Endothelin-1 causes sequential trapping of platelets and neutrophils in pulmonary microcirculation in rats

Abstract

We previously showed that endothelin-1 (ET-1) causes accumulation of leukocytes in the pulmonary microvasculature and increases vascular permeability in isolated rat lungs provided the presence of leukocytes in the perfusate. In the present study, we examined the time sequence for morphological changes induced by ET-1 in rat alveolar tissue. For this purpose we used morphometric analysis based on lung transmission electron micrographs. Morphometry was performed by point counting, and data were expressed as relative volume density. ET-1 (0.06, 0.6, and 6 nmol/kg) was infused into the internal jugular vein, and the animals were killed at certain points of time. The lungs were fixed by endotracheal instillation of McDowell's fixative. Infusion of ET-1 (0.06 or 0.6 nmol/kg) caused no significant morphological changes in the rat alveolar tissue as assessed by morphometric examination. A sevenfold increase in volume density of platelets was seen 5 min after infusion of ET-1 6 nmol/kg. The platelets were loosely aggregated, adhered partly to the endothelium, and some of them had a spherical shape with vacuoles, indicating activation. The volume density of erythrocytes increased threefold, lasting 30 min. At 120 min, the volume density of polymorphonuclear leukocytes (PMN) increased 10-fold. The PMN adhered closely to the endothelium and partly occluded the capillary lumen. Simultaneously, the endothelial cell surface showed morphological signs of injury. No significant changes were observed in the volume density of alveolar macrophages or monocytes. No significant changes were seen in lung volumes or the volume of the alveolar tissue compartment. The results showed that ET-1 causes a time- and dose-dependent sequential entrapment of platelets and neutrophils in the pulmonary circulation.

Endothelin<SUB>A</SUB>-receptor antagonism attenuates pulmonary hypertension in porcine endotoxin shock

“…As the decrease in MPAP and PVRI in response to PD 155080 is almost instant and similar responses are seen under noninflammatory states using the mixed ET-receptor antagonist bosentan [18], this is probably due to vasodilation. However, ET-1 infusion given to rats promotes activation of platelets and neutrophils, with resulting microembolism in the pulmonary circulation [27]. These reports are consistent with the authors previous Data are presented as meanSEM.…”

Platelet Kinetics in the Pulmonary Microcirculation in vivo Assessed by Intravital Microscopy

“…Recent studies on platelet kinetics within the pulmonary microcirculation used radioactive cell labeling techniques [14]or morphometric analysis based on lung transmission electron micrographs [15]. Both techniques do not enable direct visualization and quantitative assessment of platelet kinetics in all segments of the pulmonary microcirculation in vivo.…”

Endothelin Receptor Antagonists

“…It also induces fibrosis by stimulating the activation and contraction of fibroblasts (Shi-Wen et al 2001, and the synthesis of extracellular matrix compounds (Shi-Wen et al 2001). Another effect of ET-1 is the induction of inflammation through various mechanisms, including the increase in vascular permeability (Filep et al 1995), the stimulation of pro-inflammatory cytokine production (Browatzki et al 2000), the activation of platelet and neutrophils, and the promotion of cellular adhesion (Helset et al 1996). Finally, there is increasing evidence suggesting that ET-1 increases reactive oxygen species production in the vasculature (Loomis et al 2005).…”