Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)
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 eff...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/5/2573 |
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| author | Dilip Shah Pragnya Das Suchismita Acharya Beamon Agarwal Dale J. Christensen Stella M. Robertson Vineet Bhandari |
| author_facet | Dilip Shah Pragnya Das Suchismita Acharya Beamon Agarwal Dale J. Christensen Stella M. Robertson Vineet Bhandari |
| author_sort | Dilip Shah |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T05:32:14Z |
| format | Article |
| id | doaj.art-5cc4efff5a464815bbe90c04f2d88809 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:32:14Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5cc4efff5a464815bbe90c04f2d888092023-12-03T12:31:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01225257310.3390/ijms22052573Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)Dilip Shah0Pragnya Das1Suchismita Acharya2Beamon Agarwal3Dale J. Christensen4Stella M. Robertson5Vineet Bhandari6Division of Neonatology, Department of Pediatrics, Drexel University, Philadelphia, PA 19197, USADivision of Neonatology, Department of Pediatrics, Drexel University, Philadelphia, PA 19197, USAAyuVis Research, Inc., 1120 South Freeway, Fort Worth, TX 76104, USAGenomeRxUS, Secane, PA 19018, USADale J. Christensen Consulting LLC, Cary, NC 27511, USAAyuVis Research, Inc., 1120 South Freeway, Fort Worth, TX 76104, USADivision of Neonatology, Department of Pediatrics, Drexel University, Philadelphia, PA 19197, USABackground: 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.https://www.mdpi.com/1422-0067/22/5/2573lung inflammationacute lung injurypulmonary edemasepsisAVR-25AVR-48 |
| spellingShingle | Dilip Shah Pragnya Das Suchismita Acharya Beamon Agarwal Dale J. Christensen Stella M. Robertson Vineet Bhandari 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 lung inflammation acute lung injury pulmonary edema sepsis AVR-25 AVR-48 |
| title | Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) |
| title_full | Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) |
| title_fullStr | Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) |
| title_full_unstemmed | Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) |
| title_short | Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) |
| title_sort | small immunomodulatory molecules as potential therapeutics in experimental murine models of acute lung injury ali acute respiratory distress syndrome ards |
| topic | lung inflammation acute lung injury pulmonary edema sepsis AVR-25 AVR-48 |
| url | https://www.mdpi.com/1422-0067/22/5/2573 |
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