Prostaglandin bronchoconstriction

It is not clear where prostaglandins and related products of arachidonic cascade fit into this pathophysiologic schema. The bronchodilating and bronchoconstricting prostaglandins may act through the cyclic AMP route. 

In sensitized asthmatic individuals, antigen challenge generally causes a Type I (IgE-mediated) immediate hypersensitivity response by release of preformed mediators, including histamine, and prostaglandins, which are responsible for bronchoconstric-tion and increased vascular permeability. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hyper-secretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is driven by leukotrienes, chemokines and cytokines synthesized by activated mast cells and Th2 cells. Both proteins and haptens have been associated with these types of reactions. 

There are only a few reports on the efficacy of feverfew in an in vivo situation. Inhibition of collagen-induced bronchoconstriction in an in vivo guinea-pig model was demonstrated [56] and it was concluded that this was consistent with in vivo phospholipase A2 inhibition. In a rat model of experimentally induced nephrocalcinosis, parthenolide was shown to protect the rats against this condition. Inhibition of prostaglandin biosynthesis may have been the mechanism of action of parthenolide in this case, as prostaglandins are thought to be involved in nephrocalcinosis [57]. 

Adrenaline (epinephrine) is a sympathomimetic agent that causes bronchodilatation. It is used to relieve bronchospasm in anaphylactic shock reactions. Histamine, kinins and prostaglandins, such as prostaglandin E2, are inflammatory mediators. In response to allergic stimuli, inflammatory mediators may cause bronchoconstrictions. Guaifenesin is an expectorant preparation that increases bronchial secretions to promote the expulsion of the mucus coughed up. 

Beta-adrenoceptor blockers block the sympathetic system antagonising the effect on the lungs, resulting in bronchoconstriction. Non-steroidal anti-inflammatory drugs inhibit prostaglandin synthesis, which may lead to bronchoconstriction. 

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. As discussed in Chapter 18, the cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. 

The stimulation of C fibers by capsaicin causes a subset of sensory airway neurons to release several neuropeptides, which include tachykinin, substance P and neurokinin A. In addition to capsaicin, other endogenous mediators including histamine, prostaglandins and bradykinins can also result in their release. These neuropeptides are responsible for neurogenic inflammation, which is characterized by vasodilation, mucus secretion, plasma protein extravasation, increased expression of the adhesion molecules and bronchoconstriction. 

Anaphylactic shock, the most severe type of anaphylaxis, occurs when an allergic response triggers a quick release from mast cells of large quantities of immunological mediators (histamines, prostaglandins, leukotrienes), leading to systemic vasodilation (associated with a sudden drop in blood pressure) and bronchoconstriction (difficulty in breathing). Anaphylactic shock can lead to death in a matter of minutes if untreated. 

Episodes of airway obstruction or bronchoconstriction may be induced in asthmatics by exposure to stimuli to which they are sensitized, such as inhalation of a specific pollen or house dust mite, or exposure to an occupational stimulus, e.g., red cedar dust [47]. Binding of antigen (e.g., pollen) to specific receptors (antibodies) on the surface of an inflammatory cell (e.g., mast cell) results in the elaboration of prestored mediators, such as histamine, and in the synthesis of newly formed mediators, such as arachidonic acid metabolites (e.g., prostaglandins and leukotrienes). Cellular sources of the various mediators are shown in Table 3. Cytokines and chemokines are proteins that participate in pulmonary immune and inflammatory responses. While important, these have not been subjected to discussion in this chapter because these fields are changing very... 

Once arachidonic acid is released, it can be broken down by the enzyme cyclooxygenase to form the prostaglandins. A further breakdown product, prostaglandin D2, has been weU characterized and is a potent bronchoconstricting agent. It is unlikely that prostaglandin D2 can produce sustained effects on airway function or inflammation however, its role in asthma remains to be determined. Sim-... 

In addition to inhibition of mediator release, cromoglycate has the property of inhibiting vagal reflex-mediated bronchoconstriction in dogs, which results from the stimulation of irritant nerve fibers with substances such as histamine and prostaglandins (Dixon et al., 1980). The importance of this latter mechanism in the therapeutic actions of cromoglycate is unclear. 

Nedocromil sodium is a mast-cell stabilizer that inhibits release of mediators from inflammatory cell types associated with asthma, including histamine from mast cells and beta-glucuronidase from macrophages. It may also suppress local production of leukotrienes and prostaglandins and inhibit development of bronchoconstriction responses to inhaled antigen and other challenges such as cold air. It is... 

This phenomenon is not a true allergy, nor is it specifically caused by aspirin. It is the result of decreased synthesis of bronchodilatory prostanoids in the lung. In susceptible individuals, prostaglandin synthesis inhibitors may inhibit the synthesis not only of inflammatory prostanoids, but also of those prostanoids that contribute to patent airways. Thus, sensitivity to prostaglandin synthesis inhibitors can precipitate bronchoconstriction and blockade of airways. These events can arise from increased dosing of NSAIDs, increased frequency of dosage, or concurrent administration of more than one drug (e.g.. naproxen with ibuprofen). 

The mediators probably most important in causing asthmatic bronchoconstriction are leukotrienes LTC and LTD. Another leukotriene (LTB ), prostaglandins, peptides, some enzymes, and histamine probably also play a role. 

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