Thrombincollagenepinephrine

The Big Asthma Lie

Asthma Causes and Treatments

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FIGURE 16-21 Interrelationships between platelet cell membrane stimulators (thrombin, collagen, epinephrine), TX (TXA), Ca2+, PGI^ and adenylate cyclase.

Newly formed, membrane-derived

FIGURE 16-22 Mast cell-derived pharmacological mediators of hypersensitivity. Reproduced from Kay, A. B. (1982). Eur. J. Respir. Dis. 63 (Suppl. 122), 9-16. Copyright 1982 Munksgaard International Publishers Ltd., Copenhagen, Denmark.

outside inside phospholipase a2

outside inside

phospholipase a2

pgd2 pgi2 pge2 Txa2 pgf 2i

FIGURE 16-23 Membrane events and the release of free arachidonic acid. Reproduced from Kay, A. B. (1982). Eur. ]. Respir. Dis. 63 (Suppl. 122), 9-16. Copyright 1982 Munksgaard International Publishers Ltd., Copenhagen, Denmark.

pgd2 pgi2 pge2 Txa2 pgf 2i

FIGURE 16-23 Membrane events and the release of free arachidonic acid. Reproduced from Kay, A. B. (1982). Eur. ]. Respir. Dis. 63 (Suppl. 122), 9-16. Copyright 1982 Munksgaard International Publishers Ltd., Copenhagen, Denmark.

LTD4 > LTC4 > LTE4. The polar LTs, LTB4 especially (Figure 16-11), are potent chemotactic factors.

The other PGs and TXA2 also have effects on smooth muscle. PGD2, PGF2a, and TXA2 constrict, but PGE2 has a slight dilatory effect. PGDz, PGEz, and PGI2 add to the effects on the permeability of histamine and brady-kinin. Thus, while histamine gives a transient contraction of human lung smooth muscle in vitro, LTC4 and LTD4 cause prolonged responses and may be critical agents in asthma.

Thus, bronchial obstruction can be arbitrarily divided into three phases: a rapid spasmogenic phase, a late sustained phase, and a subacute inflammatory phase. These phases might occur in sequence following the initial release of agents from the mast cell resulting from the interaction of allergen and IgE or other nonim-munological stimuli, such as infection, exercise, or complement activation. These phases are represented in Figure 16-24. The rapid phase is probably histamine-mediated. A more severe stage of the reaction undoubtedly is related to the LTs. The late reaction may be associated with the reactivation of mast cells. LTs probably play a role in the late reaction as well since there is prolonged contraction of bronchial smooth muscle. Late reactions are inhibited by glucocorticoids, which act to prevent the release of arachidonic acid by induc ing the synthesis of a peptide (lipocortin/annexin I) inhibitor of phospholipase Ay although the mechanism needs further clarification. This is the same reaction that was discussed in connection with prostaglandin-induced pain (Figure 16-17). Corticosteroid-resistant asthma is a very serious problem in which LTs may

Normal

Normal

Rapid, spasmogenic

Subacute / chronic inflammatory

Rapid, spasmogenic

Subacute / chronic inflammatory

Histamine

Leukotrienes ^ Prostaglandins Thromboxanes

Eosinophils Neutrophils Mononuclear cells

Histamine

Leukotrienes ^ Prostaglandins Thromboxanes

Neutrophils

Chemotactic factors ( NCF, LTB4, ECF-A)

Eosinophils Neutrophils Mononuclear cells

FIGURE 16-24 Mast cell mediators and airway obstruction in bronchial asthma. Reproduced from Kay, A. B. (1982). Eur. }. Respir. Dis. 63 (Suppl. 122), 9-16. Copyright 1982 Munksgaard International Publishers Ltd., Copenhagen, Denmark.

play an influential part. Prostaglandin relatives thus are important in producing the alterations in asthma. The cysteinyl LTs have special importance in the production of bronchospasm and bronchial hyperrespon-siveness, and PGE2 is involved in the bronchospastic and inflammatory responses. The contribution of other PG relatives is smaller than those mediators listed earlier. Not to be forgotten is a considerable variation from one patient to the next. An outline of the reactions occurring in asthma is shown in Figure 16-25. Glucocorticoids are a main therapy for asthma, as seen from this figure, in that they inhibit phospholipase A^ presumably through the induction of lipocortin/annexin I, which inhibits the enzyme directly or indirectly. Glucocorticoids may also induce the cell death of eosinophils, which flood the lungs and account for some of the inflammatory problems. Little is known about the therapeutic effects of glucocorticoids on eosinophils, but glucocorticoids probably induce the eosinophil cell death mechanism and probably interfere with GM-CSF production/utilization needed for eosinophil proliferation.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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