Deleterious role of TLR3 during hyperoxia-induced acute lung injury.
BACKGROUND
Acute respiratory distress syndrome (ARDS) manifests clinically as a consequence of septic and/or traumatic injury in the lung. Oxygen therapy remains a major therapeutic intervention in ARDS, but this can contribute further to lung damage. Patients with ARDS are highly susceptible to viral infection and it may be due to altered Toll-like receptor (TLR) expression.


OBJECTIVE
To evaluate the role of TLR3 in ARDS.


METHODS
TLR3 expression and signaling was determined in airway epithelial cells after in vitro hyperoxia challenge. Using a murine model of hyperoxia-induced lung injury, the role of TLR3 was determined using either TLR3-gene deficient mice or a specific neutralizing antibody directed to TLR3.


RESULTS
Increased TLR3 expression was observed in airway epithelial cells from patients with ARDS. Further, hyperoxic conditions alone were a major stimulus for increased TLR3 expression and activation in cultured human epithelial cells. Interestingly, TLR3(-/-) mice exhibited less acute lung injury, activation of apoptotic cascades, and extracellular matrix deposition after 5 days of 80% oxygen compared with wild-type (TLR3(+/+)) mice under the same conditions. Administration of a monoclonal anti-TLR3 antibody to TLR3(+/+) mice exposed to hyperoxic conditions likewise protected these mice from lung injury and inflammation.


CONCLUSIONS
The potential for redundancy in function as well as cross-talk between distinct TLRs may indeed contribute to whether the inflammatory cascade can be effectively disrupted once signaling has been initiated. Together, these data show that TLR3 has a major role in the development of ARDS-like pathology in the absence of a viral pathogen.
Immunobiology Department, Centocor, Radnor, PA, USA. lmurray@promedior.com
Lynne A
LA
Murray
Darryl A
DA
Knight
Laura
L
McAlonan
Rochelle
R
Argentieri
Amrita
A
Joshi
Furquan
F
Shaheen
Mark
M
Cunningham
Lena
L
Alexopolou
Richard A
RA
Flavell
Robert T
RT
Sarisky
Cory M
CM
Hogaboam
D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012313:RNA / Q000235:genetics*; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis / Q000235:genetics*
C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D012313:RNA