Airway smooth muscles

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. 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

Airway cross-sections have the nominal anatomy shown in Fig. 5.16. Airway surface liquid (AST), primarily composed of mucus gel and water, surrounds the airway lumen with a thickness thought to vary from 5 to 10 mm. AST lies on the apical surface of airway epithelial cells (mostly columnar ciliated epithelium). This layer of cells, roughly two to three cells thick in proximal airways and eventually thinning to a single cell thickness in distal airways, rests along a basement membrane on its basal surface. Connective tissue (collagen fibers, basement membranes, elastin, and water) lies between the basement membrane and airway smooth muscle. Edema occurs when the volume of water within the connective tissue increases considerably. Interspersed within the smooth muscle are respiratory supply vessels (capillaries, arteriovenous anastomoses), nerves, and lymphatic vessels. 

Bratton, D. 1.., Tanaka, D. T, and Gnmstein, M. M. (1987). Effects of temperature on cholinergic contractility of rabbit airway smooth muscle. /. Appl. Physiol. 63, 1933-1941. 

Souhrada, M., and Souhrada, J. E (1981). The direct effect of temperature on airway smooth muscle. Resp. Physiol. 44, 311-323. 

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. 

Jiang, H Rao, K., Halayko, A.J., Liu. X., Stephens, N.L. (1992). Ragweed sensitization-induced increase of myosin light chain kinase content in canine airway smooth muscle. Am. J. Respir. Cell. Mol. Biol. 7, 567-573. 

Airway obstruction manifests itself as symptoms such as chest tightness, cough, and wheezing. Airway obstruction can be caused by multiple factors including airway smooth muscle constriction, airway edema, mucus hypersecretion, and airway remodeling. Airway smooth muscle tone is maintained by an interaction between sympathetic, parasympathetic, and non-adrenergic mechanisms. Acute bronchoconstriction usually... 

P2-Agonists cause airway smooth muscle relaxation by stimulating adenyl cyclase to increase the formation of cyclic adenosine monophosphate (cAMP). Other non-bronchodilator effects have been observed, such as improvement in mucociliary transport, but their significance is uncertain.11 P2-Agonists are available in inhalation, oral, and parenteral dosage forms the inhalation route is preferred because of fewer adverse effects. 

Theophylline is a non-specific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle resulting in bronchodilation. It has a modest bronchodila-tor effect in patients with COPD, and its use is limited due to a narrow therapeutic index, multiple drug interactions, and adverse effects. Theophylline should be reserved for patients who cannot use inhaled medications or who remain symptomatic despite appropriate use of inhaled bronchodilators. 

Brightling CE, Ammit AJ, Kaur D, et al. The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle. Am J Respir Crit Care Med 2005 171(10) 1103-1108. 

Joubert P, Lajoie-Kadoch S, Labonte I, et al. CCR3 expression and function in asthmatic airway smooth muscle cells. J Immunol 2005 175(4) 2702-2708. 

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. 

Hirshman CA, Zhu D, Panettieri RA, Fmala CW. Actin depolymerization via the beta-adrenoceptor in airway smooth muscle cells a novel PKA-independent pathway. Am J Physiol Cell Physiol 2001 281(5) C1468-1476. 

McGraw DW, Mihlbachler KA, Schwarb MR, et al. Airway smooth muscle prostaglandin-EPl receptors directly modulate beta2-adrenergic receptors within a unique heterodimeric complex. J Clin Invest 2006 116 1400-1409. 

Beta receptors are also unevenly distributed with P2-receptors the more common subtype on the effector tissues. Beta-two receptors tend to be inhibitory for example, P2-receptor stimulation causes relaxation of vascular smooth muscle and airway smooth muscle, resulting in vasodilation and bronchodilation, respectively. Beta-two receptors have a significantly greater affinity for epinephrine than for norepinephrine. Furthermore, terminations of sympathetic pathways are not found near these receptors, so P2-receptors are stimulated only indirectly by circulating epinephrine instead of by direct sympathetic nervous activity. 

Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of beta 2-adre-nergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995 13(1) 25—33. 

At the cellular level, eosinophils, mast cells, alveolar macrophages, lymphocytes and neutrophils recruited to the airways of asthmatics produce a variety of inflammatory mediators, such as histamine, kinins, neuropeptides, and leukotrienes, which lead to airway smooth muscle constriction and obstruction of airflow, and the perpetuation of airway inflammation [20, 21]. An understanding of the inflammatory processes and the molecular pathways of these mediators has led to the development and widespread use of several pharmacologic agents that mitigate airway inflammation and bronchoconstriction. 

McGraw DW, Forbes SL, Kramer LA et al. Transgenic overexpression of beta[2]-adrenergic receptors in airway smooth muscle alters myocyte function and ablates bronchial hyperreactivity. J Biol Chem 1999 274 32241-32247. 

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