Lung Metabolism of Eicosanoids: Prostaglandins, Prostacyclin, Thromboxane, and Leukotrienes

Abstract

History of Eicosanoids Overview of Eicosanoid Biosynthesis Antagonists of Eicosanoids and Inhibitors of Their Synthesis Lung Pharmacology of Eicosanoids Inactivation of Eicosanoids in Lung Synthesis of Eicosanoids by LungSynthesis from exogenous arachidonic acid Synthesis from endogenous arachidonic acid Release of eicosanoids after anaphylactic reactions Release of eicosanoids by mechanical stimulation Release of eicosanoids by endogenous mediators Summary SINCE THE RENAISSANCE of interest in metabolic functions of the lung in the late 1960s, our knowledge of these functions has grown at an exponential rate common to many fields of research. Within this rapidly growing field, however, one area has expanded in an almost explosive manner: the study of the metabolism of arachidonic acid (AA) and its oxygenated metabolites in the lung. These metabolites [prostaglandins (PGs), prostacyclin, thromboxanes, and leukotrienes] are all, like AA, basically molecules containing 20 carbon atoms. Because the chemical name for AA is eicosatrienoic acid, these metabolites and their precursors are often called eicosanoids.An early paper on PG biosynthesis demonstrated a highly active enzyme in guinea pig lung extracts (16), and the most recent advance in eicosanoid biochemistry was the identification of leukotrienes generated by lung tissue during anaphylaxis (195). These developments increased our knowledge of the lung and are important and sometimes essential elements in the development of our understanding of the eicosanoids in general. HISTORY OF EICOSANOIDS

PGI₂ Aerosol versus Nitric Oxide for Selective Pulmonary Vasodilation in Hypoxic Pulmonary Vasoconstriction

“…In contrast, prostacyclin administered as aerosol is neither transformed into an active form nor metabolized by the lung [26], Although we did not measure dynamic compliance and airway resistance, we observed no change in total static compliance and in plateau airway pres sure during PGU inhalation. Hence, PGU 337 aerosolized at low concentrations appears to act as pulmonary vasodilator without causing side effects (e.g.…”

“…PGH has a rapid onset of action and a short half-life (2-3 min) when infused intravenously. Due to the lack of a carrier mechanism to transfer PGI2 across the cell membrane, it is, unlike most other prosta glandins, not metabolized by the lung and retains its pulmonary vasodilatory properties [26], Therefore, and because of its lack of known toxicity, PGH aerosol was chosen for inhalation.…”

Bronchodilatation of guinea‐pig perfused bronchioles induced by the H3‐receptor for histamine: role of epithelium

“…The interval between consecutive concentrations did not exceed 10 min. In some experiments, tissues were pretreated for 30 min with either the HI-antagonist mepyramine (10 LM), the H2-antagonist cimetidine (1O gM), the cyclo-oxygenase inhibitor, indomethacin (10 ,UM ;Orehek et al, 1975;Korbut et al, 1981), the NO synthetase inhibitor L-NAME (1 and 5011M; Rees et al, 1990;Tucker et al, 1990) or the prostacyclin synthetase inhibitor tranylcypromine (10IM; Gryglewski et al, 1975;Bakhle & Ferreira, 1985;Ea-Kim et al, 1992). In our model, at these concentrations, the cyclo-oxygenase-, NO synthetase-and prostacyclin synthetase-inhibitors did not modify significantly the baseline pressure when added to the perfusate reservoir.…”

Cationic factors affecting phospholipase activities from human lung

“…Second, where animal models still must be used, we can now select those species whose phospholipase activities most clearly resemble those in human lung. There are important species differences in the biosynthesis of cyclo-oxygenase products in lung (Bakhle & Ferreira, 1985) and these differences could extend to the phospholipases involved. Both considerations will allow a more accurate analysis of how human lung responds to pathological conditions such as endotoxin shock or immunological challenge and to drug treatments aimed at preventing such responses.…”

“…The eicosanoids exhibit a wide range of potent biological activities on a variety of cells in the lung and these activities are expressed in both physiological and pathological conditions (Bakhle & Ferreira, 1985). Phospholipase action has also been linked to receptor activation by many different agonists effective in lung (Fain et al, 1988).…”