© 1996 American Heart Association, Inc.
Articles |
Locally Produced Tumor Necrosis Factor-
Mediates Interleukin-2Induced Lung Injury
From the Departments of Surgery (R.R., F.A., M.W., P.B., E.S., D.-R.P., P.O., L.F.N.) and Medicine (L.B., O.B.), Jefferson Medical College, Philadelphia, Pa, and SmithKline Beecham (G.F.), King of Prussia, Pa.
Correspondence to Reuven Rabinovici, MD, Department of Surgery, Jefferson Medical College, 1025 Walnut St, Philadelphia, PA 19107-5083.
Abstract Interleukin (IL)-2–induced microvascular lung
injury is an experimental paradigm commonly used to investigate the
pathogenesis of the adult respiratory distress syndrome. Since tumor
necrosis factor-
(TNF-) is known to induce such an injury in vivo
and since TNF- is involved in other models of lung injury, we
postulated that it might also mediate pulmonary toxicity after
IL-2 administration. The present study tested this hypothesis by
evaluating the effect of TNF- inhibition on IL-2–induced lung
injury in the rat. Recombinant human IL-2 (106 U IV
per rat, n=6) elevated lung water, myeloperoxidase activity, and
protein accumulation in bronchoalveolar lavage fluid and induced tissue
hypoxia. Also, IL-2 enhanced lung tissue TNF- mRNA and
peptide (1543±496 pg/g lung wet weight) localized to alveolar
macrophages by in situ hybridization. In marked contrast, IL-2
failed to affect serum TNF-, which remained at undetectable levels.
Pretreatment with anti–TNF- monoclonal antibody (25 mg/kg IV,
n=7)
or the TNF- synthesis inhibitor rolipram (200 µg/kg
IV, n=7) attenuated lung injury and reverted tissue hypoxia.
Furthermore, TNF- inhibition prevented the upregulation of lung
tissue IL-1ß, IL-6, cytokine-induced neutrophil
chemoattractant, and E-selectin (ELAM-1) but not intercellular adhesion
molecule-1 mRNAs in response to IL-2. These data imply that locally
produced TNF- mediates IL-2–induced lung inflammation and tissue
injury and point to the potential utilization of TNF-
inhibitors in treating the pulmonary toxicity of
IL-2 immunotherapy.
Key Words: cytokines • adult respiratory distress syndrome • immunotherapy
This article has been cited by other articles:
 |
|
 |
|
  R. H. Sohn, C. B. Deming, D. C. Johns, H. C. Champion, C. Bian, K. Gardner, and J. J. Rade Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B Blood, May 15, 2005; 105(10): 3910 - 3917. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Odoms, T. P. Shanley, and H. R. Wong Short-term modulation of interleukin-1{beta} signaling by hyperoxia: uncoupling of I{kappa}B kinase activation and NF-{kappa}B-dependent gene expression Am J Physiol Lung Cell Mol Physiol, March 1, 2004; 286(3): L554 - L562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. KOSHIKA, A. ISHIZAKA, I. NAGATOMI, Y. SUDO, N. HASEGAWA, and T. GOTO Pretreatment with FK506 Improves Survival Rate and Gas Exchange in Canine Model of Acute Lung Injury Am. J. Respir. Crit. Care Med., January 1, 2001; 163(1): 79 - 84. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. A. Tio, J. Nieken, E. G.E. de Vries, C. Pfeiffer, M. J.L. de Jongste, E. Pieper, H. Moshage, P. C. Limburg, and N. H. Mulder Negative inotropic effects of recombinant interleukin 2 in patients without left ventricular dysfunction Eur J Heart Fail, June 1, 2000; 2(2): 167 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. HÄFNER and P.-G. GERMANN Additive Effects of Phosphodiesterase-4 Inhibition on Effects of rSP-C Surfactant Am. J. Respir. Crit. Care Med., May 1, 2000; 161(5): 1495 - 1500. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. Rabinovici, K. Kabir, M. Chen, Y. Su, D. Zhang, X. Luo, and J.-H. Yang ADAR1 Is Involved in the Development of Microvascular Lung Injury Circ. Res., May 25, 2001; 88(10): 1066 - 1071. [Abstract] [Full Text] [PDF]
|
|