Prostaglandins in asthma and allergic diseases

Abstract

Prostaglandins are synthesized through the metabolism of arachidonic acid via the cyclooxygenase pathway. There are five primary prostaglandins, PGD, PGE, PGF, PGI, and thromboxane B, that all signal through distinct seven transmembrane, G-protein coupled receptors. The receptors through which the prostaglandins signal determines their immunologic or physiologic effects. For instance, the same prostaglandin may have opposing properties, dependent upon the signaling pathways activated. In this article, we will detail how inhibition of cyclooxygenase metabolism and regulation of prostaglandin signaling regulates allergic airway inflammation and asthma physiology. Possible prostaglandin therapeutic targets for allergic lung inflammation and asthma will also be reviewed, as informed by human studies, basic science, and animal models.

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…Eicosanoids are proinflammatory lipid mediators, including the prostanoid family: PG (PG12, PGF2, PGD2, and PGE2), cyclopentenone PG (15d-PGJ2, Δ12-PGJ2, PGJ2, PGC2, PGA1, and PGA2), and thromboxane A2 (TxA2); the LT family (LTC4, LTD4, LTE4, LTF4, LTD4, LTA4, and LTB4); and the eoxin family (A4, C4, D4, and E4) [100]. Eicosanoids play a key role in the initiation of the acute inflammatory process [101][102][103][104][105][106][107][108][109][110] (see Table 2).…”

“…PG synthesis is the result of the metabolism of arachidonic acid, and their action results from various G-proteinrelated receptors that determine their immunological effects. Therefore, the same PG can have the opposite effect depending on the activated signaling pathways [107]. Most PGs have a proinflammatory effect (for example, PGE2 and PGD2), but some of them, cyclopentenone PG (PGA2 and 15d-PGJ2) in particular, are characterized by anti-inflammatory and antioxidant properties and participate in the regulation of glucose metabolism [92].…”

Cysteinyl maresins regulate the prophlogistic lung actions of cysteinyl leukotrienes

“…10,11 Thus in addition to substrate availability, expression of these biosynthetic enzymes can determine tissue LTC 4 and MCTR1 levels. In addition, further conversion of LTC 4 to LTD 4 and LTE 4 , as well as further conversion of MCTR1 to MCTR2 and MCTR3, can affect lung levels. Human lung tissue rapidly metabolizes LTC 4 to LTD 4 and LTE 4 (see Fig E1, F), 24 whereas MCTR1 conversion to MCTR2 and MCTR3 was slower, suggesting distinct temporal regulation between CysLTs and MCTRs in the lung.…”

“…1 The absence of SPMs results in tissue injury, failed resolution, and chronic inflammation, raising the potential that SPMs and their circuits can be harnessed for therapies. 2,3 In asthmatic patients arachidonic acid (AA) is converted to LTC 4 , LTD 4 , and LTE 4 , which serve as highly potent prophlogistic mediators for airway smooth muscle contraction, tissue edema, and airway secretions. [4][5][6][7] These cysteinyl leukotrienes (CysLTs) exert their bioactions by binding and activating specific receptors that transduce contraction of human airway smooth muscle and vascular permeability.…”

“…2,3 In asthmatic patients arachidonic acid (AA) is converted to LTC 4 , LTD 4 , and LTE 4 , which serve as highly potent prophlogistic mediators for airway smooth muscle contraction, tissue edema, and airway secretions. [4][5][6][7] These cysteinyl leukotrienes (CysLTs) exert their bioactions by binding and activating specific receptors that transduce contraction of human airway smooth muscle and vascular permeability. 8 Selective cysteinyl leukotriene receptor 1 (CysLT1) antagonists are drugs in clinical use for asthma treatment but with surprisingly limited clinical effectiveness.…”