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Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema.

Publication ,  Journal Article
Zanotti, G; Casiraghi, M; Abano, JB; Tatreau, JR; Sevala, M; Berlin, H; Smyth, S; Funkhouser, WK; Burridge, K; Randell, SH; Egan, TM
Published in: Am J Physiol Lung Cell Mol Physiol
July 2009

Toll-like receptors (TLRs) of the innate immune system contribute to noninfectious inflammatory processes. We employed a murine model of hilar clamping (1 h) with reperfusion times between 15 min and 3 h in TLR4-sufficient (C3H/OuJ) and TLR4-deficient (C3H/HeJ) anesthetized mice with additional studies in chimeric and myeloid differentiation factor 88 (MyD88)- and TLR4-deficient mice to determine the role of TLR4 in lung ischemia-reperfusion injury. Human pulmonary microvascular endothelial monolayers were subjected to simulated warm ischemia and reperfusion with and without CRX-526, a competitive TLR4 inhibitor. Functional TLR4 solely on pulmonary parenchymal cells, not bone marrow-derived cells, mediates early lung edema following ischemia-reperfusion independent of MyD88. Activation of MAPKs and NF-kappaB was significantly blunted and/or delayed in lungs of TLR4-deficient mice as a consequence of ischemia-reperfusion injury, but edema development appeared to be independent of activation of these signaling pathways. Pretreatment with a competitive TLR4 inhibitor prevented edema in vivo and reduced actin cytoskeletal rearrangement and gap formation in pulmonary microvascular endothelial monolayers subjected to simulated warm ischemia and reperfusion. In addition to its well-accepted role to alter gene transcription, functioning TLR4 on pulmonary parenchymal cells plays a key role in very early and profound pulmonary edema in murine lung ischemia-reperfusion injury. This may be due to a novel mechanism: regulation of endothelial cell cytoskeleton affecting microvascular endothelial cell permeability.

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Published In

Am J Physiol Lung Cell Mol Physiol

DOI

EISSN

1522-1504

Publication Date

July 2009

Volume

297

Issue

1

Start / End Page

L52 / L63

Location

United States

Related Subject Headings

  • Warm Ischemia
  • Toll-Like Receptor 4
  • Respiratory System
  • Reperfusion Injury
  • Pulmonary Edema
  • Paracrine Communication
  • NF-kappa B
  • Mitogen-Activated Protein Kinases
  • Mice, Inbred C57BL
  • Mice
 

Citation

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MLA
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Zanotti, G., Casiraghi, M., Abano, J. B., Tatreau, J. R., Sevala, M., Berlin, H., … Egan, T. M. (2009). Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema. Am J Physiol Lung Cell Mol Physiol, 297(1), L52–L63. https://doi.org/10.1152/ajplung.90406.2008
Zanotti, Giorgio, Monica Casiraghi, John B. Abano, Jason R. Tatreau, Mayura Sevala, Hilary Berlin, Susan Smyth, et al. “Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema.Am J Physiol Lung Cell Mol Physiol 297, no. 1 (July 2009): L52–63. https://doi.org/10.1152/ajplung.90406.2008.
Zanotti G, Casiraghi M, Abano JB, Tatreau JR, Sevala M, Berlin H, et al. Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema. Am J Physiol Lung Cell Mol Physiol. 2009 Jul;297(1):L52–63.
Zanotti, Giorgio, et al. “Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema.Am J Physiol Lung Cell Mol Physiol, vol. 297, no. 1, July 2009, pp. L52–63. Pubmed, doi:10.1152/ajplung.90406.2008.
Zanotti G, Casiraghi M, Abano JB, Tatreau JR, Sevala M, Berlin H, Smyth S, Funkhouser WK, Burridge K, Randell SH, Egan TM. Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema. Am J Physiol Lung Cell Mol Physiol. 2009 Jul;297(1):L52–L63.

Published In

Am J Physiol Lung Cell Mol Physiol

DOI

EISSN

1522-1504

Publication Date

July 2009

Volume

297

Issue

1

Start / End Page

L52 / L63

Location

United States

Related Subject Headings

  • Warm Ischemia
  • Toll-Like Receptor 4
  • Respiratory System
  • Reperfusion Injury
  • Pulmonary Edema
  • Paracrine Communication
  • NF-kappa B
  • Mitogen-Activated Protein Kinases
  • Mice, Inbred C57BL
  • Mice