Apolipoprotein E-deficient mice are susceptible to the development of acute lung injury.

BACKGROUND: Apolipoprotein E (apoE) has been shown to play a pivotal role in the development of cardiovascular disease, attributable to its function in lipid trafficking and immune modulating properties; however, its role in modulating inflammation in the setting of acute lung injury (ALI) is unknown. OBJECTIVE: To determine whether apoE-deficient mice (apoE-/-) are more susceptible to ALI compared to wild-type (WT) animals. METHODS: Two independent models of ALI were employed. Firstly, WT and apoE-/- mice were randomized to acid aspiration (50 µl of 0.1 N hydrochloric acid) followed by 4 h of mechanical ventilation. Secondly, WT and apoE-/- mice were randomized to 72 h of hyperoxia exposure or room air. Thereafter, the intrinsic responses of WT and apoE-/- mice were assessed using the isolated perfused mouse lung (IPML) setup. Finally, based on elevated levels of oxidized low-density lipoprotein (oxLDL) in apoE-/-, the effect of oxLDL on lung endothelial permeability and inflammation was assessed. RESULTS: In both in vivo models, apoE-/- mice demonstrated greater increases in lung lavage protein levels, neutrophil counts, and cytokine expression (p < 0.05) compared to WT mice. Experiments utilizing the IPML setup demonstrated no differences in intrinsic lung responses to injury between apoE-/- and WT mice, suggesting the presence of a circulating factor as being responsible for the in vivo observations. Finally, the exposure of lung endothelial cells to oxLDL resulted in increased monolayer permeability and IL-6 release compared to native (nonoxidized) LDL. CONCLUSIONS: Our findings demonstrate a susceptibility of apoE-/- animals to ALI that may occur, in part, due to elevated levels of oxLDL.

Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins.

Acute lung injury (ALI) leads to progressive loss of breathing capacity and hypoxemia, as well as pulmonary surfactant dysfunction. ALI's pathogenesis and management are complex, and it is a significant cause of morbidity and mortality worldwide. Exogenous surfactant therapy, even for research purposes, is impractical for adults because of the high cost of current surfactant preparations. Prior in vitro work has shown that poly-N-substituted glycines (peptoids), in a biomimetic lipid mixture, emulate key biophysical activities of lung surfactant proteins B and C at the air-water interface. Here we report good in vivo efficacy of a peptoid-based surfactant, compared with extracted animal surfactant and a synthetic lipid formulation, in a rat model of lavage-induced ALI. Adult rats were subjected to whole-lung lavage followed by administration of surfactant formulations and monitoring of outcomes. Treatment with a surfactant protein C mimic formulation improved blood oxygenation, blood pH, shunt fraction, and peak inspiratory pressure to a greater degree than surfactant protein B mimic or combined formulations. All peptoid-enhanced treatment groups showed improved outcomes compared to synthetic lipids alone, and some formulations improved outcomes to a similar extent as animal-derived surfactant. Robust biophysical mimics of natural surfactant proteins may enable new medical research in ALI treatment.

Exogenous surfactant therapy for ARDS.

Regardless of the cause, a common pathophysiological feature of patients with acute respiratory distress syndrome is a dysfunction of the endogenous surfactant system. Although exogenous surfactant therapy has proven to be an effective treatment for neonatal respiratory distress syndrome, no similar current effective therapy exists for patients with acute respiratory distress syndrome. This is mainly due to the complexity of the lung injury that is involved with this disorder. Results from clinical trials, to date, have failed to show an improvement in patient survival after administration of exogenous surfactant; however, ongoing and future research efforts suggest that this therapy may eventually be feasible.