Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection

Abstract

The role of thromboxane (Tx) in hyperacute rejection of pig lung by human blood was studied in an ex vivo model, wherein lungs from juvenile piglets were perfused with fresh heparinized human blood. In this model, hyperacute lung rejection was characterized by an abrupt rise in pulmonary vascular resistance (PVR; >1 cmH2O x ml(-1) x min) and prolific Tx elaboration (>15 ng/ml) within 5 min and loss of function within 10 min. Although papaverine significantly blunted the rise in PVR (<0.2 cmH2O x ml(-1) x min), Tx production was not inhibited (>20 ng/ml), and florid tracheal edema was usually evident within 20 min. In contrast, both inhibition of Tx synthesis (Tx < 3 ng/ml) with OKY-046 and blockade of the Tx receptor with SQ-30741 (Tx > 20 ng/ml) were not only associated with significantly lower peak PVRs (<0.2 cmH2O x ml(-1) x min) but also with attenuated increase in lung wet-to-dry ratio and airway edema. In concert, elaboration of histamine and tumor necrosis factor was blunted, and median survival increased >10-fold to 2 h (SQ-30741) and >4 h (OKY-046). Depletion of the pig lung macrophages with dichloromethyl bisphosphonate in liposomes, but not Pall filtration of the human blood or liposomes alone, significantly inhibited Tx elaboration (<0.2 vs. >8 ng/ml for Pall filtration or liposomes) and blunted PVR elevation (<0.3 cmH(2)O x ml(-1) x min) during initial perfusion. C3a and histamine elaboration were inhibited, and median survival was significantly prolonged (>4 h). These findings implicate Tx in the inflammation associated with hyperacute lung rejection and demonstrate that pulmonary intravascular macrophages are critical to its elaboration.

Prolonged Function of Macrophage, von Willebrand Factor-Deficient Porcine Pulmonary Xenografts

“…addition to their scavenging function, PIMs, produce arachidonate metabolites including thromboxane, cytokines including IL-1, IL-2, and TNF-a, and procoagulant factors, including tissue factor and PAI-1 (27)(28)(29). In acute lung injury and some xenotransplant models, evidence suggest PIMs may contribute significantly to the rapid development of pulmonary hypertension and edema (24,26,30).…”

Effects of U-46619 on Pulmonary Hemodynamics Before and After Administration of BM-573, a Novel Thromboxane A2 Inhibitor

“…Pulmonary vasonctriction caused by the release of predominantly vasoconstrictive mediators, is an important contributor to the increase in pulmonary vascular resistance in patients with acute pulmonary embolism, hyperacute lung rejection or during the early phase of septic shock (Collins et al, 2001;Lambermont et al, 1999;Smulders, 2000). In septic shock, right heart failure can lead to death (Kimchi et al, 1984) and, in pulmonary embolism, most patients who succumb do so within minutes to few hours after onset of symptoms.…”

“…Wether TXA 2 directly affects pulmonary microvascular integrity is controversial. Nevertheless, TXA 2 has postvenular vasoconstrictive effects (Schuster et al, 2001) and therefore increases microvascular fluid transudation by causing increased hydrostatic pressure in pulmonary capillary beds (Collins et al, 2001).…”

“…TXA 2 has also proinflammatory effects and reduced TXA 2 effects generally correlates with a blunted inflammatory response (Collins et al, 2001).…”

“…TXA 2 has been implicated as a pro-inflammatory mediator during the pulmonary hypertensive phase of Gramnegative sepsis (Wise et al, 1981) and of hyperacute lung rejection (Collins et al, 2001;Ogletree & Brigham, 1982). It is also an agent responsible for pulmonary vasoconstriction in pulmonary embolism (Smulders, 2000) and a pathophysiological mediator in thrombosis, vasospasm, arrhythmias and progression of ischemic damage after coronary occlusion (Oates et al, 1988).…”