The survival of pig to rabbit renal xenografts during inhibition of thromboxane synthesis

Jørgensen, Kaj Anker; Kemp, E; Barfort, Per; Starklint, H; Larsen, Svend; Petersen, Per Hyltoft; Knudsen, Jens

doi:10.1016/0049-3848(83)90060-9

Cited by 10 publications

(2 citation statements)

References 5 publications

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“…The eicosanoid pathway, like the complement system, is a primitive yet potent component of the innate immune system. There exists circumstantial evidence that thromboxane may contribute to the increased vascular resistance and subsequent inflammation observed in organ xenografts other than the lung (6,16,33,40). Indeed, direct manipulation of the eicosanoid balance has been used experimentally to facilitate short-term survival of kidney and lung xenografts in the setting of complement regulation (30,44).…”

Section: Discussionmentioning

confidence: 99%

Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection

Collins¹,

Blum²,

Parker

et al. 2001

Journal of Applied Physiology

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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.

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Section: Discussionmentioning

confidence: 99%

Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection

Collins¹,

Blum²,

Parker

et al. 2001

Journal of Applied Physiology

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“…However, this seems unlikely since administration in the schedule chosen, even if it did not induce complete inhibition of the throm boxane synthetase in vivo throughout the whole 24 h, actually made the nephritis worse in both clinical and histological terms. Jorgensen et al [39] observed a wors ening of xenograft survival in piglet-to-rabbit renal trans plants treated with dazoxiben, a thromboxane synthetase inhibitor. More difficult to interpret are data on cyclo oxygenase inhibition using aspirin, which in two differ ent models of renal injury [40,41] worsened clinical and histological damage.…”

Section: Observations In Animals Treated With Oky-046mentioning

confidence: 99%

Rabbit Nephrotoxic Nephritis: Effect of a Thromboxane Synthetase Inhibitor on Evolution and Prostaglandin Excretion

Shinkai¹,

Cameron²

1987

Nephron

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Accelerated anti-glomerular basement membrane nephritis was induced in rabbits, and the immunological, clinical and histological evolution studied in relation to urinary immunoreactive thromboxane B₂ (i-TXB₂) and immunoreactive prostaglandin E₂ (i-PGE₂) excretion. In control nephritic animals, urinary i-TXB₂ increased 5-fold on day +1, but was normal again by day +5. The urinary i-TXB₂ showed a positive correlation with creatinine clearance (CCr), proteinuria and anti-sheep immunoglobuhn antibody. Urinary i-PGE₂ excretion increased by 50% on day +1, but was indistinguishable later from controls. The effects of the specific thromboxane synthetase inhibitor OKY-046 on this model was studied. In non-nephritic control animals, OKY-046 did not affect the CCr, the urinary protein excretion or the number of monocytes in glomeruli but reduced the excretion of i-TXB₂. Although OKY-046 markedly inhibited the i-TXB₂ excretion throughout the experiment in nephritic animals, the creatinine clearances were significantly worse, the proteinuria greater, and the number of infiltrating monocytes greater at day + 5; by day + 10 there was no difference from controls. There was no evidence that TXB₂ is involved in the induction of proteinuria, and increased PGE₂ synthesis did not protect against later proteinuria and fall in creatinine clearance. Inhibition of thromboxane synthetase appears to make this model of nephritis worse, rather than better.

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Histopathology of Kidney Xenograft Rejection

Larsen¹,

Starklint²

1997

Xenotransplantation

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The survival of pig to rabbit renal xenografts during inhibition of thromboxane synthesis

Cited by 10 publications

References 5 publications

Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection

Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection

Rabbit Nephrotoxic Nephritis: Effect of a Thromboxane Synthetase Inhibitor on Evolution and Prostaglandin Excretion

Histopathology of Kidney Xenograft Rejection

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