Functional role of thromboxane production by acutely rejecting renal allografts in rats.

Abstract

We investigated the role of thromboxane in mediating the reduction in renal function and renal blood flow characteristic of acute renal allograft rejection. We transplanted kidneys from Lewis rats to Brown-Norway recipients. By the third day after transplantation, histologic changes that were consistent with cellular rejection occurred in the kidney. These changes were associated with a moderate reduction in renal function. By day 6, histologic changes of rejection were advanced and included interstitial and perivascular infiltration by mononuclear cells. The clearances of inulin and para-aminohippuric acid were also markedly reduced.As renal function deteriorated, thromboxane B2 (TXB2) production by ex vivo perfused renal allografts increased progressively from 2 to 6 d after transplantation. However, prostaglandin (PG) E2 and 6-keto PGFI. production remained essentially unchanged. There was a significant inverse correlation between the in vivo clearance of inulin and the log of ex vivo TXB2 production. Infusion of the thromboxane synthetase inhibitor UK-37248-01 into the renal artery of 3-d allografts significantly decreased urinary TXB2 excretion and significantly increased renal blood flow (RBF) and glomerular filtration rate (GFR). Although renal function improved significantly after the acute administration of UK-37248-O1, GFR and RBF did not exceed 33 and 58% of native control values, respectively. In other animals, daily treatment with cyclophosphamide improved the clearances of inulin and para-aminohippuric acid and reduced thromboxane production by 6-d renal allografts. These studies demonstrate that histologic evidence of rejection is associated with increased renal thromboxane production. Inhibition of thromboxane synthetase improves renal function in 3-d allografts. Cytotoxic therapy improves renal function, reduces mononuclear cell infiltration, and decreases allograft thromboxane production. Thus, the potent vasoconstrictor thromboxane A2 may play a role in the impairment of renal function and renal blood flow during acute allograft rejection.

Deficiency of 5-Lipoxygenase Accelerates Renal Allograft Rejection in Mice

“…We have previously reported that macrophages from 5-LO-deficient animals released increased amounts of PGE 2 and TXB 2 , compared with wild-type controls (30), and we found an enhanced role for prostanoids in several acute inflammatory processes in 5-LO-deficient mice (30,32). Furthermore, several studies have demonstrated enhanced production of COX metabolites, specifically TXB 2 , in rat (5, 10, 41) and dog (10, 42) models of allograft rejection, and that TXB 2 contributes to transplant rejection (4,5,8,10). However, we found no differences in the levels of TXB 2 measured in renal cortical homogenates from 5-LO-deficient allograft recipients compared with wild-type controls.…”

“…We and others have previously shown that the eicosanoid TXA 2 is generated during rejection and mediates a substantial portion of the renal dysfunction observed in this model (4,5,8,10). Additional studies have demonstrated that the loss of 5-LO may result in enhanced synthesis and activity of other eicosanoids, particularly COX metabolites (30,32).…”

Rat kidney thromboxane receptor: molecular cloning, signal transduction, and intrarenal expression localization.

“…In the kidney, TXA2 has been shown to decrease renal blood flow (2) and glomerular filtration rate (3), and to potentiate tubuloglomerular feedback (4), thus involved in the control of renal hemodynamics and water and electrolyte metabolism. TXA2 is also implicated in the etiology or pathophysiology of many renal diseases such as nephritis (5-7), allograft transplantation rejection (8), and urinary tract obstruction (9). Blockade of TX synthase activity or TXA2 receptor binding has been shown to prevent exacerbation of renal injury caused by these diseases (9)(10)(11)(12)(13).…”

Eicosanoids, Mesangial Contraction, and Intracellular Signal Transduction.

“…It is released at the site of vascular injury or inflammation, such as in the course of experimental nephritis (Lianos et al 1983), ureteral obstruction (Okegawa et al 1983), renal allograft rejection (Coffman et al 1985), and lupus nephritis in man (Patrono et al 1985).…”