Monohydroxyeicosatetraenoic acids (5-HETE and 15-HETE) induce pulmonary vasoconstriction and edema.

Abstract

5-, 15-, and 12-HETE (monohydroxyeicosatetraenoic acids) are products of the lipoxygenation of arachidonic acid. We investigated their role as possible mediators of pulmonary vasoactivity and pulmonary edema. Pulmonary artery pressure (?"), capillary pressure (P ap ), the change in lung wet weight (Awt) from baseline, and capillary filtration coefficient (K,) (as a measure of vascular permeability) were determined following an intravenous injection of each mono-HETE in lungs perfused at constant flow with either a phosphate-buffered Ringer's-albumin solution (PBR) or diluted blood. Injection of 2 (xg of each compound into the pulmonary artery of lungs perfused with either PBR or diluted blood did not produce any effect. However, in PBR-perfused lungs, 4 (ig 15-HETE induced increases in Pp., P^., and lung wet weight (p<0.05), which were greater than the increases observed after 4 jig 5-HETE. K r increased following both 5-and 15-HETE. The pulmonary vasoconstrictor and edemagenic responses were attenuated by increasing perfusate albumin concentration from 0.5 to 1.5 g%. In contrast, 12-HETE (4 |i.g) had no effect on these parameters. In blood-perfused lungs, the pulmonary vascular responses to all HETE compounds (4 |xg) were attenuated. In both RingerValbumin-perfused and blood-perfused lungs, the relative magnitude of the hemodynamic and fluid filtration responses to each mono-HETE were as follows: 15-HETE > 5-HETE > 12-HETE. In conclusion, the pulmonary vasoconstrictor and edemagenic effects of 5-and 15-HETE occur independently of blood-formed elements. 15-HETE causes greater pulmonary vasoconstriction and edema than 5-HETE. The role of mono-HETEs in mediating changes in pulmonary hemodynamics and vascular permeability is not clear. The purpose of the present study was: 1) to compare the pulmonary microvascular responses to injection of 5-, 15-, and 12-HETE in the isolated Ringer's-albumin-perfused guinea pig lung; 2) to compare the responses of the mono-HETEs in bloodperfused lungs to examine the role of blood-formed elements in the response; and 3) to evaluate the role of mono-HETEs as possible mediators of pulmonary edema. Materials and Methods Isolated, Perfused Guinea Pig LungGuinea pigs (400-500 g) were anesthetized with sodium pentobarbital (50 mg/kg i.v.; Abbott, Chicago, Illinois) and tracheotomized. Following a thoracotomy, intracardiac heparin (700 U/kg, Invenex, Chagrin Falls, Ohio) was administered, and the animals were exsanguinated. The lungs and heart were removed together and suspended from one end of a counterweighted beam balance to monitor lung weight. The pulmonary artery and left atrium were cannulated. Perfusion was begun at a low flow rate within 5 minutes of pneumothorax using a peristaltic roller pump (model 1215, Harvard Apparatus, Millis, Massachusetts). Airway pressure was maintained at 1 cm H 2 O with 95% O 2 -5% CO 2 , and venous outflow pressure was set at 3 cm H 2 O so all lungs remained in the Zone III condition to minimize changes in vascular surface area. Lungs were covered w...

Oxidative Stress in Hypobaric Hypoxia and Influence on Vessel-Tone Modifying Mediators

“…In agreement, other studies have shown that a lack of NO (which has vasorelaxant properties in the pulmonary arteries) may also contribute to endothelial dysfunction, especially in pulmonary hypertension-induced HAPE (Bailey et al, 2010). In addition, we found significant increase in ROS-dependent 15-HETE and 12-HETE, which both are known to have vasoconstrictive properties (Burhop et al, 1988;Nishiyama et al, 1998;Yiu et al, 2003). The essential amino acid tryptophan, the biogenic amines serotonin, and SDMA, which all are supposed to have vasoconstrictive function in pulmonary vessels, also increased significantly during the high altitude stay.…”

Human CYP2S1 Metabolizes Cyclooxygenase- and Lipoxygenase-Derived Eicosanoids

“…Thus, CYP2S1 may divert the metabolism of arachidonic acid away from HETEs by converting HpETEs into oxoETEs and epoxy alcohols. This result is of interest because several studies suggest that 5-, 12-, and 15-HETEs are inflammatory mediators and that their levels are elevated in several inflammatory diseases such as asthma and arthrosclerosis (Burhop et al, 1988;Damon et al, 1989;Rubin and Mollison, 2007).…”

Short-term Physical Inactivity Impairs Vascular Function

“…15-HETE has also been observed to affect vascular reactivity, though it remains unclear whether it promotes vasoconstriction or vasodilation. One view holds that 15-HETE may have a direct vasoconstrictive effect, as evidenced by its role in pulmonary vasculature, 42,43 promote leukocyte activation and inhibit prostacyclin production. 44 The steady and sustained increase of 15-HETE in our study may help explain the concurrent increase in DBP and decreases in FMD.…”