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Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS).
Shah, Dilip; Das, Pragnya; Acharya, Suchismita; Agarwal, Beamon; Christensen, Dale J; Robertson, Stella M; Bhandari, Vineet.
  • Shah D; Division of Neonatology, Department of Pediatrics, Drexel University, Philadelphia, PA 19197, USA.
  • Das P; Division of Neonatology, Department of Pediatrics, Drexel University, Philadelphia, PA 19197, USA.
  • Acharya S; AyuVis Research, Inc., 1120 South Freeway, Fort Worth, TX 76104, USA.
  • Agarwal B; Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76104, USA.
  • Christensen DJ; GenomeRxUS, Secane, PA 19018, USA.
  • Robertson SM; Dale J. Christensen Consulting LLC, Cary, NC 27511, USA.
  • Bhandari V; Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC 27722, USA.
Int J Mol Sci ; 22(5)2021 Mar 04.
Article in English | MEDLINE | ID: covidwho-1129732
ABSTRACT

BACKGROUND:

Acute lung injury (ALI) or its most advanced form, acute respiratory distress syndrome (ARDS) is a severe inflammatory pulmonary process triggered by a variety of insults including sepsis, viral or bacterial pneumonia, and mechanical ventilator-induced trauma. Currently, there are no effective therapies available for ARDS. We have recently reported that a novel small molecule AVR-25 derived from chitin molecule (a long-chain polymer of N-acetylglucosamine) showed anti-inflammatory effects in the lungs. The goal of this study was to determine the efficacy of two chitin-derived compounds, AVR-25 and AVR-48, in multiple mouse models of ALI/ARDS. We further determined the safety and pharmacokinetic (PK) profile of the lead compound AVR-48 in rats.

METHODS:

ALI in mice was induced by intratracheal instillation of a single dose of lipopolysaccharide (LPS; 100 µg) for 24 h or exposed to hyperoxia (100% oxygen) for 48 h or undergoing cecal ligation and puncture (CLP) procedure and observation for 10 days.

RESULTS:

Both chitin derivatives, AVR-25 and AVR-48, showed decreased neutrophil recruitment and reduced inflammation in the lungs of ALI mice. Further, AVR-25 and AVR-48 mediated diminished lung inflammation was associated with reduced expression of lung adhesion molecules with improvement in pulmonary endothelial barrier function, pulmonary edema, and lung injury. Consistent with these results, CLP-induced sepsis mice treated with AVR-48 showed a significant increase in survival of the mice (80%) and improved lung histopathology in the treated CLP group. AVR-48, the lead chitin derivative compound, demonstrated a good safety profile.

CONCLUSION:

Both AVR-25 and AVR-48 demonstrate the potential to be developed as therapeutic agents to treat ALI/ARDS.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Respiratory Distress Syndrome / Small Molecule Libraries / Acute Lung Injury / Immunologic Factors Type of study: Observational study / Prognostic study Topics: Vaccines Limits: Animals Language: English Year: 2021 Document Type: Article Affiliation country: Ijms22052573

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Respiratory Distress Syndrome / Small Molecule Libraries / Acute Lung Injury / Immunologic Factors Type of study: Observational study / Prognostic study Topics: Vaccines Limits: Animals Language: English Year: 2021 Document Type: Article Affiliation country: Ijms22052573