Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection

The role of thromboxane (Tx) in hyperacute rejection of pig lung by human b lood was studied in an ex vivo model, wherein lungs from juvenile piglets w ere perfused with fresh heparinized human blood. In this model, hyperacute lung rejection was characterized by an abrupt rise in pulmonary vascular re sistance (PVR; >1 cmH(2)O . ml(-1). min) and prolific Tx elaboration (>15 n g/ml) within 5 min and loss of function within 10 min. Although papaverine significantly blunted the rise in PVR (<0.2 cmH(2)O<bullet>ml(-1). min), Tx production was not inhibited (>20 ng/ml), and florid tracheal edema was us ually 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 (T x. 20 ng/ml) were not only associated with significantly lower peak PVRs (< 0.2 cmH(2)O . ml(-1). 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<bullet>ml(-1). min) during initial perfusion. C3a and histam ine elaboration were inhibited, and median survival was significantly prolo nged (>4 h). These findings implicate Tx in the inflammation associated wit h hyperacute lung rejection and demonstrate that pulmonary intravascular ma crophages are critical to its elaboration.