This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Klausner, J. M. Articles by Hechtman, H. B. Search for Related Content PubMed PubMed Citation Articles by Klausner, J. M. Articles by Hechtman, H. B.

Role of Thromboxane in Interleukin 2-induced Lung Injury in Sheep¹

Department of Surgery, Brigham and Women's Hospital and Harvard Medical School [J. M. K., I. S. P., G. G., T. J. E., H. B. H.]; the Naval Blood Research Laboratory, Boston University School of Medicine [A. D. G., R. V.]; and the Biological Science Center, Boston University [N. M. L. M., D. S.], Boston, Massachusetts 02115

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, 10⁵ 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 TxB₂ 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 (L) 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 L 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 38.9–40.3°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 TxB₂ (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). PaO₂ decreased from 89 to 81 mm of Hg (P < 0.05). The initial increase in L and the L/P protein ratio were delayed by 1.5 h. Thereafter, there was a lesser permeability effect, since L 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 L 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 PaO₂, 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.

¹ Supported in part by NIH Grants GM24891-10, GM 35141-03, and HL16714-13; the United States Navy Office of Naval Research, Contract NIL-214-79-C-0168; the Brigham Surgical Group, Inc.; and the Trauma Research Foundation.

² To whom requests for reprints should be addressed, at Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Received 6/27/88. Revised 9/ 6/88. Accepted 3/20/89.

This article has been cited by other articles:

				E. Assier, V. Jullien, J. Lefort, J.-L. Moreau, J. P. Di Santo, B. B. Vargaftig, J. R. Lapa e Silva, and J. Theze NK Cells and Polymorphonuclear Neutrophils Are Both Critical for IL-2-Induced Pulmonary Vascular Leak Syndrome J. Immunol., June 15, 2004; 172(12): 7661 - 7668. [Abstract] [Full Text] [PDF]