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Open AccessArticle

Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)

1
Division of Neonatology, Department of Pediatrics, Drexel University, Philadelphia, PA 19197, USA
2
AyuVis Research, Inc., 1120 South Freeway, Fort Worth, TX 76104, USA
3
Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76104, USA
4
GenomeRxUS, Secane, PA 19018, USA
5
Dale J. Christensen Consulting LLC, Cary, NC 27511, USA
6
Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC 27722, USA
7
Arrochar Consulting LLC, Fort Worth, TX 76104, USA
*
Author to whom correspondence should be addressed.
Current affiliation: Division of Neonatology, Department of Pediatrics, The Children’s Regional Hospital at Cooper, Camden, NJ 08103, USA.
These authors contributed equally to this work.
Academic Editor: Cecilia Prata
Int. J. Mol. Sci. 2021, 22(5), 2573; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052573
Received: 5 February 2021 / Revised: 25 February 2021 / Accepted: 27 February 2021 / Published: 4 March 2021
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. View Full-Text
Keywords: lung inflammation; acute lung injury; pulmonary edema; sepsis; AVR-25; AVR-48 lung inflammation; acute lung injury; pulmonary edema; sepsis; AVR-25; AVR-48
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MDPI and ACS Style

Shah, D.; Das, P.; Acharya, S.; Agarwal, B.; Christensen, D.J.; Robertson, S.M.; Bhandari, V. Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS). Int. J. Mol. Sci. 2021, 22, 2573. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052573

AMA Style

Shah D, Das P, Acharya S, Agarwal B, Christensen DJ, Robertson SM, Bhandari V. Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS). International Journal of Molecular Sciences. 2021; 22(5):2573. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052573

Chicago/Turabian Style

Shah, Dilip; Das, Pragnya; Acharya, Suchismita; Agarwal, Beamon; Christensen, Dale J.; Robertson, Stella M.; Bhandari, Vineet. 2021. "Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)" Int. J. Mol. Sci. 22, no. 5: 2573. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052573

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