W. M. Selig

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

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 (Ppa), capillary pressure (Pcap), the change in lung wet weight (δwt) from baseline, and capillary nitration coefficient (Kr) (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 Ringers-albumin solution (PBR) or diluted blood. Injection of 2 μg 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 μg 15-HETE induced increases in Ppa, Pcap, and lung wet weight (p<0.05), which were greater than the increases observed after 4 μg 5-HETE. Kr 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 μg) had no effect on these parameters. In blood-perfused lungs, the pulmonary vascular responses to all HETE compounds (4 μg) were attenuated. In both Ringers-albumin-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. Both 5- and 15-HETE induce pulmonary edema, probably as a result of increased lung vascular permeability. The results indicate that 5- and 15-HETE are potent pulmonary inflammatory mediators.

Cellular and humoral mediators of pulmonary edema

Pulmonary edema results from increases in pulmonary capillary hydrostatic pressure and microvascular protein permeability. Mediators that induce pulmonary edema can be subdivided into two classes: (1) mediators that alter pulmonary hydrostatic pressure such as serotonin and (2) mediators that increase capillary permeability and result in increased transport of protein. A recognized important permeability increasing factor in the pulmonary microcirculation is the process of neutrophil activation and concomitant mediator release subsequent to neutrophil sequestration. Increased pulmonary capillary pressure occurring concomitantly with increased permeability greatly enhances protein flux and extravascular fluid accumulation. The rise in capillary hydrostatic pressure is determined by precapillary and postcapillary vessel resistances. Recent data indicate that pulmonary veins are not inert conduits but possess active smooth muscle components which respond to vasoactive agents such as histamine and arachidonic acid metabolites through venoconstriction. It appears that few humoral factors acting independently actually increase pulmonary capillary permeability. In comparison to the systemic microcirculation, the lung microcirculation appears to be more resistant to agents such as histamine and bradykinin which are known permeability-increasing agents in systemic microvessels. This may be important teleologically as the pulmonary microcirculation receives the entire cardiac output.

Substance P-induced pulmonary vasoreactivity in isolated perfused guinea pig lung.

We examined the effects of the neuropeptide substance P on pulmonary hemodynamic and transvascular fluid filtration in isolated Ringers-perfused and blood-enriched Ringers-perfused guinea pig lung and on albumin flux across bovine pulmonary artery endothelial monolayer. Mean pulmonary artery, left atrial, and capillary pressures were determined and used to calculate arterial and venous resistances, and lung weight was continuously monitored. Substance P (0.01–1.0 μM) caused marked increases in pulmonary arterial pressure, capillary pressure, venous resistance, and lung weight within 3–5 minutes after adminstration. These responses remained elevated above baseline at the end of the 30-minute experimental period in the Ringers-perfused lungs but not in the blood-enriched Ringers-perfused lungs. Substance P did not alter the capillary filtration coefficient in isolated lungs and transendothelial albumin permeability in the endothelial monolayer. Substance P resulted in an increase in venous effluent thromboxane B2 concentrations in perfused lungs but had no effect on 6-keto-prostaglandin F1a concentrations. Papaverine (0.27 mM) (a smooth-muscle relaxant) abolished the pulmonary microvascular response to substance P in Ringers-perfused lungs, and meclofenamate (0.15 mM) (a cyclooxygenase inhibitor) attenuated the pulmonary vasoconstriction and lung weight increase. Pyrilamine (1.0 μM) (a histamine1-receptor antagonist) did not alter the responses to substance P. In conclusion, substance P does not affect pulmonary vascular permeability to water and protein. Substance P induces an intense pulmonary vasoconstriction (due to greater constriction of postcapillary vessels) and an elevation in pulmonary capillary pressure that increases net transvascular fluid filtration. The generation of cyclooxygenase metabolites contributes to substance P-induced pulmonary vasoactivity.