KL₄‐surfactant prevents hyperoxic and LPS‐induced lung injury in mice

Abstract

KL(4)-surfactant contains the novel KL(4) peptide, sinapultide, which mimics properties of the hydrophobic pulmonary surfactant protein SP-B, in a phospholipid formulation and may be lung protective in experimental acute respiratory distress syndrome/acute lung injury. Our objective was to determine the protective role of airway delivery of KL(4)-surfactant in murine models of hyperoxic and lipopolysaccharide (LPS)-induced lung injury and further explore the mechanisms of protection. For the hyperoxic injury model, mice exposed to 80% O(2) for 6 days received an intranasal bolus of vehicle, beractant, or KL(4)-surfactant on days 3, 4, 5, and 6 of the exposure, and lungs were evaluated on day 7. Mice in the LPS-induced lung injury model received an intratracheal bolus of LPS followed by an intranasal bolus of KL(4)-surfactant or control at 1, 3, and 19 hr post-LPS challenge, and lungs were evaluated after 24 hr. To explore the mechanisms of protection, in vitro assays were performed with human and murine endothelial cell monolayers, and polymorphonuclear leukocyte (PMN) transmigration in the presence or absence of KL(4)-surfactant or lipid controls was evaluated. Based on morphology, histopathology, white blood cell count, percentage of PMNs, and protein concentration in bronchoalveolar lavage fluid, our data showed KL(4)-surfactant, unlike vehicle or beractant, blocked neutrophil influx into alveoli and suppressed lung injury. Furthermore, in vitro assays showed KL(4)-surfactant decreased neutrophil transmigration at the endothelial cell level. KL(4)-surfactant decreased inflammation and lung permeability compared with controls in both mouse models of lung injury. Evidence suggests the anti-inflammatory mechanism of the KL(4)-peptide is through inhibition of PMN transmigration through the endothelium.

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

“…Furthermore, Lucinactant improved cell function over an animal-derived surfactant by 72 h. These findings are consistent with the effects of KL 4 peptide that prevents hyperoxic and lipopolysaccharideinduced lung injury in mice (31). There is much clinical interest in the potential differences and possible advantages of natural surfactant preparations compared with synthetic surfactant preparations.…”

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.…”

The endothelium in acute lung injury/acute respiratory distress syndrome

“…Kinniry et al [69 ] described a novel role for KL(4)-surfactant in ALI protection. KL(4)-surfactant, containing the novel peptide sinapultide, administered intranasaly diminished PMN infiltration in lungs of mice challenged with hyperoxia or LPS.…”