KL4-Surfactant (Lucinactant) Protects Human Airway Epithelium from Hyperoxia

Abstract

Exogenous surfactant is critical in the treatment of neonates with respiratory distress syndrome. Lucinactant (Surfaxin; Discovery Laboratories, Inc.) is a surfactant replacement therapy containing sinulpeptide, which may reduce lung inflammation. This study tested whether Lucinactant reduces markers of inflammation, damage and remodeling in human airway epithelial cells exposed to hyperoxia. Calu-3 monolayers cultured at an air-liquid interface were treated apically with 140 L of normal saline, Lucinactant or Beractant (Survanta; Abbott Laboratories, Inc.). Treated monolayers were exposed to 60% O 2 /5% CO 2 for 24 or 72 h. Transepithelial resistance (TER; p Ͻ 0.001) and cell viability (p Ͻ 0.05) were greater in both surfactant groups compared with saline; by 72 h Lucinactant cells had greater TER than Beractant (p Ͻ 0.001). Surfactant treated groups secreted less IL-8 than saline (p Ͻ 0.001), whereas Lucinactant cells secreted less IL-6 than saline and Beractant (p Ͻ 0.001). P reterm birth is complicated by respiratory distress syndrome (RDS), a condition that threatens survival in this population. In the preterm infant, decreased lung compliance and neonatal RDS are related to deficiencies in the lung surfactant pool (1). In addition, deficiencies in antioxidants (2,3) and antiinflammatory modulators (4,5) potentially worsen RDS and lead to development of chronic lung disease, most notably bronchopulmonary dysplasia (BPD).RDS necessitates life-sustaining treatment with supplemental oxygen and mechanical ventilation. These therapies independently have been shown to injure the lung and are implicated in the pathogenesis of BPD (6). Surfactant replacement therapy has become standard of care for preventing and treating RDS (7,8). Although effective at acutely improving lung mechanics, oxygenation, and reducing mortality, surfactant replacement therapy has been linked to exaggerated inflammatory responses (9,10) and has not significantly impacted the incidence of BPD.Lung inflammation in RDS is central to the pathogenesis of BPD (11), and is a complex process involving upregulation of proinflammatory cytokines, including IL-6 and IL-8, and influx of inflammatory cells to the airways (7). Neonatal deficiencies in antioxidants and antiinflammatory modulators favor a proinflammatory process that furthers epithelial injury and pulmonary remodeling by activated matrix modeling proteins such as matrix metalloproteinases (MMPs). MMPs released by injured cells contribute to greater microvascular permeability and release matrix components that function as proinflammatory mediators or growth factors to further inflammation and remodeling (12). MMP activity in the lung and airways has been associated with fibrotic lung diseases, including BPD (13,14).Surfactant-associated proteins play important roles in maintaining pulmonary homeostasis. Deficiency of surfactantassociated proteins causes severe respiratory distress, and in the case of surfactant protein B (SP-B), is incompatible with life (15). SP-B is a hydrophob...

A pilot, randomized, controlled clinical trial of lucinactant, a peptide-containing synthetic surfactant, in infants with acute hypoxemic respiratory failure

“…The replenishment of the phospholipid pool and the presence of an SP-B mimic are essential for full biophysical and biological activity of the surfactant system, subsequent recruitment of alveoli, and ultimately better lung compliance and oxygenation. Additionally, lucinactant has been shown in preclinical models to modulate inflammatory processes following ALI and reduce plasma protein and neutrophil influx into the alveolar space, in addition to showing resistance to inactivation by plasma proteins and reactive oxidant species (36)(37)(38)(39)(40).…”

“…Potential benefits of lucinactant include its synthetic nature, resistance to inactivation by plasma proteins and oxidant species (36)(37)(38), and potential modulation of the pulmonary inflammatory response (39,40). We hypothesized that administration of surfactant to infants on MV with AHRF is safe and would improve clinical outcomes and reduce the duration of MV.…”

Beneficial effects of synthetic KL4surfactant in experimental lung transplantation

“…Thus, increased CRP levels in BAL of untreated transplanted lungs might be produced locally by alveolar macrophages [34] and/ or epithelial cells [35,36], as production of CRP by these cells is upregulated by proinflammatory stimuli [34][35][36]. The fact that KL 4 surfactant reduced CRP levels, and lipid and protein oxidation in the alveolar compartment suggests that KL 4 surfactant might modulate the activation of alveolar cells and inflammation, as has been previously demonstrated in human airway epithelial cells exposed to hyperoxia [37].…”

A Pharmacoeconomic Analysis of In-Hospital Costs Resulting from Reintubation in Preterm Infants Treated with Lucinactant, Beractant, or Poractant Alfa

“…34 In addition, lucinactant appears to be more resistant to inactivation by plasma proteins and oxidant species than other exogenous surfactants [35][36][37][38] and has also been shown to reduce plasma protein and neutrophil influx into the alveolar space in vivo and to modulate the inflammatory processes in vitro. 39,40 These factors may have resulted in improved overall lung function, potentially leading to lower rates of reintubation.…”