Published ahead of print on October 10, 2008, doi:10.1164/rccm.200807-1020OC Am. J. Respir. Crit. Care Med., Volume 178, Number 12, December 2008, 1227-1237 A more recent version of this article appeared on December 15, 2008
Submitted on July 3, 2008 Deleterious Role of TLR3 During Hyperoxia-Induced Acute Lung InjuryLynne Anne Murray1*,1 Immunobiology Department, Centocor, Radnor, Pennsylvania, United States; Promedior Inc, Malvern, Pennsylvania, United States, 2 James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St Paul's Hospital, Vancouver, Canada, 3 Toxicology and Investigational Pharmacology Department, Centocor, Radnor, Pennsylvania, United States, 4 Tissue Remodeling and Metabolism Department, Centocor, Radnor, Pennsylvania, United States, 5 Immunology Program, Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States, 6 Molecular Discovery Technologies, Centocor, Radnor, Pennsylvania, United States, 7 Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Universite de la Mediterranee, Marseille, France, 8 Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, United States, 9 Immunobiology Department, Centocor, Radnor, Pennsylvania, United States, 10 Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States * To whom correspondence should be addressed. E-mail: lmurray{at}promedior.com.
Rationale: 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. ARDS patients are highly susceptible to viral infection and it may be due to altered toll like receptor (TLR) expression. Objectives: To evaluate the role of TLR3 in ARDS. Methods: TLR3 expression and signaling was determined in airway epithelial cells following 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. Measurements and Main Results: Increased TLR3 expression was observed in airway epithelial cells from ARDS patients. 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 ECM deposition after 5 days of 80% oxygen compared with wildtype (TLR3+/+) mice under the same conditions. Administration of a monoclonal anti-TLR3 antibody to TLR3+/+ mice exposed to hyperoxic conditions likewise protected these mice to 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. Key words: ARDS • hyperoxia • lung • TLR3 • apoptosis
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