Effects of the New Generation Synthetic Reconstituted Surfactant CHF5633 on Pro- and Anti-Inflammatory Cytokine Expression in Native and LPS-Stimulated Adult CD14+ Monocytes

Abstract

BackgroundSurfactant replacement therapy is the standard of care for the prevention and treatment of neonatal respiratory distress syndrome. New generation synthetic surfactants represent a promising alternative to animal-derived surfactants. CHF5633, a new generation reconstituted synthetic surfactant containing SP-B and SP-C analogs and two synthetic phospholipids has demonstrated biophysical effectiveness in vitro and in vivo. While several surfactant preparations have previously been ascribed immunomodulatory capacities, in vitro data on immunomodulation by CHF5633 are limited, so far. Our study aimed to investigate pro- and anti-inflammatory effects of CHF5633 on native and LPS-stimulated human adult monocytes.MethodsHighly purified adult CD14+ cells, either native or simultaneously stimulated with LPS, were exposed to CHF5633, its components, or poractant alfa (Curosurf®). Subsequent expression of TNF-α, IL-1β, IL-8 and IL-10 mRNA was quantified by real-time quantitative PCR, corresponding intracellular cytokine synthesis was analyzed by flow cytometry. Potential effects on TLR2 and TLR4 mRNA and protein expression were monitored by qPCR and flow cytometry.ResultsNeither CHF5633 nor any of its components induced inflammation or apoptosis in native adult CD14+ monocytes. Moreover, LPS-induced pro-inflammatory responses were not aggravated by simultaneous exposure of monocytes to CHF5633 or its components. In LPS-stimulated monocytes, exposure to CHF5633 led to a significant decrease in TNF-α mRNA (0.57 ± 0.23-fold, p = 0.043 at 4h; 0.56 ± 0.27-fold, p = 0.042 at 14h). Reduction of LPS-induced IL-1β mRNA expression was not significant (0.73 ± 0.16, p = 0.17 at 4h). LPS-induced IL-8 and IL-10 mRNA and protein expression were unaffected by CHF5633. For all cytokines, the observed CHF5633 effects paralleled a Curosurf®-induced modulation of cytokine response. TLR2 and TLR4 mRNA and protein expression were not affected by CHF5633 and Curosurf®, neither in native nor in LPS-stimulated adult monocytes.ConclusionThe new generation reconstituted synthetic surfactant CHF5633 was tested for potential immunomodulation on native and LPS-activated adult human monocytes. Our data confirm that CHF5633 does not exert unintended pro-inflammatory effects in both settings. On the contrary, CHF5633 significantly suppressed TNF-α mRNA expression in LPS-stimulated adult monocytes, indicating potential anti-inflammatory effects.

Surface Active Agents and Their Health-Promoting Properties: Molecules of Multifunctional Significance

“…CHF5633 has been thoroughly examined for its ability to elicit an anti-inflammatory response in naive or activated neonatal or adult monocytes. In each model used, CHF5633 decreased the expression of the inflammatory mediators like tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), but had no effect on the expression levels of interleukin-8, -10, Toll-like receptor 2 (TLR2) and 4 (TLR-4) [ 143 , 144 ]. Similarly, the activated CD4+T human lymphocytes that were exposed to CHF5633 exhibited higher transcriptional levels of the anti-inflammatory cytokines, interleukin-4 and -10 [ 145 ].…”

Cerebral and lung effects of a new generation synthetic surfactant with SP‐B and SP‐C analogs in preterm lambs

“…4,5,20 As expected, in our preterm lambs, the improvement in oxygenation, V T and C dyn was very fast at 30 min after both SF treatments, suggesting quite similar distributions of SF to that observed in earlier studies. 4,5 Moreover, we should recall that CHF5633 contains both an SP-B analog in which methionine in the original SP-B sequence has been replaced by leucine, to increase resistance to oxidation processes, and POPG, which has been described to have anti-inflammatory properties, [23][24][25] hemorrhage. 10 However, the influence of hypercapnia on the brain of premature neonates depends on the speed of onset, degree, and duration of P aCO2 elevation, hypoxia, or ischemia, and intracranial disease or other complications.…”

New Generation Surfactants, Are They A Hope For Better Outcomes?

“…CHF5633 did not exert unintended proinflammatory effects in both settings. On the contrary, CHF5633 significantly suppressed TNF-α mRNA expression in LPS-stimulated adult monocytes, indicating potential anti-inflammatory effects (49).…”