Bronchoconstrictor response

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

Jones et al. (49) also point to a possible connection between atopy and risk of byssinosis. Most but not all persons with extrinsic asthma exhibit atopy (50). From observations on 255 workers in four cottonseed crushing mills, Jones et al. (49) conclude that "Atopy and exposure to dust were found to have significant interaction large mean declines in FEVi and FEF25-75 occurred only in the workers exposed to 1 inter dust who were also atopic." They also state "These findings point to atopy as a risk factor in the bronchoconstrictor response to cotton dust aerosol, and, by inference, a risk in byssinosis. 

Fig. 1.1 Interaction between allergen and adenosine receptor agonists with respect to histamine release from guinea-pig chopped lung (left) or bronchoconstriction in the guinea pig in vivo (right). Tissues and animals were passively sensitized to ovalbumin. In the histamine release assay, a threshold response to allergen is augmented concentration-dependently by NECA. In the whole animal, a single intravenous injection of APNEA markedly enhances the bronchoconstrictor response to allergen (J.R. Fozard and H.J. Pfannkuche, unpublished observations 1994)...

An Atypical Receptor Mechanism Mediates the Bronchoconstrictor Response to Adenosine Augmented Following Allergen Challenge... 

In both cases the response to adenosine is mainly mast cell mediated. Indeed, at the doses of adenosine used the contribution of the Aj receptor (which is not mast cell mediated) to the bronchoconstrictor response in vivo is minimal (Hannon et al. 2002b). The pharmacological analysis gave generally similar results although... 

Hannon JP, Tigani B, Williams I, Wolber C, Howes C, Mazzoni L, Fozard JR (2002b) Evidence for an atypical receptor mediating the augmented bronchoconstrictor response to adenosine induced by allergen challenge in actively sensitised Brown Norway rats. Br J Pharmacol 135 685-696... 

Thome JR, Danahay H, Broadley KJ (1996) Analysis of the bronchoconstrictor responses to adenosine receptor agonists in sensitized guinea-pig lungs and trachea. Eur J Pharmacol 316(2—3) 263—271... 

As noted previously, the airways are richly supplied with afferent and efferent vagal nerves. The cholinergic motor fibers are clearly responsible in some patients for a portion of the bronchoconstriction characteristic of acute asthma. Such fibers innervate M3 receptors on the smooth muscle and contain modulatory M2 receptors on the nerve terminals. Selective inhibition of M2 receptors can increase bronchoconstrictor responses to a variety of stimuli, while M3 inhibitors can produce dilation of constricted airways. 

Following alleigen challengp, up to 50% of asthmatic subjects exhibit a dual bronchoconstrictor response. There is a rapid tall in pulmonary function (e.g FEVi) at 10-20 min which gradually recovers over the Following 2 h, defined as the EAR. Between 4 and 6 h there is a further fiill in FEVi, the LAR. This may last up to 12 h and in some individuals may be followed by recurring airway obstruction for several days or even weeks (Booij Noord ad., 1972). 

A characteristic pathophysiological feature of asthma is bronchial hyperresponsiveness (BHR), the exj erated bronchoconstrictor response of the airways to a wide... 

The activation of NOS or the products thereof modulates airway constrictor responses as well. Atropine-sensitive, electrical field stimulation-induced bronchoconstrictor responses in the guinea-pig are enhanced by NOS inhibitors (Belvisi etal., 1991). Nitrogen oxides also modulate the effects of non-cholinergic bronchoconstrictors. H stimulation of Hi receptors in the guinea-pig lung leads... 

Challenge of sensitized subjects with inhaled allergen has been a vital experimental approach in asthma research since the first bronchoprovocation studies were performed by Max Samter in Berlin in 1933. Allergen inhalation results in an early bronchoconstrictor ( asthmatic ) response (EAR) at 5 to 10 minutes lasting up to an hour and, in about half of subjects, a late bronchoconstrictor response (LAR) starting at 2 to 3 hours and lasting for 12 to 24 hours (Pepys, 1973). 

Bronchial hyperreactivity Pathologic increase in the bronchoconstrictor response to antigens and irritants caused by broixihial inflammation... 

Fuller RW (1991) Pharmacology of inhaled capsaicin in humans. Respir Med 85 31-34 Fuller RW, Dixon CM, Barnes PJ (1985) Bronchoconstrictor response to inhaled capsaicin in humans. J Appl Physiol 58 1080-1084... 

Koenig, J. G., Pierson, W. E., Horike, M., Frank, R., 1982, Bronchoconstrictor responses to sulfur dioxide or sulfur dioxide plus sodium chloride droplets in allergic, non-asthmatic adolescents, /. Allergy Clin. Immunol. 69 339. 

Elevated eosinophil counts have consistently been shown in the airways in asthma both at baseline and after segmental allergen challenge, and eosinophil influx has been closely related to the late phase bronchoconstrictor response (21). Eosinophils have been closely associated with the degree of airway inflammation, epithelial damage, and disease severity in asthma as confirmed by eosinophil counts in the airway lumen, mucosal tissue, and induced sputum (38) IL-3, IL-5, and GM-CSF release has been shown to prolong airway eosinophil survival by inhibiting apoptosis and to prime eosinophils for mediator release (39). 

In summary, current information suggests that the mechanism of airway narrowing during the early asthmatic response is an acute bronchoconstrictor response caused mainly by an IgE-dependent immediate hypersensitivity reaction. Of the preformed and newly synthesized mediators released from mast cells during these reactions, the cysteinyl leukotrienes appear to be the most important in the pathogenesis of the EAR. 

---