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

Dilip Shah,Stella M Robertson,Suchismita Acharya,Pragnya Das,Beamon Agarwal,Dale J Christensen,Vineet Bhandari

doi:10.3390/ijms22052573

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.

Highlights

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with a variety of insults, including massive hemorrhage, systemic bacterial or viral infection, inhalation of noxious agents, burns, and blast trauma, and have an overall mortality of 30–40% [1]
Here, the safety and PK profiling of compound AVR-48 to determine the maximum tolerated dose (MTD) and drug concentration in plasma and bronchoalveolar lavage fluid (BALF) in rats, as we wanted to use this compound as a candidate drug for ARDS
Our studies show that the treatment of LPS or hyperoxia-induced ALI mice with either AVR-25 or AVR-48 results in decreased lung inflammation, cell death, and improved pulmonary endothelial barrier function with overall recovery in pulmonary edema and injury

Summary

Introduction

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with a variety of insults, including massive hemorrhage, systemic bacterial or viral infection, inhalation of noxious agents, burns, and blast trauma, and have an overall mortality of 30–40% [1]. 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. 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

Objectives

Methods

Conclusion