@article{4e6282988c4c4fcc94e8baeb66310553,
title = "Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody",
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.",
keywords = "Acute Lung Injury, Animals, Antibodies, Monoclonal, COVID-19, Humans, Mice, Mice, Inbred C57BL, SARS-CoV-2",
author = "Hector Quijada and Tadeo Bermudez and Kempf, {Carrie L.} and Valera, {Daniel G.} and Garcia, {Alexander N.} and Camp, {Sara M.} and Song, {Jin H.} and Evelyn Franco and Burt, {Jessica K.} and Belinda Sun and Mascarenhas, {Joseph B.} and Kimberlie Burns and Amir Gaber and Oita, {Radu C.} and {Reyes Hernon}, Vivian and Christy Barber and Liliana Moreno-Vinasco and Xiaoguang Sun and Cress, {Anne E.} and Diego Martin and Zhonglin Liu and Desai, {Ankit A.} and Viswanathan Natarajan and Jacobson, {Jeffrey R.} and Dudek, {Steven M.} and Christian Bime and Saad Sammani and Garcia, {Joe G.N.}",
note = "Funding Information: Author contributions: J.G.N. Garcia and S. Sammani: 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; C. Bime, A.E. Cress, Z. Liu and D. Martin: 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; T. Bermudez, S.M. Camp, A.N. Garcia, C.L. Kempf, H. Quijada, D.G. Valera and J.H. Song: collection and analysis of data, revision of the manuscript, and approval of the final version to be published; C. Barber, K. Burns, J.K. Burt, A.A. Desai, S.M. Dudek, E. Franco, A. Gaber, J.R. Jacobson, J.B. Mascarenhas, L. Moreno-Vinasco, V. Natarajan, R.C. Oita, V. Reyes Hernon, B. Sun and X. Sun: collected data and assisted with processing and manuscript revision Conflict of interest: H. Quijada has nothing to disclose. T. Bermudez has nothing to disclose. C.L. Kempf has nothing to disclose. D.G. Valera has nothing to disclose. A.N. Garcia has nothing to disclose. S.M. Camp has nothing to disclose. J.H. Song has nothing to disclose. E. Franco has nothing to disclose. J.K. Burt has nothing to disclose. B. Sun has nothing to disclose. J.B. Mascarenhas has nothing to disclose. K. Burns has nothing to disclose. A. Gaber has nothing to disclose. R.C. Oita has nothing to disclose. V. Reyes Hernon has nothing to disclose. C. Barber has nothing to disclose. L. Moreno-Vinasco has nothing to disclose. X. Sun has nothing to disclose. A.E. Cress has nothing to disclose. D. Martin has investments in Aqualung, outside the submitted work. Z. Liu has nothing to disclose. A.A. Desai reports grants from NIH R01 (HL136603) and consultancy for Novartis, outside the submitted work. V. Natarajan has nothing to disclose. J.R. Jacobson has nothing to disclose. S.M. Dudek has nothing to disclose. C. Bime has nothing to disclose. S. Sammani has nothing to disclose. J.G.N. Garcia reports grants and non-financial support (provision of research materials) from Aqualung Therapeutics, Corp., during the conduct of the study; grants and personal fees from Aqualung Therapeutics, Corp., outside the submitted work; and has a US Patent No. 9,409,983 issued. Funding Information: Support statement: This work was supported by the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grants P01HL126609, R01HL094394 and P01HL134610. Funding information for this article has been deposited with the Crossref Funder Registry. Publisher Copyright: Copyright {\textcopyright} ERS 2021.",
year = "2021",
month = may,
day = "1",
doi = "10.1183/13993003.02536-2020",
language = "English (US)",
volume = "57",
journal = "Eur Respir J",
number = "5",
}