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9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant

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Abstract

9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, induces apoptosis via the generation of reactive oxygen species (ROS) because of 9,10-PQ redox cycling. We have found that intratracheal infusion of 9,10-PQ facilitates the secretion of surfactant into rat alveolus. In the cultured rat lung, treatment with 9,10-PQ results in an increase in a lower-density surfactant by ROS generation through redox cycling of the quinone. The surfactant contains aldo-keto reductase (AKR) 1C15, which reduces 9,10-PQ and the enzyme level in the surfactant increases on treatment with 9,10-PQ suggesting an involvement of AKR1C15 in the redox cycling of the quinone. In six human cell types (A549, MKN45, Caco2, Hela, Molt4 and U937) only type II epithelial A549 cells secrete three human AKR1C subfamily members (AKR1C1, AKR1C2 and AKR1C3) with the surfactant into the medium; this secretion is highly increased by 9,10-PQ treatment. Using in vitro enzyme inhibition analysis, we have identified AKR1C3 as the most abundantly secreted AKR1C member. The AKR1C enzymes in the medium efficiently reduce 9,10-PQ and initiate its redox cycling accompanied by ROS production. The exposure of A549 cells to 9,10-PQ provokes viability loss, which is significantly protected by the addition of the AKR1C3 inhibitor and antioxidant enzyme and by the removal of the surfactants from the culture medium. Thus, the AKR1C enzymes secreted in pulmonary surfactants probably participate in the toxic mechanism triggered by 9,10-PQ.

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Abbreviations

AKR:

Aldo-keto reductase

BALF:

Bronchoalveolar lavage fluid

CuZn-SOD:

Copper, zinc-superoxide dismutase

DEP:

Diesel exhaust particles

DMEM:

Dulbecco’s modified Eagle medium

DMSO:

Dimethylsulfoxide

DPBS:

Dulbecco’s phosphate-buffered saline

FBS:

Fetal bovine serum

PEG-cat:

Polyethylene glycol-conjugated catalase

9,10-PQ:

9,10-Phenanthrenequinone

ROS:

Reactive oxygen species

SP:

Surfactant protein

S-tetralol:

(S)-(+)-1,2,3,4-tetrahydro-1-naphthol

U:

unit

NADPH:

Reduced nicotinamide-adenine dinucleotide

RT-PCR:

Reverse transcription-polymerase chain reaction

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Authors and Affiliations

  1. Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu, 501-1196, Japan

    Toshiyuki Matsunaga, Mariko Haga, Gou Watanabe, Yuhki Shinoda, Satoshi Endo & Akira Hara

  2. Laboratory of Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan

    Yu Kajiwara, Hiroyuki Tanaka & Naoki Inagaki

  3. Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia

    Ossama El-Kabbani

  4. Laboratory of Biochemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan

    Toshiyuki Matsunaga

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  1. Toshiyuki Matsunaga
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  2. Mariko Haga
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  3. Gou Watanabe
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  4. Yuhki Shinoda
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  5. Satoshi Endo
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  9. Ossama El-Kabbani
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  10. Akira Hara
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Correspondence to Toshiyuki Matsunaga.

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This work was supported in part by a grant for encouragement of young scientists from Gifu Pharmaceutical University.

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Matsunaga, T., Haga, M., Watanabe, G. et al. 9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant. Cell Tissue Res 347, 407–417 (2012). https://doi.org/10.1007/s00441-011-1304-5

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