| Autor: |
Camp SM; Department of Medicine and Arizona Respiratory Center, The University of Arizona., Ceco E; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Evenoski CL; Department of Medicine and Arizona Respiratory Center, The University of Arizona., Danilov SM; Department of Anesthesiology, University of Illinois at Chicago., Zhou T; Department of Medicine and Arizona Respiratory Center, The University of Arizona., Chiang ET; Department of Medicine and Arizona Respiratory Center, The University of Arizona., Moreno-Vinasco L; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Mapes B; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Zhao J; Department of Bioengineering, University of Illinois at Chicago., Gursoy G; Department of Bioengineering, University of Illinois at Chicago., Brown ME; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Adyshev DM; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Siddiqui SS; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Quijada H; Department of Medicine and Arizona Respiratory Center, The University of Arizona., Sammani S; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Letsiou E; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Saadat L; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago., Yousef M; Life Science Group, Bio-Rad Laboratories, Inc., Wang T; Department of Medicine and Arizona Respiratory Center, The University of Arizona., Liang J; Department of Bioengineering, University of Illinois at Chicago., Garcia JG; Department of Medicine and Arizona Respiratory Center, The University of Arizona. |
| Abstrakt: |
Ventilator-induced inflammatory lung injury (VILI) is mechanistically linked to increased NAMPT transcription and circulating levels of nicotinamide phosphoribosyl-transferase (NAMPT/PBEF). Although VILI severity is attenuated by reduced NAMPT/PBEF bioavailability, the precise contribution of NAMPT/PBEF and excessive mechanical stress to VILI pathobiology is unknown. We now report that NAMPT/PBEF induces lung NFκB transcriptional activities and inflammatory injury via direct ligation of Toll-like receptor 4 (TLR4). Computational analysis demonstrated that NAMPT/PBEF and MD-2, a TLR4-binding protein essential for LPS-induced TLR4 activation, share ~30% sequence identity and exhibit striking structural similarity in loop regions critical for MD-2-TLR4 binding. Unlike MD-2, whose TLR4 binding alone is insufficient to initiate TLR4 signaling, NAMPT/PBEF alone produces robust TLR4 activation, likely via a protruding region of NAMPT/PBEF (S402-N412) with structural similarity to LPS. The identification of this unique mode of TLR4 activation by NAMPT/PBEF advances the understanding of innate immunity responses as well as the untoward events associated with mechanical stress-induced lung inflammation. |
