction of airways smooth muscle and excessive bronchial edema. Edema, a characteristic of inflammatory states, is accompanied, ia this case, by the formation of a viscous mucus which can completely block the small airways. 

Bronchial Asthma. Figure 2 Mechanisms of bronchial hyperresponsiveness. Toxic products from eosinophils [cationic peptides, reactive oxygen species (ROS)] cause epithelial injury. Nerve endings become easily accessible to mediators from mast cells, eosinophils [eosinophil-derived neurotoxin (EDN)], and neutrophils, and to airborne toxicants such as S02. Activation of nerve endings stimulates effector cells like mucosal glands and airway smooth muscle either directly or by cholinergic reflexes. 

Asthma is a complex respiratory disorder that involves mast cell degranulation, mucous secretions, and smooth muscle hypertrophy and hyperresponsiveness. Smooth muscle hyperresponsiveness has suggested some defect in the regulation of smooth muscle contractility. Therefore, a number of studies concerning asthma have centered on whether alterations in the regulation of smooth muscle contraction (Figure 4) are responsible for hyperactivity in asthmatic airway smooth muscle. 

El-Shazly A, Berger P, Girodet PO, et al. Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma. J Immunol 2006 176(3) 1860-1868. 

WARNING Long-acting p2-agonists may t risk of asthma-related death Uses COPD maint Action LA p2-agonist, relaxes airway smooth muscles Dose 15 meg neb bid, 30 meg/d max Caution [C, ] w/ CV Dz, X Contra Not for acute asthma component hyp sensitivity peds w/ phenothiazines Disp Meg neb SE Chest/back pain, D, sinusitis, leg cramps, dyspnea, rash, flu-synd, t BP, arrhythmias, heart block J-K EMS Monitor ECG for arrhythmias, heart block, and hypokalemia (flattened T waves) t risk of acute asthma attack, treat w/ shortacting p-agonist OD May cause CP, palpitations, muscle tremors and cramps, and syncope symptomatic and supportive... 

C. Glaucoma as a preexisting condition does not contraindicate an AChE inhibitor. The other preexisting conditions preclude the administration of AChE inhibitors. Potentiation of parasympathetic stimulation can constrict airway smooth muscle and aggravate asthma, further weaken A-V conduction, and risk perforation of the bowel if an obstruction is present. 

Like mast cell stabilizer, corticosteroids do not relax airway smooth muscle directly but reduce bronchial reactivity, increase airway caliber, suppress inflammatory response to antigen antibody reaction or trigger stimuli and reduce the frequency of asthma exacerbations. They produce more sustained symptomatic relief than any bronchodilator and mast cell stabilizer. 

The causes of airway narrowing in acute asthmatic attacks (or "asthma exacerbations") include contraction of airway smooth muscle inspissation of viscid mucus plugs in the airway lumen and thickening of the bronchial mucosa from edema, cellular infiltration, and hyperplasia of secretory, vascular, and smooth muscle cells. Of these causes of airway obstruction, contraction of smooth muscle is most easily reversed by current therapy reversal of the edema and cellular infiltration requires sustained treatment with antiinflammatory agents. 

The bronchodilation produced by the methylxanthines is the major therapeutic action in asthma. Tolerance does not develop, but adverse effects, especially in the central nervous system, may limit the dose (see below). In addition to their effect on airway smooth muscle, these agents—in sufficient concentration—inhibit antigen-induced release of histamine from lung tissue their effect on mucociliary transport is unknown. 

Corticosteroids have been used to treat asthma since 1950 and are presumed to act by their broad anti-inflammatory efficacy, mediated in part by inhibition of production of inflammatory cytokines (see Chapter 39). They do not relax airway smooth muscle directly but reduce bronchial reactivity and reduce the frequency of asthma exacerbations if taken regularly. Their effect on airway obstruction may be due in part to their contraction of engorged vessels in the bronchial mucosa and their potentiation of the effects of 13-receptor agonists, but their most important action is inhibition of the infiltration of asthmatic airways by lymphocytes, eosinophils, and mast cells. 

Cromolyn sodium (disodium cromoglycate) and nedocromil sodium are stable but extremely insoluble salts (see structures below). When used as aerosols (by nebulizer or metered-dose inhaler), they effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times daily) slightly reduces the overall level of bronchial reactivity. However, these drugs have no effect on airway smooth muscle tone and are ineffective in reversing asthmatic bronchospasm they are only of value when taken prophylactically. 

Preliminary studies in animals suggest that airway smooth muscle, like that in the vasculature, is effectively relaxed by nitric oxide. This very lipophilic drug can be inhaled as a gas in acute asthma and dilates the pulmonary blood vessels as well as the airway smooth muscle. Although nitric oxide itself—or nitric oxide donors—may prove of value in acute severe asthma, it appears likely that they will be more useful in pulmonary hypertension (for which nitric oxide is already approved). 

---