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Caveolar Uptake and Endothelial-Protective Effects of Nanostructured Lipid Carriers in Acid Aspiration Murine Acute Lung Injury

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ABSTRACT

Purpose

Nanostructured lipid carriers (NLC), nanosized phospholipids/triglyceride particles developed for drug delivery, are considered biologically inactive. We assessed the efficacy of unloaded NLC as experimental treatment for acute lung injury (ALI).

Methods

To induce ALI, C57Black/6 male mice received intratracheal injections of HCl or saline; A single dose of 16 mg/Kg NLC or saline was injected intravenously concomitantly with HCl challenge. NLC uptake mechanisms and effects on endothelial permeability and signaling were studied in cultured endothelial cells and neutrophils.

Results

NLC pre-treatment attenuated pulmonary microvascular protein leak, airspace inflammatory cells, thrombin proteolytic activity and histologic lung injury score 24 h post insult. Using fluorescence measurements and flow cytometry in mouse lung microvascular endothelial cell culture homogenates, we determined that NLC rendered fluorescent by curcumin labeling are taken up by endothelial cells from mice expressing caveolin-1, the coat protein of caveolar endocytic vesicles, but not from caveolin-1 gene-disrupted mice, which lack caveolae. In contrast, conventional emulsions (CE), consisting of larger particles, were not incorporated. In addition, NLC pre-treatment of cultured human lung microvascular endothelial cells abrogated thrombin-induced activation of p44/42, albumin permeability response, actin cytoskeletal remodeling and interleukin-6 production. Finally, NLC but not CE abrogated lipopolysaccharide-triggered interleukin-8 release.

Conclusions

NLC are engulfed by endothelial caveolae and possess endothelial-protective effects. These novel properties may be of potential utility in ALI.

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Abbreviations

ALI:

Acute lung injury

BAL:

Broncho-Alveolar Lavage

CE:

Conventional emulsions

FACS:

Fluorescence-activated cell sorting

FITC-BSA:

Fluorescein-isothiocyanate labelled bovine serum albumin

HPEMC-ST1:

Human Pulmonary Microvascular Endothelial cells

IL-6:

Interleukin-6

It:

Intratracheal

Iv:

Intravenous

MLMVEC:

Mouse Lung microvascular endothelial cells

NLC:

Nanostructured lipid carriers

NS:

Normal saline

PBS:

Phosphate-buffered saline

PI:

Polydispersity Index

RI:

Real refractive index

SDS-PAGE:

Sodium Dodecacyl Sulfate Polyacrylamide Gel Electrophoresis

WT:

Wild-type

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was funded by an American Thoracic Society/Sepsis Alliance Research Grant and by the “THORAX” Research Center for Intensive and Emergency Thoracic Medicine, Athens, Greece

The preparation and characterization of NLC and CE formulations was performed at the Laboratory of Pharmaceutical Technology, Dept of Pharmacy, National and Kapodistrian University of Athens, Greece, under the kind hospitality of Professor C. Demetzos.

Author information

Authors and Affiliations

  1. First Department of Critical Care Medicine & Pulmonary Services GP Livanos and M Simou Laboratories, Evangelismos Hospital, Medical School of Athens University, Athens, Greece

    Matina Kardara, Aggeliki Sfika, Aliki G. Vassiliou, Apostolos Armaganidis, Charalambos Roussos, Stylianos E. Orfanos, Anastasia Kotanidou & Nikolaos A. Maniatis

  2. 1st Department of Critical Care and Pulmonary Services “Evangelismos” Hospital, Medical School of Athens University, Athens, Greece

    Charalambos Roussos & Anastasia Kotanidou

  3. 2nd Department of Critical Care, “Attikon” Hospital, Medical School of Athens University, Athens, Greece

    Stylianos E. Orfanos & Nikolaos A. Maniatis

  4. Department of Pharmaceutical Technology, School of Pharmacy of Athens University, Athens, Greece

    Sophia Hatziantoniou & Elena Mourelatou

  5. Department of Pathology, “Evangelismos” Hospital, Athens, Greece

    Christina Μagkou

  6. Ploutarhou 3, 2nd Floor, Athens, 10675, Greece

    Nikolaos A. Maniatis

Authors
  1. Matina Kardara
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  2. Sophia Hatziantoniou
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  3. Aggeliki Sfika
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  4. Aliki G. Vassiliou
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  5. Elena Mourelatou
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  6. Christina Μagkou
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  7. Apostolos Armaganidis
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  8. Charalambos Roussos
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  9. Stylianos E. Orfanos
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  10. Anastasia Kotanidou
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  11. Nikolaos A. Maniatis
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Corresponding author

Correspondence to Nikolaos A. Maniatis.

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Kardara, M., Hatziantoniou, S., Sfika, A. et al. Caveolar Uptake and Endothelial-Protective Effects of Nanostructured Lipid Carriers in Acid Aspiration Murine Acute Lung Injury. Pharm Res 30, 1836–1847 (2013). https://doi.org/10.1007/s11095-013-1027-2

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  • DOI: https://doi.org/10.1007/s11095-013-1027-2

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