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Efficacy of synthetic surfactant (CHF5633) bolus and/or lavage in meconium-induced lung injury in ventilated newborn rabbits

Pediatric Research volume 93, pages 541–550 (2023)Cite this article

Abstract

Background

The pathogenesis of neonatal meconium aspiration syndrome (MAS) involves meconium-induced lung inflammation and surfactant inactivation. Bronchoalveolar lavage (BAL) with diluted surfactant facilitates the removal of meconium. CHF5633, one of the most promising synthetic surfactants, is effective in neonatal respiratory distress syndrome. Here we investigated its efficacy via BAL in an experimental MAS model.

Methods

Experimental MAS was induced at birth in near-term newborn rabbits by intratracheal instillation of reconstituted human meconium. First, undiluted CHF5633 was compared with a porcine-derived surfactant (Poractant alfa) via intratracheal bolus (200 mg/kg). Second, the efficacy of BAL with diluted CHF5633 (5 mg/mL, 20 ml/kg) alone, or followed by undiluted boluses (100 or 300 mg/kg), was investigated.

Results

Meconium instillation caused severe lung injury, reduced endogenous surfactant pool, and poor survival. CHF5633 had similar benefits in improving survival and alleviating lung injury as Poractant alfa. CHF5633 BAL plus higher boluses exerted better effects than BAL or bolus alone in lung injury alleviation by reversing phospholipid pools and mitigating proinflammatory cytokine mRNA expression, without fluid retention and function deterioration.

Conclusions

CHF5633 improved survival and alleviated meconium-induced lung injury, the same as Poractant alfa. CHF5633 BAL plus boluses was the optimal modality, which warrants further clinical investigation.

Impact

  • To explore the efficacy of a synthetic surfactant, CHF5633, in neonatal lung protection comparing with Poractant alfa in a near-term newborn rabbit model with meconium-induced lung injury.

  • Similar effects on improving survival and alleviating lung injury were found between CHF5633 and Poractant alfa.

  • Optimal therapeutic effects were identified from the diluted CHF5633 bronchoalveolar lavage followed by its undiluted bolus instillation compared to the lavage or bolus alone regimens.

  • Animals with CHF5633 lavage plus bolus regimen exerted neither substantial lung fluid retention nor lung mechanics deterioration but a trend of higher pulmonary surfactant-associated phospholipid pools.

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Fig. 1: Experimental Phase I. Methodology, survival, lung function, and serum lactate.
Fig. 2: Experimental Phase I. Lung injury and morphometry.
Fig. 3: Experimental Phase I. Analysis of phospholipids and associated phospholipase in bronchoalveolar lavage fluid.
Fig. 4: Experimental Phase II. Methodology, survival, lung function, and serum lactate.
Fig. 5: Experimental Phase II. Lung injury and morphometry.
Fig. 6: Experimental Phase II. Analysis of phospholipids and associated phospholipase in bronchoalveolar lavage fluid.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We cordially thank the parents for generous donation of their babies’ meconium, and Dr. Hongyi He and Dr. Yangyang Ma for kind advice in the measurements of lung histology and morphometry.

Funding

This research was supported by Chiesi Farmaceutici S.p.A. The company contributed to the study design but had no influence in the performance, analysis, and interpretation of experimental data and in writing the manuscript. B.S. is a recipient of research grants from Laboratory of Neonatal Diseases, National Commission of Health, and Children’s Hospital of Fudan University.

Author information

Authors and Affiliations

  1. The Laboratory of Neonatal Diseases of National Commission of Health; National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China

    Yaling Xu, Xiaojing Guo, Meimei Chen & Bo Sun

  2. Neonatology and Pulmonary Rare Disease Unit, Pharmacology & Toxicology Department, Corporate Preclinical R&D, CHIESI, Parma, Italy

    Francesca Ricci & Fabrizio Salomone

  3. Scientific Consultancy, Bilbao, Spain

    Xabier Murgia

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  1. Yaling Xu
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Contributions

Y.X. performed animal experiments, analyzed data, and drafted the manuscript; X.G. and M.C. contributed to animal experiments and data analysis; F.R., F.S., and X.M. conceptualized the study plan, supervised experiment protocol, and reviewed and modified manuscript; B.S. conceptualized the study plan, designed the experiment, interpreted the data, and edited and finalized the manuscript. All the authors agreed and approved this version to be submitted for publication.

Corresponding author

Correspondence to Bo Sun.

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Competing interests

This research was supported by Chiesi Farmaceutici S.p.A, which owns the marketing rights for Poractant alfa and patent rights of CHF5633. F.R. and F.S. are Chiesi Farmaceutici employees. X.M. is a Chiesi consultant. The company contributed to the study design but had neither influence on the performance, analysis, and interpretation of experimental data nor in writing the manuscript.

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Xu, Y., Guo, X., Chen, M. et al. Efficacy of synthetic surfactant (CHF5633) bolus and/or lavage in meconium-induced lung injury in ventilated newborn rabbits. Pediatr Res 93, 541–550 (2023). https://doi.org/10.1038/s41390-022-02152-2

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