Role of Thromboxane in Interleukin 2-induced Lung Injury in Sheep

Joseph M. Klausner, Ian S. Paterson, Gideon Goldman, Timothy Eberlein, Herbert B. Hechtman, Alan D. Gray, Robert Valeri, Nicole M.L. Morel, David Shepro

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Abstract

Interleukin (IL)-2 administration leads to respiratory dysfunction due to increased vascular permeability. This study examines the role of thromboxane (Tx)A2 in IL-2 induced lung injury in sheep with chronic lung lymph fistulae. This preparation enables evaluation of permeability prior to the development of gross edema. IL-2, 10s units/kg (n = 6), or its excipient control (n = 5) was given as an i.v. bolus over 2 min. After 2 h of IL-2 administration, plasma Txlfc increased from 168 to 388 pg/ ml (P < 0.05) and lung lymph TxB2 from 235 to 694 pg/ml (P < 0.05). Mean pulmonary artery pressure (MPAP) rose from 13 to 29 mm of Hg (P < 0.05) at 30 min and remained elevated for 4 h while the pulmonary artery wedge pressure was unchanged at 4 mm of Hg. Arterial oxygen tension (Pao2) fell from 88 to 77 mm of Hg (P < 0.05). Lung lymph flow (0L) rose from 2.2 to 3.8 ml/30 min (P < 0.05) at 1 h and to 6.4 ml/30 min at 3 h. This rise coincided with an increase in the lymph/plasma (L/ P) protein ratio from 0.67 to 0.77 (P < 0.05). In contrast, the non-IL-2-infused sheep (n = 3) recruitment of the lung vasculature by left atrial balloon inflation led to a rise in QL from 2.4 to 8.2 ml/30 min, whereas the L/P ratio declined from 0.62 to 0.25, suggesting that the protein-rich lymph flow after IL-2 administration reflected increased microvascular permeability. In further proof of an increase in permeability, IL-2 administration into sheep (n = 2) with an inflated left atrial balloon led, after a pressure-independent L/P protein ratio had been achieved, to an increase in L/P protein ratio and decrease in protein reflection coefficient. At 2 h after IL-2, the blood leukocyte count fell from 8156 to 4375/mm3 (P < 0.05) primarily due to a 73% drop in lymphocytes. The platelet count declined from 292 to 184 x 103/mm3 (P < 0.05). Body temperature rose from 38.9–403·C (P < 0.05), and shaking chills were common. Pretreatment with the Tx synthetase inhibitor OKY 046 (n = 7) lowered baseline plasma and lymph TxB2 levels to 22 and 52 pg/ml (P < 0.05) and prevented the IL-2-induced increase in plasma and lung lymph Txlfe (P < 0.05). Tx inhibition prevented the increase in MPAP at 30 min and limited its rise at 2 h to 14 mm of Hg, a value lower than untreated IL-2-infused animals (P < 0.05). Pa02 decreased from 89 to 81 mm of Hg (P < 0.05). The initial increase in QL and the L/P protein ratio were delayed by 1.5 h. Thereafter, there was a lesser permeability effect, since 0L but not the L/P ratio reached levels similar to IL-2-treated controls. The leukopenia and lymphopenia were unaffected by Tx inhibition, while the fall in platelet count was prevented (P < 0.05). The rise in temperature to 39.4·C was lower than IL-2 controls (P < 0.05). Shaking chills were not seen. Infusion of the excipient control did not affect plasma or lymph TxB2 levels, but there were increases in MPAP from 12 to 16 mm of Hg (P < 0.05) and QL from 2.5 to 3.7 ml/30 min, while the L/P protein ratio fell from 0.71 to 0.63 (P < 0.05). Body temperature rose from 39.2– 39.8·C. The Pad, WBC, lymphocyte, and platelet counts were unaffected. Incubation of IL-2 with sheep neutrophils but not sheep lymphocytes, platelets, or bovine pulmonary artery endothelial cell monolayers led to TxB2 generation. These data indicate that IL-2 leads to pulmonary hypertension and increased microvascular permeability. The former effect is mediated by TxA2, derived in part from neutrophils. The role of Tx in mediating IL-2-induced permeability is less clear. It can be due to a direct action on the vascular barrier or secondary to induction of pulmonary hypertension and increased filtration pressure.

Original languageEnglish
Pages (from-to)3542-3549
Number of pages8
JournalCancer research
Volume49
Issue number13
StatePublished - Jul 1 1989

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    Klausner, J. M., Paterson, I. S., Goldman, G., Eberlein, T., Hechtman, H. B., Gray, A. D., Valeri, R., Morel, N. M. L., & Shepro, D. (1989). Role of Thromboxane in Interleukin 2-induced Lung Injury in Sheep. Cancer research, 49(13), 3542-3549.