Ann Thorac Surg 2006;82:2023
© 2006 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Invited commentary
David R. Jones, MD
Thoracic and Cardiovascular Surgery, University of Virginia, Lee St, 4th Floor, Suite 4823, Charlottesville, VA 22908-0679
(Email: djones{at}virginia.edu).
Using a well-known lung ischemia-reperfusion animal model Shimamoto and colleagues [1] provided strong evidence that lung ischemia-reperfusion injury (IRI) is regulated through activation of the toll-like receptor 4 (TLR4). It is not surprising that this receptor is an important regulator of lung IRI, as it has already been demonstrated by this group, and others, to be involved in hepatic and cardiac IRI model systems. The observation that TLR4 deficient mice have significantly decreased lung vascular permeability indices, myeloperoxidase activities, and inflammatory cytokine profiles after an IRI compared with wild-type mice is certainly compelling, but is likely to be just the beginning of the story. As suggested by the authors, multiple ligands are known to bind TLR4 and initiate the downstream signal transduction cascades involved in the cell inflammatory response. The promiscuity of this receptor to a variety of ligands and stimuli (leukocytes, platelets, thrombin, and so forth) that are postulated to mediate IRI may in fact be fortuitous. Provided many of these stimuli act through a common receptor (such as TLR4), then future treatment strategies can focus on receptor-specific pharmacologic approaches and avoid the trap of attempting to modulate individual deleterious stimuli in isolation.
The author’s effort to implicate the transcription factors NF- 
B and AP1 as mediators of TLR4 signal transduction pathways involved in IRI is correlative, but is supported by other better designed studies in numerous organ IRI systems. The authors suggest that there are multiple downstream signal transduction pathways that are activated through IRI upregulation of TLR4. This is most certainly true and likely involves activation of cascades antagonistic to ones regulated by these transcription factors. This, combined with the fact that there was only a 50% reduction in many of the physiologic measurements of IRI in this study, suggests that there other important targets, such as the TLR4, that need to be identified. The importance of this study is that it addresses a clinically relevant problem using transgenic TLR4 knockout mice, which permits a direct examination of the importance of this receptor in lung IRI. Finally this study does what good studies are supposed to do (ie, stimulate others to advance the field even further).
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References
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- Shimamoto A, Pohlman TH, Shomura S, Tarukawa T, Takao M, Shimpo H. Toll-like receptor 4 mediates lung ischemia-reperfusion injury Ann Thorac Surg 2006;82:2017-2023.[Abstract/Free Full Text]
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