Protection of bleomycin-induced fibrosis and inflammation by taurine

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Abstract

Taurine has been shown to protect against lung injury induced by various oxidants including ozone, nitrogen dioxide, amiodarone, and paraquat and to protect against bleomycin-induced lung injury in combination with niacin. In this study, Spraque-Dawley rats were treated with 5% taurine in the drinking water for 10 days prior to bleomycin instillation. Fibrosis in the rats pretreated with taurine (BT) was absent, along with fewer inflammatory infiltrates compared to the untreated rats (BW). A significant decrease in the number of PMNs and a decrease in hydroxyproline levels were found in the bronchoalveolar lavage fluid in the BT group compared to the BW group. By immunohistochemical staining, inducible nitric oxide synthase was evident in the lungs of bleomycin-treated rats, and minimal when rats were treated with taurine. Tumor necrosis factor-alpha (TNF-α) as measured by immunohistochemical staining, was present in lungs of both taurine-treated and untreated rats, but was more abundant in the BW group compared to the BT group. In addition, decreased ICAM presentation was detected by EM immunogold staining in the BT group compared to the BW group. These data demonstrate that rats pretreated with 5% taurine in their drinking water prior to bleomycin instillation are protected from fibrosis, inflammatory infiltrates, as well as nitric oxide and TNF-α production, which are hallmarks of bleomycin lung injury.

Introduction

Taurine, 2-aminoethansulfonic acid, is well known as an antioxidant and is present in most mammalian tissues and cells. It is the most abundant single amino acid in leukocytes (20–50 mM), and is present in particularly high concentrations in tissues exposed to elevated levels of oxidants [1], [2], [3]. This natural substance has been used to protect against bleomycin-induced lung injury [4], [5]. In a murine model of lung fibrosis, Gurujeyalakshmi et al. [6] showed both nitric oxide (NO) and NFKB were decreased in taurine and niacin-treated mice compared to untreated mice. Taurine has also been shown to protect against lung injury induced by various oxidants such as ozone, nitrogen dioxide, amiodarone and paraquat [4], [5], [6], [7], [8], [9]. The protective effects of taurine may be explained by its detoxification of hypochlorous acid, a potent oxidant that can cause extensive tissue damage. However, recent evidence from our laboratories [10], [11], [12], [13], [14], [15], [16] and others [17], [18], [19] demonstrates that taurine chloramine (Tau–Cl), produced from highly toxic hypochlorous acid and taurine, is thought to be pivotal in regulating inflammation. Our previous data demonstrate that Tau–Cl inhibits proinflammatory mediators such as NO and TNF-α in a variety of both primary macrophages and cultured macrophage-like lines from rodents [10], [13]. Additionally, our results demonstrate that Tau–Cl down regulates several functions of both the adherent and non-adherent population of human peripheral blood leukocytes [15], [16]. Previously, we demonstrated that MMP-9 was inhibited by Tau–Cl in LPS-activated murine peritoneal macrophages [20].

Bleomycin treatment results in dysregulated matrix remodeling, leading to thickened alveolar walls, alveolar collapse and scarring (interstitial fibrosis) [21]. Fibrosis culminates in the overproduction of interstitial collagen as a reparative response to injury. Data from this study show that fibrosis is strikingly absent from the lung of rats pretreated with taurine in the drinking water ten days prior to bleomycin instillation.

Section snippets

Animals and bleomycin treatment

Female Sprague-Dawley rats, ages 8–12 weeks (Taconic Farms, Germantown, NY), were kept in Thoren ventilated racks and cages for protection from airborne infection and given water or water with 5% taurine for 10 days prior to instillation of 1 U (1 U/200 g) bleomycin via direct intratracheal injection (i.t.) with cervical cut-down with Nembutal anesthesia (Abbott Labs, North Chicago, Ill.). Animals were divided into the following 4 groups with at least 4 rats per group: saline and water (SW),

Taurine levels, inflammatory cell counts and hydroxylproline in BALF

Our laboratory has established animal models to study the protective role of taurine in ozone- and bleomycin-induced lung injury [7]. In this study, female Sprague-Dawley rats (180–210 g) (4 rats/group) were injected i.t. with bleomycin (1 U/rat) with (BT) or without (BW) taurine supplementation. Taurine supplementation consisted of 5% taurine in the drinking water for 10 days prior to bleomycin i.t. with Nembutal anesthesia (Abbott Labs., North Chicago, IL). Taurine concentrations were

Discussion

Previous studies from our laboratory have shown that pretreating rats for 10 days with 5% taurine in the drinking water prior to exposure to 2 ppm ozone for 3 h protected the bronchioles from acute lung inflammation and hyperplasia [7]. When bleomycin is administered to rodents, a multifocal inflammatory response occurs that progresses to fibrosis [21]. The present studies show that pretreatment of rats with 5% taurine prevents fibrosis and decreases the inflammatory infiltrate in the lungs of

Acknowledgments

This work was supported by the National Institutes of Health (Grant HL-49942) and the New York State Office of Mental Retardation and Developmental Disabilities. We would like to thank Dr. William Levis for reviewing this manuscript and Vanessa DeBello for typing this manuscript.

References (46)

  • K.C. Teixeira et al.

    Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine

    Pulm Pharmacol Ther

    (2008)
  • D. Vanhee et al.

    Modulation of endothelial cell adhesion molecule expression in a situation of chronic inflammatory stimulation

    Cell Immunol

    (1994)
  • Y. Hamaguchi et al.

    Intercellular adhesion molecule-1 and L-selection regulate bleomycin-induced lung fibrosis

    Am J Pathol

    (2002)
  • K. Fukuda et al.

    Free amino acid content of lymphocytes and granulocytes compared

    Clin Chem

    (1982)
  • D.B. Learn et al.

    Taurine and hypotaurine contents of human leukocytes

    J Leukocyte Biol

    (1996)
  • R.E. Gordon et al.

    Taurine protection of lungs in hamster models of oxidant injury; a morphological time study of paraquat and bleomycin treatment

  • Q. Wang et al.

    Effects of taurine on bleomycin induced lung fibrosis in hamsters

    Proc Soc Exp Biol Med

    (1989)
  • G. Gurujeyalakshmi et al.

    Taurine and niacin block lung injury and fibrosis by down-regulating bleomycin-induced activation of transcription nuclear factor-kB in mice

    J Pharmacol Exp Ther

    (2000)
  • G.B. Schuller-Levis et al.

    Taurine protects rat bronchioles from acute ozone-induced lung inflammation and hyperplasia

    Exp Lung Res

    (1995)
  • Q.J. Wang et al.

    Attenuation of amiodarone-induced lung fibrosis and phospholipidosis in hamsters by taurine and/or niacin treatment

    J Pharmacol Exp Ther

    (1992)
  • R.E. Gould et al.

    Taurine protects hamster bronchioles from acute NO2 induced alteration

    Am J Pathol

    (1986)
  • E. Park et al.

    Taurine chloramine inhibits the synthesis of nitric oxide and the release of tumor necrosis factor alpha in RAW 264.7 cells

    J Leukoc Biol

    (1993)
  • E. Park et al.

    Taurine chloramine inhibits production of nitric oxide and TNF-α in activated RAW 264.7 cells by mechanisms that induce transcriptional and translational events

    J Immunol

    (1995)
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