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.