AJP - Lung Cellular and Molecular Physiology, Vol 267, Issue 3 282-L290, Copyright © 1994 by American Physiological Society

ARTICLES

Activation of protein kinase C mediates altered pulmonary vasoreactivity induced by tumor necrosis factor-alpha

G. Serfilippi, T. J. Ferro and A. Johnson
Samuel S. Stratton Veterans Affairs Medical Center, Albany, New York.

We postulated that tumor necrosis factor-alpha (TNF) "primes" the lung for the development of pulmonary vasoconstriction and edema by activating protein kinase C (PKC). Guinea pigs were injected with TNF (1.6 x 10(5) U/kg i.p.), and the lungs were isolated 4 h later. Compared with controls, TNF pretreatment resulted in greater increases in pulmonary vascular resistance and pressure and lung weight, in response to the thromboxane A2 mimetic, U-46619 (122 pmol/min). Treatment with TNF resulted in 1) pulmonary arterial endothelial PKC activation, 2) increased lung polymorphonuclear neutrophil (PMN) sequestration, 3) increased levels of superoxide radical (O2.) in lung effluent, and 4) decreased nitrite levels (NO2-, oxidation product of nitric oxide) in lung effluent. Intraperitoneal treatment with calphostin C (3 microM, 15 min prior to treatment with TNF) prevented the effects of TNF on 1) PKC activation, 2) the hemodynamic responses to U-46619, and 3) the levels of NO2- and O2(.). PKC activation does not mediate TNF-induced lung sequestration of PMN, since calphostin C had no effect on lung myeloperoxidase activity. The data suggest that PKC activation mediates TNF-induced 1) increases in O2., 2) decreases in NO2-, and 3) increases in vasoreactivity and edema in response to U-46619.

This article has been cited by other articles:

				A. Siflinger-Birnboim and A. Johnson Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury Am J Physiol Lung Cell Mol Physiol, March 1, 2003; 284(3): L435 - L451. [Abstract] [Full Text] [PDF]

				K. Bove, P. Neumann, N. Gertzberg, and A. Johnson Role of ecNOS-derived NO in mediating TNF-induced endothelial barrier dysfunction Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L914 - L922. [Abstract] [Full Text] [PDF]

				A. Johnson The conundrum of oxidant-induced barrier dysfunction Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L439 - L440. [Full Text] [PDF]

				T. Ferro, P. Neumann, N. Gertzberg, R. Clements, and A. Johnson Protein kinase C-alpha mediates endothelial barrier dysfunction induced by TNF-alpha Am J Physiol Lung Cell Mol Physiol, June 1, 2000; 278(6): L1107 - L1117. [Abstract] [Full Text] [PDF]

				B. M. Fischer, L. G. Rochelle, J. A. Voynow, N. J. Akley, and K. B. Adler Tumor Necrosis Factor-alpha Stimulates Mucin Secretion and Cyclic GMP Production by Guinea Pig Tracheal Epithelial Cells In Vitro Am. J. Respir. Cell Mol. Biol., March 1, 1999; 20(3): 413 - 422. [Abstract] [Full Text]

				W. Steudel, H.-J. Kramer, D. Degner, S. Rosseau, H. Schutte, D. Walmrath, and W. Seeger Endotoxin priming of thromboxane-related vasoconstrictor responses in perfused rabbit lungs J Appl Physiol, July 1, 1997; 83(1): 18 - 24. [Abstract] [Full Text] [PDF]