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

Autor: Dale J. Christensen, Vineet Bhandari, Stella M. Robertson, Beamon Agarwal, Suchismita Acharya, Pragnya Das, Dilip Shah
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Lipopolysaccharides
Male
0301 basic medicine
ARDS
Lipopolysaccharide
Chitin
Pharmacology
Rats
Sprague-Dawley
sepsis
lcsh:Chemistry
Mice
chemistry.chemical_compound
0302 clinical medicine
Medicine
Lung
lcsh:QH301-705.5
Spectroscopy
Hyperoxia
Respiratory Distress Syndrome
General Medicine
respiratory system
Pulmonary edema
Computer Science Applications
medicine.anatomical_structure
AVR-25
Female
medicine.symptom
Inflammation
Lung injury
Article
Catalysis
Small Molecule Libraries
Inorganic Chemistry
Sepsis
03 medical and health sciences
Animals
Immunologic Factors
pulmonary edema
Physical and Theoretical Chemistry
Molecular Biology
business.industry
Organic Chemistry
lung inflammation
Pneumonia
medicine.disease
Rats
respiratory tract diseases
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
chemistry
acute lung injury
lcsh:Biology (General)
lcsh:QD1-999
AVR-48
business
030215 immunology
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 2573, p 2573 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 5
ISSN: 1661-6596
1422-0067
Popis: 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
100µg) for 24h or exposed to hyperoxia (100% oxygen) for 48h 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.
Databáze: OpenAIRE
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