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Deleterious Role of TLR3 during Hyperoxia-induced Acute Lung Injury

¹ Immunobiology Department, ³ Toxicology and Investigational Pharmacology Department, ⁴ Tissue Remodeling and Metabolism Department, and ⁶ Molecular Discovery Technologies, Centocor, Radnor, Pennsylvania; ² James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Vancouver, British Columbia, Canada; ⁵ Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; ⁷ Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Université de la Méditerranée, Parc Scientifique de Luminy, Marseille, France; and ⁸ Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut

Correspondence and requests for reprints should be addressed to Lynne Murray, Ph.D., Promedior, Inc., 371 Phoenixville Pike, Malvern, PA, 19355. 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. Patients with ARDS 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 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.

Measurements and Main 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.

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Therapy for acute respiratory distress syndrome (ARDS) is limited to supportive ventilatory therapy that can further damage the lung and exacerbate the inflammatory milieu. Mortality is high, especially in sepsis-induced ARDS, and thus new treatments are required. What This Study Adds to the Field Targeting an innate immunity–associated receptor, Toll-like receptor 3, during hyperoxia-induced lung injury inhibits the hallmarks associated with the pathology, thus providing a novel therapeutic approach.

 

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