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Silencing of Fas-associated Death Domain Protects Mice from Septic Lung Inflammation and Apoptosis

¹ Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama; ² Department of Primary Care and Emergency Medicine, Graduate School of Medicine, Kyoto University, Kyoto; and ³ Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

Correspondence and requests for reprints should be addressed to Yuichi Hattori, M.D., Ph.D., Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan. E-mail: yhattori{at}med.u-toyama.ac.jp

Rationale: A better understanding of the molecular mechanisms involved in the pathogenesis of sepsis and its resultant organ failure and new therapeutic approaches and targets are urgently needed. Accumulating evidence suggests that apoptosis plays an important role in the pathophysiology of sepsis and that apoptosis may be detrimental in septic acute lung injury (ALI).

Objectives: We tested the hypothesis that systemic administration of small interfering RNA (siRNA) targeting Fas-associated death domain (FADD), which recruits procaspase-8 into the death-inducing signaling complex, may be protective in septic ALI and mortality.

Methods: Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice. In vivo delivery of siRNA was performed by using a transfection reagent at 10 hours after CLP. As a negative control, animals received nonsense (scrambled) siRNA.

Measurements and Main Results: In CLP-induced septic mice, surface expression of death receptors was up-regulated, and FADD was highly expressed. DNA fragmentation ladder and transferase-mediated dUTP nick end labeling assays showed that treatment with FADD siRNA suppressed apoptosis induction in septic lungs. This siRNA treatment prevented the ALI development in CLP mice, as indicated by the findings that blood-gas derangements, histologic lung damage, and increased pulmonary inflammatory cells were greatly improved. Finally, FADD siRNA administration dramatically improved the survival of CLP mice.

Conclusions: These results indicate the pathophysiologic significance of the death receptor apoptotic pathway, including FADD, in septic ALI and the potential usefulness of FADD siRNA for gene therapy of the septic syndrome.

Key Words: acute lung injury • caspases • death receptors • polymicrobial sepsis

AT A GLANCE SUMMARY Scientific Knowledge on the Subject The role of apoptotic cell death has been implicated in the pathophysiology of sepsis, but the therapeutic efficacy of gene silencing for apoptotic molecules with small interfering RNAs (siRNA) in septic acute lung injury has not been studied. What This Study Adds to the Field The use of siRNA targeted to Fas-associated death domain not only identifies this apoptotic adaptor molecule as a potential target in septic acute lung injury but indicates a significant role of the death receptor apoptotic pathway in the septic syndrome.

 

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