Contribution of Toll-like receptor activation to lung damage after donor brain death.
BACKGROUND
Donor brain death is the first injurious event that can produce inflammatory dysfunction after pulmonary transplantation. This study was designed to determine whether stimulation of the toll-like receptor (TLR) system contributes to the changes produced by brain death.


METHODS
Rats were repeatedly treated with specific agonists for TLR4 or TLR2/6 to desensitize these receptors. Brain death was then induced by inflation of a balloon catheter within the extradural space. Mean arterial pressure changes and inflammatory markers were measured serially by protein and mRNA analysis.


RESULTS
Both desensitizing pretreatments prevented the neurogenic hypotension (P<0.001) and metabolic acidosis (P<0.001) observed in control animals after brain death. These treatments also reduced the levels of tumor necrosis factor-α and CXCL1 in serum and bronchoalveolar lavage fluid, although desensitization of TLR4 produced a greater inhibition than desensitization of TLR2. Desensitization of TLR4 also reduced (P<0.05) expression of the adhesive integrin CD11b on blood neutrophils after brain death. Examination of mRNA levels in lung tissue 5 hr after brain death showed that desensitization of TLR4 limited the expression of interferon (IFN)-γ, IFNβ, and CXCL10, whereas desensitization of TLR2/6 reduced only the expression of IFNγ.


CONCLUSIONS
These results indicate that activation of TLR signaling pathways can contribute to the lung damage produced by brain death; this may increase subsequent graft injury after transplantation.
Rostron
Anthony J
AJ
Applied Immunobiology and Transplant Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
Cork
David M W
DM
Avlonitis
Vassilios S
VS
Fisher
Andrew J
AJ
Dark
John H
JH
Kirby
John A
JA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D001926:Brain Death / Q000473:pathology*; D039481:CD11b Antigen / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000473:pathology* / Q000502:physiology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*
D039481:CD11b Antigen; D015815:Cell Adhesion Molecules; D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D012313:RNA