Synthetic surfactant with a recombinant surfactant protein C analogue improves lung function and attenuates inflammation in a model of acute respiratory distress syndrome in adult rabbits

Abstract

Aim: In acute respiratory distress syndrome (ARDS) damaged alveolar epithelium, leakage of plasma proteins into the alveolar space and inactivation of pulmonary surfactant lead to respiratory dysfunction. Lung function could potentially be restored with exogenous surfactant therapy, but clinical trials have so far been disappointing. These negative results may be explained by inactivation and/or too low doses of the administered surfactant. Surfactant based on a recombinant surfactant protein C analogue (rSP-C33Leu) is easy to produce and in this study we compared its effects on lung function and inflammation with a commercial surfactant preparation in an adult rabbit model of ARDS. Methods: ARDS was induced in adult New Zealand rabbits by mild lung-lavages followed by injurious ventilation (V T 20 m/kg body weight) until P/F ratio < 26.7 kPa. The animals were treated with two intratracheal boluses of 2.5 mL/kg of 2% rSP-C33Leu in DPPC/egg PC/POPG, 50:40:10 or poractant alfa (Curosurf®), both surfactants containing 80 mg phospholipids/mL, or air as control. The animals were subsequently ventilated (V T 8-9 m/kg body weight) for an additional 3 h and lung function parameters were recorded. Histological appearance of the lungs, degree of lung oedema and levels of the cytokines TNFα IL-6 and IL-8 in lung homogenates were evaluated. Results: Both surfactant preparations improved lung function vs. the control group and also reduced inflammation scores, production of pro-inflammatory cytokines, and formation of lung oedema to similar degrees. Poractant alfa improved compliance at 1 h, P/F ratio and PaO 2 at 1.5 h compared to rSP-C33Leu surfactant. Conclusion: This study indicates that treatment of experimental ARDS with synthetic lung surfactant based on rSP-C33Leu improves lung function and attenuates inflammation.

Impact of synthetic surfactant CHF5633 with SP‐B and SP‐C analogues on lung function and inflammation in rabbit model of acute respiratory distress syndrome

“…Within the first 30 min after administration, we observed rapid improvement in P/F, OI, AaG, and SaO 2 compared to control animals and this effect persisted until the end of experiment (Figure 1). Similar results were shown in previous studies of surfactant therapy in animal models of ARDS (Lutz et al, 1998; Nieman et al, 1996; Sun et al, 1996; Zebialowicz Ahlstrom et al, 2019). In a first‐in‐human clinical study of neonatal RDS, CHF5633 was efficacious, resulting in sustained improvements in oxygenation that occurred immediately after instillation.…”

“…After induction of ARDS, the animals were placed in prone position to increase homogeneity of ventilation and to improve gas exchange (Scholten et al, 2017). Despite this intervention, the lung function parameters of the control group, such as P/F, OI, AaG, and SaO 2 , remained deteriorated until the end of experiment (Figure 1), similarly to results obtained in previous studies (Kalk et al, 2008; Kamiyama et al, 2015; Ricci, Catozzi, et al, 2017; Zebialowicz Ahlstrom et al, 2019). Once the criteria of ARDS (P/F < 26.7 kPa) were fulfilled, surfactant therapy was administered as a bolus intratracheally and animals were ventilated for additional 4 hours.…”

“…Several randomized clinical trials of ARDS treatment with systemic glucocorticoids and exogenous surfactant have been conducted; however, conclusive support for efficacy has not been obtained (Dushianthan et al, 2012; Marik et al, 2008; Meng et al, 2012; Ruan et al, 2014). Using both natural and synthetic surfactant preparations, randomized clinical trials generally have shown improvements in oxygenation indices but have failed to produce any demonstrable survival benefits (Meng et al, 2012), even though the response to exogenous surfactant in direct lung injury preclinical studies has been promising (Bezerra et al, 2019; Kopincova et al, 2018; Mikolka et al, 2016; Zebialowicz Ahlstrom et al, 2019). Possible reasons for this failure of a potentially successful treatment include differences in surfactant composition, drug delivery methods, and variability in surfactant biology among the target population (Dushianthan et al, 2012).…”

“…The animals were instrumented as previously described (Zebialowicz Ahlstrom et al, 2019). After initial anesthesia, tracheotomy was performed and left and right marginal ear veins and left ear artery were cannulated for continuous intravenous (i.v.)…”

“…Experimental ARDS was induced by a two‐hit model: repetitive mild lung lavages resulting in minimal surfactant depletion followed by high‐tidal volume injurious ventilation (Zebialowicz Ahlstrom et al, 2019). The lavages were performed with warm saline (5 mL/kg, 37°C) followed by suction and the process was repeated in total four times with stabilization periods in between (duration depending on SatO 2 ), until P/F ratio decreased to <70 kPa.…”