TY - JOUR
T1 - Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis
T2 - protection by eNAMPT neutralization
AU - Garcia, Alexander N.
AU - Casanova, Nancy G.
AU - Valera, Daniel G.
AU - Sun, Xiaoguang
AU - Song, Jin H.
AU - Kempf, Carrie L.
AU - Moreno-Vinasco, Liliana
AU - Burns, Kimberlie
AU - Bermudez, Tadeo
AU - Valdez, Mia
AU - Cuellar, Genesis
AU - Gregory, Taylor
AU - Oita, Radu C.
AU - Hernon, Vivian Reyes
AU - Barber, Christy
AU - Camp, Sara M.
AU - Martin, Diego
AU - Liu, Zhonglin
AU - Bime, Christian
AU - Sammani, Saad
AU - Cress, Anne E.
AU - Garcia, Joe GN
N1 - Funding Information:
Funding: NIH Grants R01 HL094394 , P01 HL134610 , R42 HL152888 .
Funding Information:
All named authors have read the journal's authorship agreement and have reviewed and approved the manuscript. Funding: NIH Grants R01 HL094394, P01 HL134610, R42 HL152888. Conflict of Interest: Joe GN Garcia MD is CEO and founder of Aqualung Therapeutics Corporation. Aqualung is the manufacturer of the eNAMPT-neutralizing humanized mAb used extensively and suggested as a translational therapy in this report. All other authors declare no competing financial interests. All authors have read the journal's authorship agreement and are in agreement. Author contributions are as follows: JGNG, AEC ? conception and design of the work, the analysis and interpretation of data for the work, the drafting and revision of the manuscript, approval of final version to be published; ANG, CB, ZL, DM ? conception and design of the work, the analysis and interpretation of data for the work, critical revision of key intellectual content and approval of final version to be published; ANG, DVG, NGC, SMC ? collection and analysis of data, revision of the manuscript, and approval of the final version to be published; ANG, JHS, CLK, LMV, KB, TB, MV, GC, SS, RO, VRH, CB ? collected data and assisted with processing and manuscript revision
Publisher Copyright:
© 2021 Elsevier Inc.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2022/1
Y1 - 2022/1
N2 - Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma. Wild type C57Bl6 mice (WT) and Nampt+/− heterozygous mice were exposed to 20Gy whole thoracic lung irradiation (WTLI) with or without weekly IP injection of IgG1 (control) or an eNAMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb). BAL protein/cells and H&E staining were used to generate a WTLI severity score. Differentially-expressed genes (DEGs)/pathways were identified by RNA sequencing and bioinformatic analyses. Radiation exposure increases in vitro NAMPT expression in lung epithelium (NAMPT promoter activity) and NAMPT lung tissue expression in WTLI-exposed mice. Nampt+/− mice and eNAMPT pAb/mAb-treated mice exhibited significant histologic attenuation of WTLI-mediated lung injury with reduced levels of BAL protein and cells, and plasma levels of eNAMPT, IL-6, and IL-1β. Genomic and biochemical studies from WTLI-exposed lung tissues highlighted dysregulation of NFkB/cytokine and MAP kinase signaling pathways which were rectified by eNAMPT mAb treatment. The eNAMPT/TLR4 pathway is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce the severity of radiation pneumonitis.
AB - Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma. Wild type C57Bl6 mice (WT) and Nampt+/− heterozygous mice were exposed to 20Gy whole thoracic lung irradiation (WTLI) with or without weekly IP injection of IgG1 (control) or an eNAMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb). BAL protein/cells and H&E staining were used to generate a WTLI severity score. Differentially-expressed genes (DEGs)/pathways were identified by RNA sequencing and bioinformatic analyses. Radiation exposure increases in vitro NAMPT expression in lung epithelium (NAMPT promoter activity) and NAMPT lung tissue expression in WTLI-exposed mice. Nampt+/− mice and eNAMPT pAb/mAb-treated mice exhibited significant histologic attenuation of WTLI-mediated lung injury with reduced levels of BAL protein and cells, and plasma levels of eNAMPT, IL-6, and IL-1β. Genomic and biochemical studies from WTLI-exposed lung tissues highlighted dysregulation of NFkB/cytokine and MAP kinase signaling pathways which were rectified by eNAMPT mAb treatment. The eNAMPT/TLR4 pathway is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce the severity of radiation pneumonitis.
UR - http://www.scopus.com/inward/record.url?scp=85110342396&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110342396&partnerID=8YFLogxK
U2 - 10.1016/j.trsl.2021.06.002
DO - 10.1016/j.trsl.2021.06.002
M3 - Article
C2 - 34139379
SN - 1931-5244
VL - 239
SP - 44
EP - 57
JO - Translational Research
JF - Translational Research
ER -