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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: 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. Methods/Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article number916159
JournalFrontiers in Physiology
Volume13
DOIs
StatePublished - Jun 22 2022

Keywords

  • ARDS
  • B-lines
  • DAMP
  • eNAMPT
  • mAb

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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