Dataset Information

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

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.

SUBMITTER: Shah D

PROVIDER: S-EPMC7961996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a critical condition that is associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far.This review was originally published in 2010 and updated in 2017.ObjectivesTo assess the benefits and harms of aerosolized prostacyclin in adults and children with ARDS.Search methodsIn this update, we searched CENTRAL (2017, Issue 4); MEDLINE (OvidSP), Embase (OvidSP), ISI BIOSIS Previews, ISI Web of Science, LILACS, CINAHL (EBSCOhost), and three trials registers. We handsearched the reference lists of the latest reviews, randomized and non-randomized trials, and editorials, and cross-checked them with our search of MEDLINE. We contacted the main authors of included studies to request any missed, unreported or ongoing studies. The search was run from inception to 5 May 2017.Selection criteriaWe included all randomized controlled trials (RCTs), irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted trial investigators and study authors to retrieve relevant and missing data.Data collection and analysisThree authors independently abstracted data and resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We planned to perform subgroup and sensitivity analyses to assess the effect of aerosolized prostacyclin in adults and children, and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of methodological trial components and the risk of random error through trial sequential analysis.Main resultsWe included two RCTs with 81 participants.One RCT involved 14 critically ill children with ARDS (very low quality of evidence), and one RCT involved 67 critically ill adults (very low quality evidence).Only one RCT (paediatric trial) provided data on mortality and found no difference between intervention and control. However, this trial was eligible for meta-analysis due to a cross-over design.We assessed the benefits and harms of aerosolized prostacyclin. One RCT found no difference in improvement of partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio (mean difference (MD) -25.35, 95% confidence interval (CI) -60.48 to 9.78; P = 0.16; 67 participants, very low quality evidence).There were no adverse events such as bleeding or organ dysfunction in any of the included trials. Due to the limited number of RCTs, we were unable to perform the prespecified subgroup and sensitivity analyses or trial sequential analysis.Authors' conclusionsWe are unable to tell from our results whether the intervention has an important effect on mortality because the results were too imprecise to rule out a small or no effect. Therefore, no current evidence supports or refutes the routine use of aerosolized prostacyclin for people with ARDS. There is an urgent need for more RCTs.