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Sulfated Caffeic Acid Dehydropolymer Attenuates Elastase and Cigarette Smoke Extract–induced Emphysema in Rats: Sustained Activity and a Need of Pulmonary Delivery

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Abstract

Background

Although emphysema destroys alveolar structures progressively and causes death eventually, no drug has been discovered to prevent, intervene, and/or resolve this life-threatening disease. We recently reported that sulfated caffeic acid dehydropolymer CDSO3 is a novel potent triple-action inhibitor of elastolysis, oxidation, and inflammation in vitro, and therefore, a potential anti-emphysema agent. However, the in vivo therapeutic potency, duration and mode of actions, and effective route remain to be demonstrated.

Methods

Emphysema was induced in rats with human sputum elastase (HSE) combined with cigarette smoke extract (CSE). CDSO3 at 5, 30, or 100 μg/kg was dosed to the lung or injected subcutaneously at 2, 6, or 24 h before or 1 or 24 h or 1 week after the HSE/CSE instillation. At 1 h or 48 h or on day 21–22 or day 28, lungs were examined for airway-to-blood injurious barrier damage; their elastolytic, oxidative, and inflammatory activities; lung luminal leukocytes infiltration; functional treadmill exercise endurance; and/or morphological airspace enlargement.

Results

CDSO3, when dosed to the lung at 30 or 100 μg/kg, but not via systemic subcutaneous injection, significantly (43–93 %) attenuated HSE/CSE-induced (1) barrier damage measured by luminal hemorrhage and protein leak; (2) elastolytic, oxidative, and inflammatory activities measured with elastase, reduced glutathione, and TNFα levels, respectively; (3) luminal neutrophil infiltration and tissue myeloperoxidase activity; (4) functional impairment of exercise endurance; and (5) airspace enlargement, in both preventive and interventional dosing protocols. Notably, the effects were shown to last for 24 h at the greater 100-μg/kg dose, and the 1-week-delayed administration was also capable of attenuating the development of emphysema.

Conclusions

CDSO3 is a novel, potent, long-acting, nonpeptidic macromolecule that inhibits HSE/CSE-induced elastolysis, oxidation, and inflammation in the lung and thereby attenuates the development of emphysema in rats, in both preventive and interventional manners, when administered locally to the lung.

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Abbreviations

AAALAC:

Association for assessment and accreditation of laboratory animal care

ANOVA:

Analysis of variance

BAL:

Bronchoalveolar lavage

BALF:

BAL fluid

BCA:

Bicinchoninic assay

βNADPH:

β-Nicotinamide adenine dinucleotide 2′-phosphate

CA:

Caffeic acid

CDSO3:

Sulfated dehydropolymer of caffeic acid

COPD:

Chronic obstructive pulmonary disease

CSE:

Cigarette smoke extract

DTNB:

5,5′-Dithiobis-(2-nitrobenzoic acid)

EDTA:

Ethylenediaminetetraacetic acid

GSSG:

Glutathione disulfide

HEPES:

(2-Hydroxyethyl)piperazine-N′-2-ethanesulfonic acid

HSE:

Human sputum elastase

HTAB:

Hexadecyltrimethyl ammonium bromide

rGSH:

Reduced glutathione

MLI:

Mean linear intercept

MPO:

Myeloperoxidase

tGSH:

Total glutathione

SD:

Standard deviation

SE:

Standard error

TNFα:

Tumor necrosis factor α

2-VP:

2-Vinyl pyridine

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Acknowledgments

This research was funded by an American Lung Association Biomedical Research Grant (MS; RG-159601-N), VCU Presidential Research Quest Fund (MS), Medical College of Virginia Foundation (BS and MS), and National Institutes of Health (URD; HL090586 and HL107152). BS acknowledges the financial support from the VCU School of Pharmacy and the VCU School of Graduate Studies Dissertation Award for her graduate studies.

Conflict of interest

The authors do not have financial or nonfinancial competing interests regarding this article. BS, URD, and MS are the inventors of a US patent titled “Cinnamic acid-based oligomers and uses thereof” (8,491,872), parts of which are included in this article.

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Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 N. 12th Street, 980533, Richmond, VA, 23298-0533, USA

    Bhawana Saluja, Hua Li & Masahiro Sakagami

  2. Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA, 23219, USA

    Umesh R. Desai

  3. Pulmonary and Critical Care Medicine Division and Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Norbert F. Voelkel

Authors
  1. Bhawana Saluja
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  2. Hua Li
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  3. Umesh R. Desai
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  4. Norbert F. Voelkel
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  5. Masahiro Sakagami
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Correspondence to Masahiro Sakagami.

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Saluja, B., Li, H., Desai, U.R. et al. Sulfated Caffeic Acid Dehydropolymer Attenuates Elastase and Cigarette Smoke Extract–induced Emphysema in Rats: Sustained Activity and a Need of Pulmonary Delivery. Lung 192, 481–492 (2014). https://doi.org/10.1007/s00408-014-9597-2

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