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Anti-Inflammatory Therapeutic Effect of Adiponectin Gene Delivery Using a Polymeric Carrier in an Acute Lung Injury Model

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Abstract

Purpose

Adiponectin (APN) is an adipokine with anti-inflammatory and cytoprotective effects. In this study, the therapeutic effect of APN gene delivery using a polymeric carrier was evaluated in an acute lung injury (ALI) model.

Methods

Polyethylenimine (2 kDa, PEI2K), PEI25K (25 kDa), polyamidoamine (generation 2, PAMG2), dexamethasone-conjugated PEI2k (PEI2K-Dexa), and dexamethasone-conjugated PAMG2 (PAMG2-Dexa) were evaluated in vitro and in vivo as gene carriers. Formation of plasmid DNA (pDNA)/carrier complexes was confirmed by gel retardation and heparin competition assays. Delivery efficiency was measured by a luciferase assay and fluorescence microscopy. In an ALI animal model, pAPN/carrier complexes were delivered by intratracheal administration. Therapeutic effects were evaluated by cytokine assays and hematoxylin and eosin (H&E) staining.

Results

Gel retardation assays showed that PEI2K-Dexa and PAMG2-Dexa formed complexes with pDNA. In L2 lung epithelial cells, PAMG2-Dexa yielded higher transfection efficiency than PEI2K, PAMG2, PEI25K, lipofectamine, and PEI2K-Dexa. In vivo experiments showed that PAMG2-Dexa delivered DNA more efficiently to lung tissue than PEI2K-Dexa and PEI25K. Delivery of pAPN/PAMG2-Dexa complexes upregulated APN expression in the lungs of mice with ALI. As a result, the levels of pro-inflammatory cytokines such as TNF-α and IL-1β were decreased. H&E staining showed that inflammation in the lungs of mice with ALI was reduced by delivery of the APN gene.

Conclusion

Delivery of the APN gene using PAMG2-Dexa reduced inflammation in the lungs of mice with ALI. The APN gene could be a useful tool in the development of gene therapy for ALI.

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Abbreviations

AdipoR1 and AdipoR2:

Adiponectin receptors 1 and 2

ALI:

Acute lung injury

APN:

Adiponectin

BAL:

Bronchoalveolar lavage

BCA:

Bicinchoninic acid

DMEM:

Dulbecco’s modified eagle’s medium

DMSO:

Dimethyl sulfoxide

DPBS:

Dulbecco’s phosphate buffered saline

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fetal bovine serum

H&E:

Hematoxylin and eosin

HO-1:

Heme oxygenase-1

IL-1β:

Interleukin-1β

LB:

Luria broth

LPS:

Lipopolysaccharide

MTT:

[4,5-dimetylthiazol-2-yl]-2,5 diphenyltetrazoliumbromide

NF-κB:

Nuclear factor-κB

PAM:

Polyamidoamine

PAMG2-Dexa:

Dexamethasone-conjugated PAM generation 2

pDNA:

Plasmid DNA

PEI2K-Dexa:

Dexamethasone-conjugated PEI2K

PEI:

Polyethylenimine

PFA:

Paraformaldehyde

RLUs:

Relative light units

S1Plyase:

Sphingosine-1-phosphate lyase

siRNA:

Small interfering RNA

TNF-α:

Tumor necrosis factor-α

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Authors and Affiliations

  1. Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea

    Chunxian Piao & Minhyung Lee

  2. Department of Internal Medicine, College of Medicine, Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea

    Jeong Hyun Park

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  1. Chunxian Piao
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Correspondence to Minhyung Lee.

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Piao, C., Park, J.H. & Lee, M. Anti-Inflammatory Therapeutic Effect of Adiponectin Gene Delivery Using a Polymeric Carrier in an Acute Lung Injury Model. Pharm Res 34, 1517–1526 (2017). https://doi.org/10.1007/s11095-017-2175-6

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  • DOI: https://doi.org/10.1007/s11095-017-2175-6

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