| Title | Toll-like receptor 4 mediates lung ischemia-reperfusion injury. | | Author(s) | Shimamoto A, Pohlman TH, Shomura S, Tarukawa T, Takao M, Shimpo H | | Institution | Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Japan. jj6jdv@clin.medic.mie-u.ac.jp | | Source | Ann Thorac Surg 2006 Dec; 82(6):2017-23. | | MeSH | Animals
Capillary Permeability
Disease Models, Animal
Lung Diseases
Male
Mice
Mice, Knockout
NF-kappa B
Reperfusion Injury
Toll-Like Receptor 4
Transcription Factor AP-1
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 17126102 |
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