Acute lung injury (ALI) and its most severe manifestation, acute respiratory distress syndrome
(ARDS), is a clinical syndrome defined by acute hypoxemic respiratory failure and bilateral
pulmonary infiltrates consistent with edema. In-hospital mortality is 38.5% for AL, and 41.1% for
ARDS. Activation of alveolar macrophages in the donor lung causes the release of pro-inflammatory chemokines and cytokines,
such as TNF-α. To determine the relevance of TNF-α in disrupting bronchial endothelial cell function, we stimulated
human THP-1 macrophages with lipopolysaccharide (LPS) and used the resulting cytokine-supplemented media to
disrupt normal endothelial cell functions. Endothelial tube formation was disrupted in the presence of LPS-activated THP-
1 conditioned media, with reversal of the effect occurring in the presence of 0.1µg/ml Enbrel, indicating that TNF-α was
the major serum component inhibiting endothelial tube formation. To facilitate lung conditioning, we tested liposomal and
porous silicon (pSi) delivery systems for their ability to selectively silence TNFR1 using siRNA technology. Of the three
types of liposomes tested, only cationic liposomes had substantial endothelial uptake, with human cells taking up 10-fold
more liposomes than their pig counterparts; however, non-specific cellular activation prohibited their use as immunosuppressive
agents. On the other hand, pSi microparticles enabled the accumulation of large amounts of siRNA in endothelial
cells compared to standard transfection with Lipofectamine® LTX, in the absence of non-specific activation of endothelia.
Silencing of TNFR1 decreased TNF-α mediated inhibition of endothelial tube formation, as well as TNF-α-induced upregulation
of ICAM-1, VCAM, and E-selection in human lung microvascular endothelial cells.