AUTHOR=Sammani Saad , Bermudez Tadeo , Kempf Carrie L. , Song Jin H. , Fleming Justin C , Reyes Hernon Vivian , Hufford Matthew , Tang Lin , Cai Hua , Camp Sara M. , Natarajan Viswanathan , Jacobson Jeffrey R. , Dudek Steven M. , Martin Diego R. , Karmonik Christof , Sun Xiaoguang , Sun Belinda , Casanova Nancy G. , Bime Christian , Garcia Joe G. N. 

TITLE=eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury

JOURNAL=Frontiers in Physiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.916159

DOI=10.3389/fphys.2022.916159

ISSN=1664-042X

ABSTRACT=<p><bold>Background:</bold> Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury.</p><p><bold>Methods/Results:</bold> Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS.</p><p><bold>Conclusions:</bold> These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.</p>