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Toll-like receptor 4 mediates lung ischemia-reperfusion injury.
Ann Thorac Surg. 2006 Dec; 82(6):2017-23.AT

Abstract

BACKGROUND

We have previously reported that nuclear factor (NF)-kappaB activation and inflammatory cytokine expression were involved in the development of lung ischemia-reperfusion injury (LIRI). Because Toll-like receptor 4 (TLR4) activates NF-kappaB-dependent transcription of inflammatory cytokine genes during myocardial ischemia-reperfusion injury, we examined whether absence of TLR4 in TLR4-deficient mice protects against LIRI.

METHODS

Left lungs of wild-type (C57BL/6J) mice or TLR4-null (TLR4-/-) mice were made ischemic for 60 minutes and then reperfused for 180 minutes. Response to injury was quantified by tissue myeloperoxidase activity, vascular permeability ([125I]-bovine serum albumin extravasation), and leukocyte and inflammatory mediator accumulation in bronchoalveolar lavage expression. Lung homogenates were also analyzed for activation of mitogen-activated protein kinases and nuclear translocation of the transcription factors NF-kappaB and activator protein-1.

RESULTS

After LIRI, lungs from TLR4-/- mice demonstrated a 52.4% reduction in vascular permeability (p = 0.001), a 52.6% reduction in lung myeloperoxidase activity (p = 0.006), and a marked reduction in bronchoalveolar lavage leukocyte accumulation when compared with lungs from wild-type mice. The TLR4-/- mice lungs, subjected to LIRI, also demonstrated marked reductions in amounts of several proinflammatory cytokines/chemokines in bronchoalveolar lavage samples. Phosphorylation of c-Jun NH2-terminal kinase, and activation of NF-kappaB and activator protein-1 were also significantly reduced in homogenates of lungs from TLR4-/- mice injured by ischemia and reperfusion (p < 0.05).

CONCLUSIONS

These data suggest that TLR4 plays a role in LIRI. Thus, TLR4 may be a potential therapeutic target to minimize ischemic-reperfusion-induced tissue damage and organ dysfunction.

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Authors+Show Affiliations

Shimamoto A
Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Japan. jj6jdv@clin.medic.mie-u.ac.jp
Pohlman TH
No affiliation info available
Shomura S
No affiliation info available
Tarukawa T
No affiliation info available
Takao M
No affiliation info available
Shimpo H
No affiliation info available

MeSH

AnimalsCapillary PermeabilityDisease Models, AnimalLung DiseasesMaleMiceMice, KnockoutNF-kappa BReperfusion InjuryToll-Like Receptor 4Transcription Factor AP-1

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17126102

Citation

Shimamoto, Akira, et al. "Toll-like Receptor 4 Mediates Lung Ischemia-reperfusion Injury." The Annals of Thoracic Surgery, vol. 82, no. 6, 2006, pp. 2017-23.
Shimamoto A, Pohlman TH, Shomura S, et al. Toll-like receptor 4 mediates lung ischemia-reperfusion injury. Ann Thorac Surg. 2006;82(6):2017-23.
Shimamoto, A., Pohlman, T. H., Shomura, S., Tarukawa, T., Takao, M., & Shimpo, H. (2006). Toll-like receptor 4 mediates lung ischemia-reperfusion injury. The Annals of Thoracic Surgery, 82(6), 2017-23.
Shimamoto A, et al. Toll-like Receptor 4 Mediates Lung Ischemia-reperfusion Injury. Ann Thorac Surg. 2006;82(6):2017-23. PubMed PMID: 17126102.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toll-like receptor 4 mediates lung ischemia-reperfusion injury. AU - Shimamoto,Akira, AU - Pohlman,Timothy H, AU - Shomura,Shin, AU - Tarukawa,Tomohito, AU - Takao,Motoshi, AU - Shimpo,Hideto, PY - 2006/03/01/received PY - 2006/06/12/revised PY - 2006/06/19/accepted PY - 2006/11/28/pubmed PY - 2006/12/13/medline PY - 2006/11/28/entrez SP - 2017 EP - 23 JF - The Annals of thoracic surgery JO - Ann Thorac Surg VL - 82 IS - 6 N2 - BACKGROUND: We have previously reported that nuclear factor (NF)-kappaB activation and inflammatory cytokine expression were involved in the development of lung ischemia-reperfusion injury (LIRI). Because Toll-like receptor 4 (TLR4) activates NF-kappaB-dependent transcription of inflammatory cytokine genes during myocardial ischemia-reperfusion injury, we examined whether absence of TLR4 in TLR4-deficient mice protects against LIRI. METHODS: Left lungs of wild-type (C57BL/6J) mice or TLR4-null (TLR4-/-) mice were made ischemic for 60 minutes and then reperfused for 180 minutes. Response to injury was quantified by tissue myeloperoxidase activity, vascular permeability ([125I]-bovine serum albumin extravasation), and leukocyte and inflammatory mediator accumulation in bronchoalveolar lavage expression. Lung homogenates were also analyzed for activation of mitogen-activated protein kinases and nuclear translocation of the transcription factors NF-kappaB and activator protein-1. RESULTS: After LIRI, lungs from TLR4-/- mice demonstrated a 52.4% reduction in vascular permeability (p = 0.001), a 52.6% reduction in lung myeloperoxidase activity (p = 0.006), and a marked reduction in bronchoalveolar lavage leukocyte accumulation when compared with lungs from wild-type mice. The TLR4-/- mice lungs, subjected to LIRI, also demonstrated marked reductions in amounts of several proinflammatory cytokines/chemokines in bronchoalveolar lavage samples. Phosphorylation of c-Jun NH2-terminal kinase, and activation of NF-kappaB and activator protein-1 were also significantly reduced in homogenates of lungs from TLR4-/- mice injured by ischemia and reperfusion (p < 0.05). CONCLUSIONS: These data suggest that TLR4 plays a role in LIRI. Thus, TLR4 may be a potential therapeutic target to minimize ischemic-reperfusion-induced tissue damage and organ dysfunction. SN - 1552-6259 UR - https://www.unboundmedicine.com/medline/citation/17126102/Toll_like_receptor_4_mediates_lung_ischemia_reperfusion_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0003-4975(06)01344-0 DB - PRIME DP - Unbound Medicine ER -