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Abstract: PO0428

The Immunomodulatory Effect of LMWF5A on Infiltrating Immune Cells Supports Its Clinical Use for AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Frederick, Elizabeth, Ampio Pharmacueticals, Englewood, Colorado, United States
  • Hausburg, Melissa, Swedish Medical Center, Englewood, Colorado, United States
  • Thomas, Gregory, Ampio Pharmacueticals, Englewood, Colorado, United States
  • Bar-Or, David, Swedish Medical Center, Englewood, Colorado, United States
Background

Infiltrating immune cells are critical to acute kidney injury (AKI) pathogenesis. They are activated to clear cellular debris, secrete pro-inflammatory mediators, and drive leukocyte recruitment, with a subsequent switch to produce anti-inflammatory mediators that promote tissue repair. However, dysregulated, continuous, or excessive immune activation can result in further tissue damage.

The <5kDa low molecular weight fraction of human serum albumin (LMWF5A) has anti-inflammatory/pro-resolution effects. This in vitro study aimed to evaluate the ability of LMWF5A to treat AKI by examining its effects on immune cells relevant to AKI.

Methods

Peripheral blood mononuclear cells (PBMC) were treated with vehicle control or LMWF5A and activated with lipopolysaccharide (LPS), LPS + interferon (IFN) γ, or interleukin (IL)-4 + IL-13. Media and total RNA were collected at 24h. Secreted molecules were analyzed using multiplex cytokine arrays or prostaglandin E2 (PGE2) ELISA, and differential gene expression was determined by mRNAseq. Data were then subjected to in silico interrogation of known AKI signaling pathways and comparison to public datasets featuring human AKI samples.

Results

Cytokine release by PBMC was significantly modulated by LMWF5A treatment. While cytokine profiles differed depending on stimulant, the most highly downregulated cytokines included C-X-C chemokine ligand 10, IFNγ, IL-10, IL-12, IL-17, monocyte chemoattractant protein (MCP)-1, and MCP-3 (n=3; p≤0.05), which have been implicated in AKI. In addition, the release of PGE2, which has been proven to be beneficial to kidney injury, was potentiated with LMWF5A treatment. In silico secretome and transcriptome analysis of LMWF5A-treated PBMC displayed predicted inhibition of pathways known to drive AKI, notably IFN and IL-17 signaling. Further, comparison to public human AKI biopsy data revealed that pathways activated by AKI were predicted to be significantly inhibited in LMWF5A-treated PBMC.

Conclusion

These data reflect the ability of LMWF5A to reduce inflammatory cytokines and shift the immune response towards resolution. Moreover, global regulation of pathways activated by AKI in kidney tissue are predicted to be inhibited by LMWF5A. This preliminary study suggests a potential role for LMWF5A as an effective AKI therapeutic.

Funding

  • Commercial Support