PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats

Abstract

Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia

“…It has been reported that the ROS generated by hypoxia can induce calcium release from sarcoplasmic reticulum stores, followed by pulmonary vasoconstriction. 5 Moreover, ROS activated VEGF, 4 PAF, [7][8][9] and MAPK, 10 which induced vascular remodeling. PAF subsequently induced oxidative bursts in macrophages, which might cause a vicious circle to advance the process of pulmonary vascular remodeling.…”

“…ROS upregulates expression of several factors to modify vascular remodeling, such as vascular endothelial growth factor (VEGF), 4 plateletactivating factor (PAF), [7][8][9] and mitogen-activated protein kinase (MAPK). 10 Thus, several intrinsic substances to modulate pulmonary ROS levels may play protecting or aggravating roles in progression of pulmonary vascular remodeling.…”

Cardiovascular Adaptation to High-Altitude Hypoxia

“…These findings suggest that EGFR plays a role in fetal ovine pulmonary vascular remodeling following long-term HAH and that inhibition of EGFR signaling may reverse high altitude-induced pulmonary vascular remodeling. Similar to EGFR, platelet-activating factor (PAF) and PAF receptor have also been implicated in the pathogenesis of long-term HAH-induced pulmonary remodeling and hypertension in different animal models [56,57]. In those studies, high PAF and PAF receptor expression levels in the pulmonary arteries have been reported in the long-term hypoxia-exposed animals [56,57].…”

“…Similar to EGFR, platelet-activating factor (PAF) and PAF receptor have also been implicated in the pathogenesis of long-term HAH-induced pulmonary remodeling and hypertension in different animal models [56,57]. In those studies, high PAF and PAF receptor expression levels in the pulmonary arteries have been reported in the long-term hypoxia-exposed animals [56,57]. Furthermore, PAF receptor antagonists attenuated hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling [56], suggesting that PAF receptor-mediated signaling also plays a key role in pulmonary vascular remodeling.…”

Oxidative Stress in Multiple Organ Damage in Hypertension, Diabetes and CKD, Mechanisms and New Therapeutic Possibilities

“…It has been reported that ROS generated by hypoxia can induce calcium release from sarcoplasmic reticulum stores, which is followed by pulmonary vasoconstriction (Waypa et al, 2002). Moreover, ROS activated several growth factors such as vascular endothelial growth factor and platelet-activating factor (PAF) (Hartung et al, 1983;Ono et al, 1992;Chandel et al, 1998), which induce vascular remodeling. In the early phase of hypoxic conditions, ROS may act as a trigger of this signaling cascade in the process of vascular remodeling.…”