Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection.

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.
AuthorsB J Collins, M G Blum, R E Parker, A C Chang, K S Blair, G L Zorn 3rd, B W Christman, R N Pierson 3rd
JournalJournal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 90 Issue 6 Pg. 2257-68 (Jun 2001) ISSN: 8750-7587 [Print] United States
PMID11356791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Inflammation Mediators
  • Thromboxanes
  • Acute Disease
  • Animals
  • Capillary Permeability (physiology)
  • Graft Rejection (metabolism, pathology, physiopathology)
  • Humans
  • Hypertension, Pulmonary (metabolism, pathology, physiopathology)
  • Inflammation Mediators (metabolism)
  • Lung (metabolism, pathology)
  • Lung Transplantation (physiology)
  • Oxygen Consumption (physiology)
  • Pneumonia (metabolism, pathology, physiopathology)
  • Pulmonary Circulation (physiology)
  • Swine
  • Thromboxanes (physiology)
  • Vascular Resistance (physiology)

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