KL4-surfactant prevents hyperoxic and LPS-induced lung injury in mice.
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.
Kinniry
Paul
P
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Pick
Jeremy
J
Stephens
Scott
S
Jain
Deepika
D
Solomides
Charalambos C
CC
Niven
Ralph
R
Segal
Robert
R
Christofidou-Solomidou
Melpo
M
D000281:Administration, Intranasal; D000818:Animals; D001688:Biological Products / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D018496:Hyperoxia; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D037701:Pulmonary Surfactant-Associated Protein B / Q000032:analysis; D011663:Pulmonary Surfactants / Q000494:pharmacology / Q000627:therapeutic use*; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D001688:Biological Products; D036341:Intercellular Signaling Peptides and Proteins; C097558:KL4 surfactant; D008070:Lipopolysaccharides; D010455:Peptides; D037701:Pulmonary Surfactant-Associated Protein B; D011663:Pulmonary Surfactants; D014409:Tumor Necrosis Factor-alpha; C072197:beractant