Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody
dc.contributor.author | Quijada, Hector | |
dc.contributor.author | Bermudez, Tadeo | |
dc.contributor.author | Kempf, Carrie L. | |
dc.contributor.author | Valera, Daniel G. | |
dc.contributor.author | Garcia, Alexander N. | |
dc.contributor.author | Camp, Sara M. | |
dc.contributor.author | Song, Jin H. | |
dc.contributor.author | Franco, Evelyn | |
dc.contributor.author | Burt, Jessica K. | |
dc.contributor.author | Sun, Belinda | |
dc.contributor.author | Mascarenhas, Joseph B. | |
dc.contributor.author | Burns, Kimberlie | |
dc.contributor.author | Gaber, Amir | |
dc.contributor.author | Oita, Radu C. | |
dc.contributor.author | Reyes Hernon, Vivian | |
dc.contributor.author | Barber, Christy | |
dc.contributor.author | Moreno-Vinasco, Liliana | |
dc.contributor.author | Sun, Xiaoguang | |
dc.contributor.author | Cress, Anne E. | |
dc.contributor.author | Martin, Diego | |
dc.contributor.author | Liu, Zhonglin | |
dc.contributor.author | Desai, Ankit A. | |
dc.contributor.author | Natarajan, Viswanathan | |
dc.contributor.author | Jacobson, Jeffrey R. | |
dc.contributor.author | Dudek, Steven M. | |
dc.contributor.author | Bime, Christian | |
dc.contributor.author | Sammani, Saad | |
dc.contributor.author | Garcia, Joe G.N. | |
dc.contributor.department | Medicine, School of Medicine | |
dc.date.accessioned | 2024-03-26T15:38:42Z | |
dc.date.available | 2024-03-26T15:38:42Z | |
dc.date.issued | 2021-05-06 | |
dc.description.abstract | Rationale: The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target. Methods: Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo. Results: Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models. Conclusions: These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Quijada H, Bermudez T, Kempf CL, et al. Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody. Eur Respir J. 2021;57(5):2002536. Published 2021 May 6. doi:10.1183/13993003.02536-2020 | |
dc.identifier.uri | https://hdl.handle.net/1805/39540 | |
dc.language.iso | en_US | |
dc.publisher | European Respiratory Society | |
dc.relation.isversionof | 10.1183/13993003.02536-2020 | |
dc.relation.journal | European Respiratory Journal | |
dc.rights | Attribution-NonCommercial 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | |
dc.source | PMC | |
dc.subject | Acute lung injury | |
dc.subject | Monoclonal antibodies | |
dc.subject | COVID-19 | |
dc.subject | SARS-CoV-2 | |
dc.title | Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody | |
dc.type | Article |