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Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome
Anub Mathew Thomas1, Camilla Schjalm1, Per H Nilsson1,2
1Department of Immunology, Oslo University Hospital and K.G. Jebsen IRC, University of Oslo, Oslo, Norway.
Background:
Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors.
Objectives:
To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model.
Methods:
Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA.
Results:
SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14.
Conclusion:
Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.
Insights
Combined inhibition of complement C5 and CD14 significantly reduces inflammation in a piglet model of meconium aspiration syndrome (MAS). This synergistic approach offers a promising new therapeutic strategy for MAS, a severe neonatal lung condition.
Area of Science:
- Neonatal Medicine
- Immunology
- Pulmonology
Background:
- Meconium aspiration syndrome (MAS) causes severe neonatal lung injury and systemic inflammation.
- Previous studies showed complement activation and cytokine release in MAS, with inflammation dependent on complement and Toll-like receptors.
- MAS can lead to a systemic inflammatory response, impacting newborn health.
Purpose of the Study:
- To evaluate the efficacy of combined C5 complement inhibition and CD14 blockade.
- To assess the impact on systemic inflammation in a piglet model of meconium aspiration syndrome (MAS).
Main Methods:
- Thirty piglets were randomized into a treatment group (C5 inhibitor SOBI002 + anti-CD14) and a control group.
- MAS was induced via intratracheal meconium instillation, with a 5-hour observation period.
- Complement, cytokines (IL-1β, IL-6), and myeloperoxidase (MPO) were measured.
Main Results:
- Combined C5 and CD14 inhibition effectively reduced IL-1β by 60% and IL-6 by 44%.
- Myeloperoxidase (MPO) activity in bronchoalveolar fluid decreased by 42% with combined treatment.
- Ex vivo studies showed synergistic effects, with minimal benefit from single inhibition.
Conclusions:
- Combined inhibition of C5 and CD14 effectively attenuates meconium-induced inflammation in vivo.
- This synergistic approach presents a potential future therapeutic regimen for meconium aspiration syndrome (MAS).
- The study highlights the crucial cross-talk between C5 and CD14 in MAS pathogenesis.
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