HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qureshi, S. T. Articles by Lee, P. J. Search for Related Content PubMed PubMed Citation Articles by Qureshi, S. T. Articles by Lee, P. J.

Inducible Activation of TLR4 Confers Resistance to Hyperoxia-Induced Pulmonary Apoptosis

Salman T. Qureshi^1,2,*, Xuchen Zhang^2,, Erika Aberg^*, Nicolas Bousette, Adel Giaid, Peiying Shan, Ruslan M. Medzhitov and Patty J. Lee

^* McGill Centre For The Study of Host Resistance and McGill Cardiovascular Research Centre, Montreal, Canada; and Howard Hughes Medical Institute and Section of Immunobiology and Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520

TLRs are essential mediators of host defense against infection via recognition of unique microbial structures. Recent observations indicate that TLR4, the principal receptor for bacterial LPS, may also be activated by noninfectious stimuli including host-derived molecules and environmental oxidant stress. In mice, susceptibility to ozone-induced lung permeability has been linked to the wild-type allele of TLR4, whereas deficiency of TLR4 predisposes to lethal lung injury in hyperoxia. To precisely characterize the role of lung epithelial TLR4 expression in the host response to oxidant stress, we have created an inducible transgenic mouse model that targets the human TLR4 signaling domain to the airways. Exposure of induced transgenic mice to hyperoxia revealed a significant reduction in pulmonary apoptosis compared with controls. This phenotype was associated with sustained up-regulation of antiapoptotic molecules such as heme oxygenase-1 and Bcl-2, yet only transient activation of the transcription factor NF-B. Specific in vivo knockdown of pulmonary heme oxygenase-1 or Bcl-2 expression by intranasal administration of short interfering RNA blocked the effect of TLR4 signaling on hyperoxia-induced lung apoptosis. These results define a novel role for lung epithelial TLR4 as a modulator of cellular apoptosis in response to oxidant stress.

This article has been cited by other articles:

				W. Chao Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H1 - H12. [Abstract] [Full Text] [PDF]

				J. W. Hollingsworth, S. Maruoka, Z. Li, E. N. Potts, D. M. Brass, S. Garantziotis, A. Fong, W. M. Foster, and D. A. Schwartz Ambient Ozone Primes Pulmonary Innate Immunity in Mice J. Immunol., October 1, 2007; 179(7): 4367 - 4375. [Abstract] [Full Text] [PDF]

				D. R. Prows, A. P. Hafertepen, A. V. Winterberg, W. J. Gibbons Jr., C. Liu, and T. G. Nick Genetic analysis of hyperoxic acute lung injury survival in reciprocal intercross mice Physiol Genomics, August 20, 2007; 30(3): 271 - 281. [Abstract] [Full Text] [PDF]