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.
Abstract
Underscoring the therapeutic potential for targeting the eNAMPT/TLR4 pathway in ARDS/VILI, a humanised eNAMPT-neutralising monoclonal antibody (mAb) was highly effective in reducing the severity of ARDS in these dual complementary pre-clinical ARDS models https://bit.ly/3ljEhBD
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.04588-2020
This article has supplementary material available from erj.ersjournals.com
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.
Conflict of interest: T. Bermudez has nothing to disclose.
Conflict of interest: C.L. Kempf has nothing to disclose.
Conflict of interest: D.G. Valera has nothing to disclose.
Conflict of interest: A.N. Garcia has nothing to disclose.
Conflict of interest: S.M. Camp has nothing to disclose.
Conflict of interest: J.H. Song has nothing to disclose.
Conflict of interest: E. Franco has nothing to disclose.
Conflict of interest: J.K. Burt has nothing to disclose.
Conflict of interest: B. Sun has nothing to disclose.
Conflict of interest: J.B. Mascarenhas has nothing to disclose.
Conflict of interest: K. Burns has nothing to disclose.
Conflict of interest: A. Gaber has nothing to disclose.
Conflict of interest: R.C. Oita has nothing to disclose.
Conflict of interest: V. Reyes Hernon has nothing to disclose.
Conflict of interest: C. Barber has nothing to disclose.
Conflict of interest: L. Moreno-Vinasco has nothing to disclose.
Conflict of interest: X. Sun has nothing to disclose.
Conflict of interest: A.E. Cress has nothing to disclose.
Conflict of interest: D. Martin has investments in Aqualung, outside the submitted work.
Conflict of interest: Z. Liu has nothing to disclose.
Conflict of interest: A.A. Desai reports grants from NIH R01 (HL136603) and consultancy for Novartis, outside the submitted work.
Conflict of interest: V. Natarajan has nothing to disclose.
Conflict of interest: J.R. Jacobson has nothing to disclose.
Conflict of interest: S.M. Dudek has nothing to disclose.
Conflict of interest: C. Bime has nothing to disclose.
Conflict of interest: S. Sammani has nothing to disclose.
Conflict of interest: 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.
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.
- Received June 27, 2020.
- Accepted November 5, 2020.
- Copyright ©ERS 2021
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