This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200303-343OCv1 169/2/201    most recent 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 Uhlig, U. Articles by Uhlig, S. Search for Related Content PubMed PubMed Citation Articles by Uhlig, U. Articles by Uhlig, S.

Phosphoinositide 3-OH Kinase Inhibition Prevents Ventilation-induced Lung Cell Activation

Research Center Borstel, Borstel; Clinical Research Group "Chronic Airway Diseases," Department of Internal Medicine (Respiratory Medicine), Philipps-University, Marburg, Germany; and Department of Anesthesiology, Erasmus MC Faculty, Rotterdam, The Netherlands

Correspondence and requests for reprints should be addressed to Stefan Uhlig, Ph.D., Division of Pulmonary Pharmacology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. E-mail: suhlig{at}fz-borstel.de

In acute respiratory distress syndrome patients, protective ventilation strategies reduce mortality and proinflammatory mediator levels. It has been suggested that some of the side effects of mechanical ventilation are caused by the excessive release of mediators capable of causing pulmonary inflammation and tissue destruction (biotrauma). Selective inhibition of this process might be used to minimize the side effects of artificial mechanical ventilation. This study was designed to identify the cell types and specific signaling mechanisms that are activated by ventilation with increased pressure/volume (overventilation). In isolated perfused mouse lungs, overventilation caused nuclear translocation of nuclear factor-B (NF-B) and enhanced expression of interleukin-6 mRNA in alveolar macrophages and alveolar epithelial type II cells. The phosphoinositide 3-OH kinase inhibitor Ly294002 prevented nuclear translocation of NF-B and the subsequent release of interleukin-6 and macrophage inflammatory protein–2 in overventilated but not in endotoxic lungs. Similar results were obtained in rats in vivo, where Ly294002 prevented NF-B activation by overventilation but not by endotoxin. These findings show that alveolar macrophages and alveolar epithelial type II cells contribute to the ventilation-induced release of proinflammatory mediators and that selective inhibition of this process is possible without inhibiting the activation of NF-B by endotoxin.

Key Words: ventilation-induced lung injury • overventilation • biotrauma nuclear factor-B • I-Bß

This article has been cited by other articles:

				A. Hoetzel, T. Dolinay, S. Vallbracht, Y. Zhang, H. P. Kim, E. Ifedigbo, S. Alber, A. M. Kaynar, R. Schmidt, S. W. Ryter, et al. Carbon Monoxide Protects against Ventilator-induced Lung Injury via PPAR-{gamma} and Inhibition of Egr-1 Am. J. Respir. Crit. Care Med., June 1, 2008; 177(11): 1223 - 1232. [Abstract] [Full Text] [PDF]

				S. Papaiahgari, A. Yerrapureddy, S. R. Reddy, N. M. Reddy, J. M. Dodd-O, M. T. Crow, D. N. Grigoryev, K. Barnes, R. M. Tuder, M. Yamamoto, et al. Genetic and Pharmacologic Evidence Links Oxidative Stress to Ventilator-induced Lung Injury in Mice Am. J. Respir. Crit. Care Med., December 15, 2007; 176(12): 1222 - 1235. [Abstract] [Full Text] [PDF]

				H. Dombrowsky and S. Uhlig Steroids and histone deacetylase in ventilation-induced gene transcription Eur. Respir. J., November 1, 2007; 30(5): 865 - 877. [Abstract] [Full Text] [PDF]

				T. Miyahara, K. Hamanaka, D. S. Weber, D. A. Drake, M. Anghelescu, and J. C. Parker Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L11 - L21. [Abstract] [Full Text] [PDF]

				M. R. Wilson, M. E. Goddard, K. P. O'Dea, S. Choudhury, and M. Takata Differential roles of p55 and p75 tumor necrosis factor receptors on stretch-induced pulmonary edema in mice Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L60 - L68. [Abstract] [Full Text] [PDF]

				T. Dolinay, N. Kaminski, M. Felgendreher, H. P. Kim, P. Reynolds, S. C. Watkins, D. Karp, S. Uhlig, and A. M. K. Choi Gene expression profiling of target genes in ventilator-induced lung injury Physiol Genomics, September 14, 2006; 26(1): 68 - 75. [Abstract] [Full Text] [PDF]

				C. Bonnans, K. Fukunaga, R. Keledjian, N. A. Petasis, and B. D. Levy Regulation of phosphatidylinositol 3-kinase by polyisoprenyl phosphates in neutrophil-mediated tissue injury J. Exp. Med., April 17, 2006; 203(4): 857 - 863. [Abstract] [Full Text] [PDF]

				A Bourbia, M A Cruz, and H J Rozycki NF-{kappa}B in tracheal lavage fluid from intubated premature infants: association with inflammation, oxygen, and outcome Arch. Dis. Child. Fetal Neonatal Ed., January 1, 2006; 91(1): F36 - F39. [Abstract] [Full Text] [PDF]

				P. Caironi, F. Ichinose, R. Liu, R. C. Jones, K. D. Bloch, and W. M. Zapol 5-Lipoxygenase Deficiency Prevents Respiratory Failure during Ventilator-induced Lung Injury Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 334 - 343. [Abstract] [Full Text] [PDF]

				D. Angus, A. Ishizaka, M. Matthay, F. Lemaire, W. MacNee, and E. Abraham Critical Care in AJRCCM 2004 Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 537 - 544. [Full Text] [PDF]

				C.C. dos Santos, B. Han, C.F. Andrade, X. Bai, S. Uhlig, R. Hubmayr, M. Tsang, M. Lodyga, S. Keshavjee, A.S. Slutsky, et al. DNA microarray analysis of gene expression in alveolar epithelial cells in response to TNF{alpha}, LPS, and cyclic stretch Physiol Genomics, November 17, 2004; 19(3): 331 - 342. [Abstract] [Full Text] [PDF]